leukemia committee 2020/ros... · 2020. 3. 19. · leukemia in their peripheral blood or bone...
TRANSCRIPT
APRIL 22 - 25, 2020 SWOG LEUKEMIA 1
LEUKEMIA COMMITTEE
APRIL 22 - 25, 2020 SWOG LEUKEMIA 2
CONTENTS
S1312 Phase I ................................................................................................................................................................ 6
S1318 Phase I-II .......................................................................................................................................................... 13
S1612 Phase II-III ........................................................................................................................................................ 19
S1712 Phase II ............................................................................................................................................................. 25
S1905 Phase II ............................................................................................................................................................. 28
S1925 Phase III ............................................................................................................................................................ 29
APRIL 22 - 25, 2020 SWOG LEUKEMIA 3
Patient Registrations to Studies
by 12 Month Intervals
LEUKEMIA COMMITTEE
Screening registrations and registrations to Biologic only studies are excluded.
SWOG LAPS MEMBER NCORP NON-SWOG
600
403
109
60
120136
0
100
200
300
400
500
600
700
Time of Registration
Jan 2014Dec 2014
Jan 2015Dec 2015
Jan 2016Dec 2016
Jan 2017Dec 2017
Jan 2018Dec 2018
Jan 2019Dec 2019
116
143
85
256
100
88
81
134
40
40 3537
45
4736
APRIL 22 - 25, 2020 SWOG LEUKEMIA 4
Patient Registrations by Study and Arm LEUKEMIA COMMITTEE
Jul 2019
Dec 2019
Jan 2019
Jun 2019
Jul 2018
Dec 2018
All
Patients
S1312 ALL, CD22+, REL/REF, Inotuzumab+CVP
Initial Registration
CVP + Inotuzumab dose level 1 0 0 0 5
CVP + Inotuzumab dose level 2 0 0 0 5
CVP + Inotuzumab dose level 3 0 0 0 11
CVP + Inotuzumab dose level 4 0 0 0 5
CVP + Inotuzumab dose level 5 0 0 0 11
CVP + Inotuzumab MTD 0 4 7 13
0 4 7 50
S1318 ALL, Age 65+, Ph±, Blinatumomab
Initial registration
Induction: Ph- 0 0 0 31
Induction: Ph+/Ph-like 4 0 0 20
4 0 0 51
S1612 AML/MDS, Age 60+, Aza/Novel Therapeutics
Specimen Submission
FLT3 Testing 0 0 67 113
Randomization
Azacitidine 0 0 14 26
Azacitidine + Nivolumab 0 0 16 26
Azacitidine + Midostaurin 0 0 14 26
0 0 44 78
S1712 CML, Chronic Phase, TKI +/- Ruxolitinib
Randomization
Single Agent TKI 4 3 1 8
TKI + Ruxolitinib 5 2 1 8
9 5 2 16
APRIL 22 - 25, 2020 SWOG LEUKEMIA 5
Non-SWOG Studies with SWOG-Credited Registrations LEUKEMIA COMMITTEE
Studies with Accrual from July 2018 - December 2019
SWOG Accrual
SWOG
Champion
Jul 2019
Dec 2019
Jan 2019
Jun 2019
Jul 2018
Dec 2018
SWOG
Total
Total
Accrued
A041501 B-Cell ALL, Frontline Tx +/- Intuzumab Ozo A Advani 3 1 0 4 85
Date Activated: 06/01/17
Most Recent Progress Report
A041701 AML, Age 60+, Conv Chemo +/- Uproleselan L Liesveld 4 2 0 6 63
Date Activated: 01/16/19
Most Recent Progress Report
A041702 CLL, Stg I-IV, IO with IM versus IVO B Hill 14 5 0 19 101
Date Activated: 01/04/19
Most Recent Progress Report
E1910 BCR-ABL-neg, B ALL, Blinatumomab M Liedke 4 13 15 119 488
Date Activated: 12/23/13 Date Closed: 10/22/19
Most Recent Progress Report
EA9161 CLL, untreated, IOV vs IO in younger pts M Shadman 41 27 0 68 297
Date Activated: 01/03/19
Most Recent Progress Report
APRIL 22 - 25, 2020 SWOG LEUKEMIA 6
S1312/I
S1312 Phase I
A Phase I Study of Inotuzumab (NSC-772518) in Combination with CVP
(Cyclophosphamide, Vincristine, Prednisone) for Patients with
Relapsed/Refractory CD22-Positive Acute Leukemia (including B-ALL,
Mixed Phenotypic Leukemia, and Burkitt's Leukemia)
Study Chairs:
A Advani, M Liedtke
Statisticians:
M Othus, A Moseley
Data Coordinator:
L Highleyman
Date Activated:
04/01/2014
Date Closed:
08/02/2019
Objectives To assess the safety of inotuzumab in combination
with cyclophosphamide, vincristine and prednisone
(CVP) and to determine the maximum tolerated dose
(MTD) of inotuzumab in this regimen for patients
with relapsed or refractory CD22-positive acute
leukemia (B-ALL, mixed phenotype, and Burkitt's).
To estimate the preliminary activity [response rate:
complete remission (CR) + complete remission with
incomplete count recovery (CRi)] of this combination
in the expansion cohort.
To estimate the frequency and severity of toxicities
of this combination in this patient population.
Patient Population Patients must have a diagnosis of relapsed or
refractory CD22-positive acute leukemia including
B-ALL, mixed phenotype leukemia (bilineal and
biphenotypic), or Burkitt's leukemia based on WHO
classification. Patients with bilineal leukemia are
excluded. Patients must have evidence of acute
leukemia in their peripheral blood or bone marrow.
Patients must have ≥ 5% blasts in the peripheral
blood or bone marrow. At least ≥ 20% of those blasts
must be CD22-positive (surface) based on local
immunophenotyping and histopathology. Patients
must be refractory or have relapsed following prior
induction therapy.
Patients may have received prior allogeneic
transplant or autologous transplant. Patients with
prior allogeneic bone marrow transplant will be
eligible only if the conditions stated in the protocol
are met. Patients known to have Ph+ ALL must have
either failed treatment or been intolerant to treatment
with at least one second or third generation tyrosine
kinase inhibitor. Patients must not have received
prior treatment with inotuzumab. Previous treatment
with other anti-CD22 antibodies must have been
completed at least 90 days prior to registration.
Patients must not have received any chemotherapy,
investigational agents, or undergone major surgery
within 14 days prior to registration with the following
exceptions: (1) Monoclonal antibodies must not have
been received for one week prior to registration; (2)
Chimeric antigen receptor (CAR) T-cells must not
have been received for 28 days prior to registration;
(3) Steroids, hydroxyurea, vincristine, 6-
mercaptopurine, methotrexate, thioguanine and
intrathecal chemotherapy are permitted within any
time frame prior to registration. FDA-approved
tyrosine kinase inhibitors may also be administered
until one day prior to start of study therapy (C1, D1).
All drug-related toxicities must have resolved to ≤
Grade 2. Treatment with hydroxyurea and steroids is
permitted to bring down peripheral blast count.
Patients must be at least 18 years of age and have
Zubrod performance status of 0-2. Patients must not
have a systemic bacterial, fungal, or viral infection
that is not controlled. Patients must not have active
APRIL 22 - 25, 2020 SWOG LEUKEMIA 7
S1312/I
CNS involvement. Patients must have < Grade 2
neuropathy (sensory/motor). Patients must not have a
history of chronic or active hepatitis B or C infection.
Patients must not have evidence or history of veno-
occlusive disease or sinusoidal obstruction syndrome.
Patients who are known to be HIV+ are eligible
providing they meet all of the criteria in the protocol.
Patients with a history of a serious allergic or
anaphylactic reaction to humanized monoclonal
antibodies are not eligible. Patients must have
adequate hematologic, renal, hepatic, and cardiac
function.
Accrual Goals Patient enrollment will follow the traditional "3+3"
algorithm until the MTD for inotuzumab is reached
or the highest dose tested is judged tolerable. This
study will accrue 3-30 eligible and evaluable patients
in the Phase I portion and 12 additional eligible
patients in the expansion cohort.
Summary Statement
Determination of MTD
This study evaluated five dose levels if inotuzumab.
The initial dose level of 0.4 mg/m2 inotuzumab
closed on November 1, 2014 with five eligible
patients registered. Two patients were not evaluable
for DLTs because they went off treatment before
their counts recovered and before prolonged
myelosuppression could be ruled out. There were no
DLTs in the first dose level.
The second dose level of inotuzumab at 0.6 mg/m2 on
day 1 and 0.4 mg/m2 on day 15 closed on May 15,
2015 with five patients registered. One patient was
ineligible due to inadequate liver function; another
patient was not evaluable for DLTs due to going off
treatment before counts recovered and before
prolonged myelosuppression could be ruled out.
There were no DLTs in the second dose level.
The third dose level of inotuzumab at 0.8 mg/m2 on
day 1 and 0.4 mg/m2 on day 15 closed on April 15,
2016 with 11 patients registered. One patient was
ineligible due to inadequate liver function. Four other
patients were not evaluable for DLTs: two went off
treatment before their counts recovered and before
prolonged myelosuppression could be ruled out, one
died before receiving a full cycle of treatment, and
one continued to take tyrosine kinase inhibitor (TKI)
while on protocol and is coded as a major protocol
deviation. Six of the 10 eligible patients were
evaluable for DLTs. One of the first three evaluable
patients experienced a DLT (prolonged
myelosuppression), so three additional patients were
evaluated at this dose level. None of these additional
patients experienced a DLT.
The fourth dose level of inotuzumab at 0.8 mg/m2 on
day 1 and 0.4 mg/m2 on days 8 and 15 closed on
August 22, 2016 with five patients registered. Two
patients were not evaluable for DLTs because they
went off treatment before their counts recovered and
before prolonged myelosuppression could be ruled
out. There were no DLTs in the fourth dose level.
The fifth dose level of inotuzumab at 0.8 mg/m2 on
day 1 and 0.5 mg/m2 on days 8 and 15 closed on July
31, 2017 with 11 patients registered. Five patients
went off treatment before their counts recovered and
before prolonged myelosuppression could be ruled
out and are not evaluable for DLTs. One patient
experienced a DLT: Grade 3 ascites, an event
considered clinically significant regardless of
duration. The fifth dose level was established as the
MTD for the expansion cohort.
There were no Grade 5 treatment-related non-
hematologic toxicities at any dose level. Two patients
treated at the third dose level experienced Grade 4
treatment-related non-hematologic toxicities: one
patient experienced Grade 4 treatment-related
hyperglycemia and another experienced Grade 4
treatment-related hyperglycemia and oral mucositis.
Expansion Cohort
The expansion cohort opened to accrual on October
25, 2017 and accrued 13 patients. The study
permanently closed to accrual on August 2, 2019.
One patient went off protocol after only one day of
treatment and was not evaluable for response. Two
patients in this cohort experienced treatment-related
Grade 4 non-hematologic toxicities: one with febrile
neutropenia and sepsis and another with sepsis (also
coded as Infections/infestations-Other). No other
Grade 4 or 5 treatment-related non-hematologic
toxicities were reported.
Though the MTD has been established and toxicities
in this cohort are not dose limiting, DLTs in the
expansion cohort will also be described in order to
better understand toxicities at this dose. Four patients
are not evaluable for DLTs: one received only one
day of treatment and three others went off treatment
before their counts recovered and before prolonged
APRIL 22 - 25, 2020 SWOG LEUKEMIA 8
S1312/I
myelosuppression could be ruled out. None of the
nine patients evaluable for DLTs experienced a DLT.
In all, 27 patients went off treatment for non-protocol
specified reasons, due to lack of treatment benefit
(10), physician decision (2) or to receive transplant
(15).
Results
The primary objective of this trial was to assess the
safety of inotuzumab ozogamicin in combination
with CVP and to determine the MTD of inotuzumab
in this treatment combination. The MTD was found
to be 0.8 mg/m2 on day 1 and 0.5 mg/m
2 on days 8
and 15. One out of 15 evaluable patients treated at
this dose (including the expansion cohort)
experienced a DLT (Grade 3 ascites). No Grade 4 or
Grade 5 treatment-related non-hematologic toxicities
were observed at this dose in the dose-finding portion
of the trial. Two patients in the expansion cohort
experienced Grade 4 treatment-related non-
hematologic toxicities.
A secondary objective was to estimate the response
rate (CR + CRi) in the expansion cohort. Of the 12
patients in the expansion cohort who were evaluable
for response, 10 achieved a CR or CRi (83%, 95% CI
52% - 98%). Of the 23 patients treated at the MTD
who were evaluable for response, 14 achieved a CR
or CRi (61%, 95% CI 39% - 80%).
Median overall survival (OS) is 7.7 months for all
eligible patients and 10.9 months for eligible patients
treated at the MTD. OS for patients treated at the
MTD was significantly higher than for patients
treated at lower dose levels (log-rank p = 0.02).
Median follow-up for patients who were alive at last
contact is 1.4 years.
Registration by Institution
Institutions Total Reg
City of Hope Med Ctr 18
Rochester, Univ of 12
Cleveland Clinic OH 11
Baylor College 7
Stanford University 2
Total (5 Institutions) 50
Registration, Eligibility, and Evaluability
TOTAL
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
CVP +
Inotuzumab
MTD
NUMBER REGISTERED 50 5 5 11 5 11 13
INELIGIBLE 2 0 1 1 0 0 0
ELIGIBLE 48 5 4 10 5 11 13
RESPONSE ASSESSMENT
Determinable 45 5 4 8 5 11 12
Not Determinable 3 0 0 2 0 0 1
ADVERSE EVENT ASSESSMENT
Evaluable 48 5 4 10 5 11 13
DLT ASSESSMENT
Evaluable 30 3 3 6 3 6 9
Not Evaluable 18 2 1 4 2 5 4
APRIL 22 - 25, 2020 SWOG LEUKEMIA 9
S1312/I
Patient Characteristics
CVP +
Inotuzumab
dose level 1
(n=5)
CVP +
Inotuzumab
dose level 2
(n=4)
CVP +
Inotuzumab
dose level 3
(n=10)
CVP +
Inotuzumab
dose level 4
(n=5)
CVP +
Inotuzumab
dose level 5
(n=11)
CVP +
Inotuzumab MTD
(n=13)
AGE
Median 48.8 42.3 42.8 49.6 37.9 43.5
Minimum 22.3 20.6 22.4 33.0 25.0 21.6
Maximum 73.7 56.4 75.3 50.1 58.7 79.8
SEX
Males 4 80% 0 0% 6 60% 3 60% 6 55% 8 62%
Females 1 20% 4 100% 4 40% 2 40% 5 45% 5 38%
HISPANIC
Yes 2 40% 2 50% 2 20% 4 80% 3 27% 3 23%
No 3 60% 2 50% 7 70% 1 20% 6 55% 9 69%
Unknown 0 0% 0 0% 1 10% 0 0% 2 18% 1 8%
RACE
White 4 80% 3 75% 6 60% 5 100% 7 64% 8 62%
Black 1 20% 1 25% 2 20% 0 0% 1 9% 0 0%
Asian 0 0% 0 0% 0 0% 0 0% 1 9% 3 23%
Unknown 0 0% 0 0% 2 20% 0 0% 2 18% 2 15%
Treatment Summary
TOTAL
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
CVP +
Inotuzumab
MTD
NUMBER ON PROTOCOL TREATMENT 0 0 0 0 0 0 0
NUMBER OFF PROTOCOL TREATMENT 48 5 4 10 5 11 13
REASON OFF TREATMENT
Treatment completed as planned 6 0 2 1 0 0 3
Adverse Event or side effects 6 0 0 2 0 1 3
Refusal unrelated to adverse event 1 1 0 0 0 0 0
Progression/relapse 7 1 1 4 0 0 1
Death 1 0 0 1 0 0 0
Other - not protocol specified 27 3 1 2 5 10 6
MAJOR PROTOCOL DEVIATIONS 1 0 0 1 0 0 0
LOST TO FOLLOW-UP 0 0 0 0 0 0 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
1 0 0 1 0 0 0
APRIL 22 - 25, 2020 SWOG LEUKEMIA 10
S1312/I
Number of Patients with a Given Type and Grade of Adverse Event
Adverse Events Unlikely or Not Related to Treatment Excluded
Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
CVP +
Inotuzumab
MTD
(n=5) (n=4) (n=10) (n=5) (n=11) (n=13)
Grade Grade Grade Grade Grade Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
Anemia 3 1 1 0 2 1 1 0 3 7 0 0 2 3 0 0 6 5 0 0 8 5 0 0
Lymphocyte count decreased 3 0 2 0 3 1 0 0 7 2 1 0 2 1 2 0 5 2 4 0 7 3 3 0
Neutrophil count decreased 2 0 3 0 1 0 3 0 1 0 9 0 1 2 2 0 3 4 4 0 5 1 7 0
Platelet count decreased 3 0 2 0 2 0 2 0 3 1 6 0 1 1 3 0 6 1 4 0 3 2 8 0
White blood cell decreased 2 0 3 0 0 1 3 0 0 1 9 0 0 0 5 0 4 1 6 0 4 0 9 0
MAX. GRADE ANY
ADVERSE EVENT 2 0 3 0 0 0 4 0 0 0 10 0 0 0 5 0 0 3 8 0 1 1 11 0
Number of Patients with a Given Type and Grade of Adverse Event
Adverse Events Unlikely or Not Related to Treatment Excluded
Non-Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
CVP +
Inotuzumab MTD
(n=5) (n=4) (n=10) (n=5) (n=11) (n=13)
Grade Grade Grade Grade Grade Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
Ascites 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 1 0 0 12 1 0 0
Dysphagia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Encephalopathy 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Enterocolitis 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 1 0 0 13 0 0 0
Fatigue 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 12 1 0 0
Febrile neutropenia 5 0 0 0 2 2 0 0 8 2 0 0 2 3 0 0 10 1 0 0 6 6 1 0
Fever 4 1 0 0 3 1 0 0 9 1 0 0 5 0 0 0 11 0 0 0 12 1 0 0
GI disorders-Other, specify 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Gastric hemorrhage 3 2 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Headache 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Hyperglycemia 5 0 0 0 4 0 0 0 6 2 2 0 1 4 0 0 9 2 0 0 13 0 0 0
Hypertension 5 0 0 0 4 0 0 0 9 1 0 0 4 1 0 0 11 0 0 0 12 1 0 0
Hypoalbuminemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Hypocalcemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Hypokalemia 5 0 0 0 4 0 0 0 10 0 0 0 4 1 0 0 11 0 0 0 13 0 0 0
Infections/infestations-Other 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 1 0 0 9 3 1 0
Intracranial hemorrhage 4 1 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0
Lipase increased 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 12 1 0 0
Lung infection 5 0 0 0 4 0 0 0 10 0 0 0 3 2 0 0 11 0 0 0 13 0 0 0
APRIL 22 - 25, 2020 SWOG LEUKEMIA 11
S1312/I
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
CVP +
Inotuzumab MTD
(n=5) (n=4) (n=10) (n=5) (n=11) (n=13)
Grade Grade Grade Grade Grade Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
Mucositis oral 5 0 0 0 4 0 0 0 9 0 1 0 5 0 0 0 11 0 0 0 12 1 0 0
Renal/urinary disorders-Other 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 12 1 0 0
Sepsis 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 11 0 2 0
Skin infection 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0
MAX. GRADE ANY
ADVERSE EVENT 1 4 0 0 2 2 0 0 3 5 2 0 0 5 0 0 8 3 0 0 3 8 2 0
Response
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
CVP +
Inotuzumab
MTD
N % N % N % N % N % N %
Complete Response 1 20 1 25 3 38 1 20 1 9 5 42
CR w/Incomplete Hem. Recovery 2 40 1 25 2 25 0 0 3 27 5 42
Partial Response 0 0 0 0 0 0 0 0 1 9 0 0
Resistant Disease 2 40 2 50 3 38 4 80 6 55 2 17
Total 5 100 4 100 8 100 5 100 11 100 12 100
The LIFETEST Procedure
Stratum 1: rowno = Total
APRIL 22 - 25, 2020 SWOG LEUKEMIA 12
S1312/I
48 13 5 2
At Risk
0 1 2 3
Years After Registration
0%
20%
40%
60%
80%
100%
At Risk
7.73548
in MonthsDeathsAt Risk
Median
Overall Survival - All Eligible PatientsData as of February 19, 2020
Stratum 1: rowno = Total
24 9 3 0
At Risk
0 1 2 3
Years After Registration
0%
20%
40%
60%
80%
100%
At Risk
10.91424
in MonthsDeathsAt Risk
Median
Overall Survival - Eligible Patients Treated at MTDData as of February 19, 2020
APRIL 22 - 25, 2020 SWOG LEUKEMIA 13
S1318/I-II
S1318 Phase I-II
Coordinating Group: SWOG
A Phase II Study of Blinatumomab (NSC-765986) and POMP (Prednisone,
Vincristine, Methotrexate, 6-Mercaptopurine) for Patients ≥ 65 Years of Age with
Newly Diagnosed Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic
Leukemia (ALL) and of Dasatinib (NSC-732517), Prednisone and Blinatumomab
for Patients ≥ 65 Years of Age with Newly Diagnosed Philadelphia-Chromosome
Positive (Ph+) ALL, Relapsed/Refractory Philadelphia-Chromosome Positive
(Ph+) ALL, and Philadelphia-Chromosome-Like Signature (Ph-Like) ALL (Newly
Diagnosed or Relapsed/Refractory) with Known or Presumed Activating
Dasatinib-Sensitive Mutations or Kinase Fusions (DSMKF)
Participants:
SWOG, CTSU (Supported by Alliance, ECOG-ACRIN)
Study Chairs:
A Advani, K O'Dwyer, M Wiedewult (Alliance), J Park
(ECOG-ACRIN)
Statisticians:
M Othus, A Moseley
Data Coordinator:
T Maher
Date Activated:
01/12/2015
SCHEMA
REGISTRATION Step 1
D28 CR/CRi?
Dasatinib / Prednisone Induction
Continue Induction Cycle
YES
Blinatumomab
Re-induction 1
Ph-positive/Ph-like DSMKF Patients
NO
Until intolerance or progression for up to 10 years from registration, then
Protocol Therapy Complete
CR/CRi?
YES
NO
Off Protocol Therapy
REGISTRATION Step 2: Post-remission therapy
Blinatumomab/Dasatinib
REGISTRATION Step 3: Maintenance
Dasatinib/Prednisone
Ph-negative Patients:
Blinatumomab Induction
CR/CRi?
REGISTRATION Step 1
YES NO
REGISTRATION Step 2:
Post-remission therapy
Blinatumomab
Continued CR/Cri?
REGISTRATION Step 3:
Maintenance
POMP Chemotherapy
Protocol Therapy Complete
Blinatumomab
Re-induction
D56 CR/CRi?
YESNO
Continue Dasatinib
to Day 84
Continued CR/Cri?
YES
Blinatumomab
Re-induction 2
CR/CRi?
NO
YESYES
Continued CR/Cri?
NO
NO
CR/CRi?
YES NO
Off Protocol Therapy
YES NO
APRIL 22 - 25, 2020 SWOG LEUKEMIA 14
S1318/I-II
Objectives To evaluate the three-year survival rate in elderly
patients with newly diagnosed Philadelphia
chromosome (Ph) negative ALL treated with
blinatumomab followed by POMP maintenance.
To evaluate in a preliminary manner (feasibility
study) the safety of dasatinib-steroid based induction
followed by blinatumomab treatment in combination
with dasatinib followed by dasatinib-based
maintenance in elderly patients with newly diagnosed
Ph-positive ALL, relapsed/refractory Ph-positive
ALL, and Ph-like DSMKF ALL (newly-diagnosed
relapsed or refractory).
To evaluate toxicities in these patient populations
treated with these regimens.
To estimate the rates of complete response (CR),
complete response with incomplete count recovery
(CRi), and disease-free survival in Ph-negative
patients.
To estimate disease-free and overall survival in Ph-
positive ALL and Ph-like DSMKF ALL.
To estimate in each cohort the rate of minimal
residual disease (MRD) negativity, and the time to
achieve MRD negativity (exploratory analysis).
To determine whether anti-idiotype antibodies
directed against blinatumomab develop with
blinatumomab treatment in this study.
To estimate the incidence of the Ph-like signature in
elderly patients (≥ 65 years of age) with newly
diagnosed Philadelphia-chromosome negative ALL.
To estimate the incidence of the various tyrosine-
kinase fusions, making up the Ph-like signature in
elderly patients with newly diagnosed Philadelphia-
chromosome negative ALL.
To evaluate outcomes (event-free survival and
overall survival) in patients with the Ph-like signature
versus those without the Ph-like signature in Ph-
negative ALL.
Patient Population Patients must have a new morphologic diagnosis of
precursor B cell acute lymphoblastic leukemia (ALL)
(non-T cell) based on WHO criteria as defined in the
protocol. Patients with Burkitt's (L3) are not eligible
for this study. Patients with Ph-positive or Ph-like
ALL with dasatinib-sensitive mutations or kinase
fusions (DSMKF) may have relapsed or refractory
diagnoses. Patients must have a diagnosis of Ph-
negative ALL or Ph-positive ALL by cytogenetics,
FISH or polymerase chain reaction (PCR). If not
already known, BCR-ABL status (p190 or p210)
must be evaluated in Ph-positive patients by PCR. To
be registered under the Ph-like DSMKF criterion, the
patient must have a known or presumed activating
Ph-like signature and dasatinib-sensitive mutation or
kinase fusion as defined in the protocol. Patients must
have evidence of ALL in their marrow or peripheral
blood with at least 20% lymphoblasts (at least 5% for
relapsed/refractory patients) within 14 days prior to
registration. At registration, relapsed/refractory
patients must submit pathology and cytogenetics
reports from time of original diagnosis.
Immunophenotyping of the blood or marrow
lymphoblasts must be performed to determine lineage
within 14 days prior to registration. Patients with
only extramedullary disease in the absence of bone
marrow or blood involvement are not eligible.
Patients must not have testicular involvement.
Patients must not have received any prior
chemotherapy, radiation therapy, or other therapy for
the treatment of ALL (other than those noted below)
and must not be receiving any immunosuppressive
therapy. Patients must not have received any prior
investigational therapy within 28 days prior to
registration. Patients may have received the following
within any time prior to registration: low dose
chemotherapy, TKI therapy, steroids, hydroxyurea,
leukapheresis, intrathecal chemotherapy, or
vincristine. Patients must not have received any
monoclonal antibody therapy within 42 days of
registration.
Patients must be at least 65 years of age and have a
Zubrod performance status of 0-2. Patients must have
adequate hepatic, cardiac and renal function. Patients
must not have a history or presence of clinically
relevant CNS pathology and must have a lumbar
puncture to determine CNS involvement of ALL
within 14 days prior to registration. Patients must not
have systemic fungal, bacterial, viral, or other
infection that is not controlled. Patients must not have
Grade 2 or higher neuropathy (cranial, motor or
sensory) within 14 days prior to registration. Patients
known to be positive for HIV may be eligible,
providing they meet the criteria in the protocol.
Patients must not be candidates for allogeneic
hematopoietic stem cell transplant. Patients must not
have any known autoimmune disease. Ph-negative
patients must have PT/PTT/INR/fibrinogen and
APRIL 22 - 25, 2020 SWOG LEUKEMIA 15
S1318/I-II
neurologic assessment tests within 28 days prior to
registration. Ph-positive patients must not have active
pericardial effusion, ascites, or pleural effusion of
any grade.
Stratification/Descriptive Factors Patients are stratified by Registration Cohort: Ph-
negative vs Ph-positive/Ph-like DSMKF.
Accrual Goals This study will accrue up to 26 eligible Ph-negative
patients. An interim analysis will be performed
among the first 11 patients. If at least five complete
remissions (CR or CRi) are observed, then the study
will continue to full accrual. The study will continue
accruing while the remission data is being reviewed.
This study will initially accrue six eligible and
evaluable Ph-positive/Ph-like DSMKF patients. If the
regimen is considered safe, then the study will accrue
14 additional eligible and evaluable Ph-positive/Ph-
like DSMKF patients.
Summary Statement The study was activated on January 12, 2015. The
Ph-positive/Ph-like DSMKF cohort was temporarily
closed to Step 1 accrual on April 15, 2017 to assess
the safety profile. During this closure, on September
29, 2017 the FDA placed a temporary clinical hold
on this cohort. The hold was lifted on December 1,
2017, but the cohort remains closed to accrual while
the study team and NCI discuss whether to expand
this cohort. A protocol revision approved in
September 2019 added translational medicine (TM)
objectives and expanded the Ph-positive/Ph-like
DSMKF cohort to 20 eligible patients who receive
post-remission therapy. The Ph-positive/Ph-like
DSMKF cohort re-opened to accrual on September
16, 2019.
Ph-negative cohort:
The Ph-negative cohort permanently closed to
accrual on September 15, 2017 after reaching its
accrual goal with 31 patients. Two patients in this
cohort were ineligible: one due to elevated alkaline
phosphatase and another due to a final diagnosis of
follicular lymphoma. One patient went off treatment
to receive an alternate therapy per physician decision.
Two patients withdrew consent for further treatment
or follow-up.
Of the 29 patients evaluable for toxicities during
induction, one patient died of treatment-related
respiratory failure. Two other patients experienced
treatment-related non-hematologic Grade 4 toxicities.
There were no Grade 4 or higher treatment-related
non-hematologic toxicities reported during post-
remission. Two patients experienced Grade 4
treatment-related non-hematologic events during
maintenance: one with sepsis and hypertension and
one with sepsis and respiratory failure.
Ph-positive/Ph-like DSMKF cohort:
As of December 31, 2019, 20 patients have enrolled
to the Ph-positive/Ph-like DSMKF cohort, all of
whom are eligible and evaluable for toxicities. Two
patients experienced treatment-related non-
hematologic Grade 4 toxicities. There have been no
Grade 4 or higher treatment-related non-hematologic
toxicities reported during post-remission or
maintenance. Four patients remain on induction
treatment.
Registration by Institution
Initial Registration
Registrations ending December 31, 2019
Institutions
Total
Reg Institutions
Total
Reg
Cleveland Clinic OH 5 Rochester, Univ of 1
City of Hope Med Ctr 4 San Diego, U of CA 1
Irvine, U of CA 3 UF Cancer Center/Arkansas, U of 1
So Calif, U of 3 Wichita NCORP 1
Michigan, U of 2 Yale University 1
Birmingham, U of AL 1 ALLIANCE 16
Greenville NCORP 1 ECOG-ACRIN 6
Heartland NCORP 1 NRG 2
Loma Linda Univ 1 Total (18 Institutions) 51
New Mexico MU-NCORP 1
APRIL 22 - 25, 2020 SWOG LEUKEMIA 16
S1318/I-II
Registration, Eligibility, and Evaluability
Initial Registration
Registrations ending December 31, 2019; Data as of February 18, 2020
TOTAL
Induction:
Ph-
Induction:
Ph+/Ph-like
NUMBER REGISTERED 51 31 20
INELIGIBLE 2 2 0
ELIGIBLE 49 29 20
Analyzable, Pend. Elig. 2 0 2
RESPONSE ASSESSMENT
Determinable 43 28 15
Not Determinable 2 1 1
Too Early 4 0 4
ADVERSE EVENT ASSESSMENT
Evaluable 49 29 20
Patient Characteristics
Initial Registration
Registrations ending December 31, 2019; Data as of February 18, 2020
Induction:
Ph-
(n=29)
Induction:
Ph+/Ph-like
(n=20)
AGE
Median 75.4 73.1
Minimum 66.3 48.1
Maximum 84.0 87.2
SEX
Males 22 76% 5 25%
Females 7 24% 15 75%
HISPANIC
Yes 2 7% 4 20%
No 27 93% 15 75%
Unknown 0 0% 1 5%
RACE
White 28 97% 15 75%
Black 0 0% 1 5%
Asian 1 3% 2 10%
Unknown 0 0% 2 10%
APRIL 22 - 25, 2020 SWOG LEUKEMIA 17
S1318/I-II
Treatment Summary
Induction
Registrations ending December 31, 2019; Data as of February 18, 2020
TOTAL
Induction:
Ph-
Induction:
Ph+/Ph-like
NUMBER ON PROTOCOL TREATMENT 4 0 4
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
45 29 16
Treatment completed as planned 36 24 12
Adverse Event or side effects 3 1 2
Refusal unrelated to adverse event 1 1 0
Progression/relapse 1 1 0
Death 3 1 2
Other - not protocol specified 1 1 0
MAJOR PROTOCOL DEVIATIONS 0 0 0
LOST TO FOLLOW-UP 0 0 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
2 2 0
Number of Patients with a Given Type and Grade of Adverse Event
Induction
Adverse Events Unlikely or Not Related to Treatment Excluded
Non-Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
Registrations ending December 31, 2019; Data as of February 18, 2020
Induction: Ph-
(n=29)
Grade
Induction: Ph+/Ph-like
(n=20)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5
ALT increased 28 1 0 0 20 0 0 0
Catheter related infection 29 0 0 0 19 1 0 0
Confusion 28 1 0 0 20 0 0 0
Cytokine release syndrome 28 1 0 0 20 0 0 0
Dehydration 29 0 0 0 19 1 0 0
Diarrhea 28 1 0 0 19 1 0 0
Dysarthria 28 1 0 0 20 0 0 0
Dyspnea 26 2 1 0 19 1 0 0
Edema limbs 29 0 0 0 19 1 0 0
Fatigue 28 1 0 0 20 0 0 0
Febrile neutropenia 26 3 0 0 19 0 1 0
Fever 28 0 1 0 20 0 0 0
Gen disorders/admin site cond 29 0 0 0 19 1 0 0
Generalized muscle weakness 29 0 0 0 19 1 0 0
Heart failure 29 0 0 0 19 1 0 0
Hematoma 29 0 0 0 19 1 0 0
APRIL 22 - 25, 2020 SWOG LEUKEMIA 18
S1318/I-II
Induction: Ph-
(n=29)
Grade
Induction: Ph+/Ph-like
(n=20)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5
Hyperglycemia 25 4 0 0 19 1 0 0
Hypertension 26 3 0 0 20 0 0 0
Hypocalcemia 28 1 0 0 20 0 0 0
Hypokalemia 29 0 0 0 19 1 0 0
Hyponatremia 29 0 0 0 19 1 0 0
Hypophosphatemia 28 1 0 0 20 0 0 0
Hypotension 28 1 0 0 19 1 0 0
Hypoxia 28 1 0 0 19 1 0 0
Infections/infestations-Other 28 1 0 0 19 1 0 0
Infusion related reaction 28 1 0 0 20 0 0 0
Lung infection 27 1 1 0 18 1 1 0
Nausea 29 0 0 0 19 1 0 0
Nervous sys disorders-Other 28 1 0 0 20 0 0 0
Pneumonitis 28 1 0 0 20 0 0 0
Respiratory failure 28 0 0 1 20 0 0 0
Sepsis 29 0 0 0 19 0 1 0
TTP 28 1 0 0 20 0 0 0
Urinary tract infection 29 0 0 0 19 1 0 0
MAX. GRADE ANY ADVERSE
EVENT
13 13 2 1 11 7 2 0
APRIL 22 - 25, 2020 SWOG LEUKEMIA 19
S1612/II-III
S1612 Phase II-III
Coordinating Group: SWOG
A Randomized Phase II/III Trial of "Novel Therapeutics" Versus Azacitidine
in Newly Diagnosed Patients with Acute Myeloid Leukemia (AML) or High-
Risk Myelodysplastic Syndrome (MDS), Age 60 or Older LEAP: LEss-Intense
AML Platform Trial
Participants:
SWOG, CTSU (Supported by CCTG, ECOG-ACRIN)
Study Chairs:
L Michaelis, R Walter, S Assouline (CCTG), A Im
(ECOG-ACRIN)
Statisticians:
M Othus, A Moseley
Data Coordinator:
T Maher
Date Activated:
12/22/2017
Date Closed*:
10/19/2018
*Temporary closure
SCHEMA
Objectives Phase II Component: To select, based on overall
survival, any or all of the "Novel Therapeutic"
regimens for further testing against azacitidine in
patients age 60 and older with newly diagnosed acute
myeloid leukemia (AML) or myelodysplastic
syndrome with excessive blasts-2 (MDS-EB-2).
Phase III Component: To compare overall survival of
the "Novel Therapeutic" regimens selected in the
Phase II portion of the trial to azacitidine in these
patient populations.
To estimate the frequency and severity of toxicities
of the regimens in these patient populations.
R
E
G
I
S
T
R
A
T
I
O
N
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm A (control):
Azacitidine
Arm B:
Azacitidine + Nivolumab
Arm C:
Azacitidine + Midostaurin
Arm D*:
Decitabine/Cytarabine
*Arm D will open to accrual when Arms B and C have met Phase II accrual
and are temporarily closed for Phase II analysis
FLT3 Testing
APRIL 22 - 25, 2020 SWOG LEUKEMIA 20
S1612/II-III
To estimate response rates, event-free survival, and
relapse-free survival for these regimens in these
patient populations.
Patient Population Patients must have morphologically confirmed,
previously untreated AML or MDS-EB-2. Patients
with acute promyelocytic leukemia, biphenotypic
leukemia, blastic transformation of chronic
myelogenous leukemia are not eligible. Patients must
have disease present in the blood or bone marrow;
patients with only extramedullary disease are not
eligible. Patients must not be known to have AML in
the CNS. Patients must be deemed, in the judgment
of the treating physician, to be ineligible for intensive
induction therapy or must have refused intensive
induction therapy.
Patients who have received prior therapy with
midostaurin, any anti-PD-1 or anti-PD-L1 therapy,
any DNA-methyltransferase inhibitor, or prior 7+3
therapy for MDS are not eligible. Patients who are
transfusion-dependent and patients receiving growth
factor support are eligible; patients must discontinue
growth factor support prior to initiation of protocol
therapy. Prior malignancy is allowed providing
concurrent therapy is not required; active hormonal
therapy is allowed.
Patients must be at least 60 years old and must be
able to swallow oral medications. Clinical evaluation
at baseline including hematologic, hepatic, renal,
cardiac, and coagulation parameters must be
completed per protocol. Women and men must be
willing to use contraception as outlined in the
protocol. Patients must not have active infection
(systemic bacterial, fungal, or viral infection) that is
not controlled. Patients must be eligible for at least
one of the currently enrolling investigational
treatment arms. Refer to the protocol for arm-specific
eligibility criteria.
Patients must have specimens submitted for FLT3
testing as outlined in the protocol for randomization
stratification. Pretreatment cytogenetics must be
performed on all patients as outlined in the protocol.
Stratification/Descriptive Factors Patient randomization will be stratified by the
following factors: (1) Zubrod performance status: 0-1
vs 2-4; (2) FLT3-ITD status based on central
laboratory results: wild type FLT3 vs mutated FLT3-
ITD vs non-evaluable; and (3) baseline blast
percentage: MDS-EB-2 (< 20%) vs AML (20% or
higher).
Up to 100 eligible patients will be enrolled to each
arm for Phase II analysis. Up to 200 additional
eligible patients will be enrolled to each arm for
Phase III analysis. If all three experimental arms
complete full Phase III accrual, this study will enroll
approximately 1,500 eligible patients.
The Phase II interim analysis to evaluate for stopping
for futility will be performed when 52 events have
been observed. For arms carried forward for Phase III
testing, two additional interim analyses will be
performed when 50% and 75% of the expected
events have been observed (207 and 311 events,
respectively).
Summary Statement This trial opened on December 22, 2017. On October
22, 2018, the study team temporarily closed all arms
to accrual after observing unexpected toxicities on
the Azacitidine + Nivolumab (Aza + Nivo) arm
during the first two cycles of therapy. The FDA
placed a partial clinical hold on this trial on October
25, 2018, mandated that all patients discontinue
nivolumab, and later denied the study team's request
to reopen the Aza + Nivo arm with revised eligibility
criteria. A protocol revision was submitted to re-open
the trial with the Azacitidine (Aza), Azacitidine +
Midostaurin (Aza + Mido), and Decitabine +
Cytarabine arms. This revision includes a quality of
life component, and was disapproved for reasons
primarily related to this component. A response to
CTEP's review is in progress. The trial remains
closed to accrual.
As of October 22, 2018, 78 patients had been
randomized (26 per arm).
Aza arm: One patient withdrew from protocol
therapy before starting treatment. This patient is
considered major protocol deviation and is not
analyzable for adverse events but will be analyzed for
other endpoints. Of the 25 patients who have been
evaluated for adverse events, two experienced Grade
5 treatment-related non-hematologic toxicities: sepsis
(1 patient) and small intestinal perforation (1). Two
others experienced Grade 4 treatment-related non-
hematologic toxicities.
Aza + Nivo arm: One patient was ineligible due to
low baseline blast count. Of the 25 patients who have
been evaluated for adverse events, five experienced
Grade 5 treatment-related non-hematologic toxicities:
sepsis (2), respiratory failure (2), and sudden death
NOS (1). One patient who died of respiratory failure
also experienced Grade 4 treatment-related lung
APRIL 22 - 25, 2020 SWOG LEUKEMIA 21
S1612/II-III
infection (coded as Infections/infestation-Other). Five
others experienced Grade 4 treatment-related non-
hematologic toxicities, including one with
hemophagocytic lymphohistiocytosis (coded as
Immune sys disorders-Other).
Aza + Mido arm: One patient was ineligible due to
low baseline blast count. One patient withdrew from
protocol therapy before starting treatment and
another died before starting treatment. These two
patients are considered major protocol deviations and
are not analyzable for adverse events but will be
analyzed for other endpoints. Of the 23 patients who
have been evaluated for adverse events, three
experienced Grade 5 treatment-related non-
hematologic toxicities: respiratory failure (1), lung
infection (1), and heart failure (1). Two others
experienced Grade 4 treatment-related non-
hematologic toxicities.
Across all arms, 27 patients went off protocol
treatment for reasons other than those specified in the
protocol, primarily due to treatment futility,
physician decision, or to receive different therapy
(24). Two patients on the Aza+Nivo arm went off
protocol treatment because of the FDA mandate to
stop nivolumab. One patient went off protocol
treatment because the patient did not wish to hold
study drug per protocol for a Grade 3 toxicity.
Registration by Institution
Randomization
Institutions
Total
Reg Institutions
Total
Reg
Kaiser Perm NCORP 9 Arizona CC, Univ of 1
Heartland NCORP 6 Carle CC NCORP 1
H Lee Moffitt CC 3 Davis, U of CA 1
Montana NCORP 3 Georgia NCORP 1
New Mexico MU-NCORP 3 Loyola University 1
Rochester, Univ of 3 Southeast COR NCORP 1
Greenville NCORP 2 ALLIANCE 23
Michigan CRC NCORP 2 NRG 12
PCRC NCORP 2 ECOG-ACRIN 2
Wayne State Univ 2 Total (19 Institutions) 78
Registration, Eligibility, and Evaluability
Data as of February 18, 2020
TOTAL Azacitidine
Azacitidine +
Nivolumab
Azacitidine +
Midostaurin
NUMBER REGISTERED 78 26 26 26
INELIGIBLE 2 0 1 1
ELIGIBLE 76 26 25 25
ADVERSE EVENT ASSESSMENT
Evaluable 73 25 25 23
Not Evaluable 3 1 0 2
APRIL 22 - 25, 2020 SWOG LEUKEMIA 22
S1612/II-III
Patient Characteristics
Data as of February 18, 2020
Azacitidine
(n=26)
Azacitidine +
Nivolumab
(n=25)
Azacitidine +
Midostaurin
(n=25)
AGE
Median 75.4 76.4 76.2
Minimum 61.9 66.4 65.7
Maximum 86.3 86.5 85.8
SEX
Males 15 58% 17 68% 16 64%
Females 11 42% 8 32% 9 36%
HISPANIC
Yes 0 0% 1 4% 1 4%
No 25 96% 23 92% 23 92%
Unknown 1 4% 1 4% 1 4%
RACE
White 23 88% 21 84% 21 84%
Black 2 8% 3 12% 2 8%
Asian 1 4% 0 0% 0 0%
Unknown 0 0% 1 4% 2 8%
BASELINE BLAST PERCENTAGE
<20% (MDS-EB-2) 8 31% 6 24% 6 24%
≥20% (AML) 18 69% 19 76% 19 76%
FLT3 - CENTRALLY REVIEWED
Wild type FLT3-ITD 25 96% 21 84% 22 88%
Mutated FLT3-ITD 1 4% 4 16% 3 12%
ZUBROD PERFORMANCE STATUS
0-1 21 81% 21 84% 20 80%
2-4 5 19% 4 16% 5 20%
Treatment Summary
Data as of February 18, 2020
TOTAL
NUMBER ON PROTOCOL TREATMENT 2
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
74
Adverse Event or side effects 9
Refusal unrelated to adverse event 9
Progression/relapse 15
Death 14
Other - not protocol specified 27
MAJOR PROTOCOL DEVIATIONS 3
LOST TO FOLLOW-UP 0
CONSENT WITHDRAWAL AFTER TREATMENT INITIATION 0
APRIL 22 - 25, 2020 SWOG LEUKEMIA 23
S1612/II-III
Number of Patients with a Given Type and Grade of Adverse Event
Adverse Events Unlikely or Not Related to Treatment Excluded
Non-Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
Data as of February 18, 2020
Azacitidine
(n=25)
Grade
Azacitidine + Nivolumab
(n=25)
Grade
Azacitidine + Midostaurin
(n=23)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
ALT increased 25 0 0 0 24 1 0 0 23 0 0 0
AST increased 25 0 0 0 24 0 1 0 23 0 0 0
Acidosis 24 1 0 0 25 0 0 0 23 0 0 0
Acute kidney injury 25 0 0 0 24 1 0 0 23 0 0 0
Anorexia 25 0 0 0 25 0 0 0 22 1 0 0
Arthralgia 25 0 0 0 24 1 0 0 23 0 0 0
Atrial fibrillation 25 0 0 0 25 0 0 0 22 1 0 0
Back pain 25 0 0 0 25 0 0 0 22 1 0 0
Cardiac troponin I increased 24 1 0 0 25 0 0 0 23 0 0 0
Catheter related infection 24 1 0 0 25 0 0 0 23 0 0 0
Chest pain - cardiac 25 0 0 0 25 0 0 0 22 1 0 0
Colitis 25 0 0 0 25 0 0 0 22 1 0 0
Constipation 25 0 0 0 24 1 0 0 23 0 0 0
Dry mouth 25 0 0 0 25 0 0 0 22 1 0 0
Dyspnea 25 0 0 0 24 1 0 0 22 1 0 0
ECG QT corrected int prolong 25 0 0 0 25 0 0 0 22 1 0 0
Ejection fraction decreased 25 0 0 0 24 1 0 0 23 0 0 0
Epistaxis 24 1 0 0 25 0 0 0 23 0 0 0
Fatigue 24 1 0 0 24 1 0 0 19 4 0 0
Febrile neutropenia 15 9 1 0 18 6 1 0 15 7 1 0
Fever 25 0 0 0 24 1 0 0 23 0 0 0
GI disorders-Other, specify 24 1 0 0 25 0 0 0 23 0 0 0
Generalized muscle weakness 25 0 0 0 24 1 0 0 22 1 0 0
Heart failure 24 1 0 0 24 0 1 0 21 1 0 1
Hyperglycemia 25 0 0 0 25 0 0 0 22 1 0 0
Hypertension 25 0 0 0 25 0 0 0 22 1 0 0
Hypoalbuminemia 24 1 0 0 24 1 0 0 23 0 0 0
Hypokalemia 24 1 0 0 24 0 1 0 23 0 0 0
Hyponatremia 25 0 0 0 24 1 0 0 22 1 0 0
Hypophosphatemia 25 0 0 0 24 1 0 0 23 0 0 0
Hypotension 25 0 0 0 23 2 0 0 19 4 0 0
Hypoxia 24 0 1 0 24 1 0 0 23 0 0 0
INR increased 25 0 0 0 25 0 0 0 22 1 0 0
Immune sys disorders-Other 25 0 0 0 24 0 1 0 23 0 0 0
Infections/infestations-Other 25 0 0 0 23 1 1 0 20 3 0 0
Joint infection 25 0 0 0 25 0 0 0 22 1 0 0
Lung infection 23 1 1 0 19 4 2 0 19 3 0 1
Mucositis oral 25 0 0 0 25 0 0 0 21 2 0 0
Pneumonitis 25 0 0 0 24 0 1 0 23 0 0 0
Pruritus 24 1 0 0 25 0 0 0 23 0 0 0
Pulmonary edema 25 0 0 0 25 0 0 0 22 0 1 0
Rash maculo-papular 24 1 0 0 25 0 0 0 23 0 0 0
Respiratory failure 25 0 0 0 23 0 0 2 22 0 0 1
APRIL 22 - 25, 2020 SWOG LEUKEMIA 24
S1612/II-III
Azacitidine
(n=25)
Grade
Azacitidine + Nivolumab
(n=25)
Grade
Azacitidine + Midostaurin
(n=23)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
Sepsis 23 0 1 1 21 0 2 2 22 0 1 0
Skin infection 25 0 0 0 24 1 0 0 23 0 0 0
Small intestinal perforation 24 0 0 1 25 0 0 0 23 0 0 0
Sudden death NOS 25 0 0 0 24 0 0 1 23 0 0 0
Supraventricular tachycardia 24 1 0 0 25 0 0 0 23 0 0 0
Typhlitis 25 0 0 0 25 0 0 0 22 1 0 0
MAX. GRADE ANY ADVERSE
EVENT
10 11 2 2 9 6 5 5 8 10 2 3
APRIL 22 - 25, 2020 SWOG LEUKEMIA 25
S1712/II
S1712 Phase II
Coordinating Group: SWOG
A Randomized Phase II Study of Ruxolitinib (NSC-752295) in Combination
with BCR-ABL Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
(CML) Patients with Molecular Evidence of Disease
Participants:
SWOG, CTSU
Study Chairs:
K Sweet, J Radich
Statisticians:
M Othus, A Moseley
Data Coordinator:
L Highleyman
Date Activated:
07/20/2018
SCHEMA
Objectives To compare the rate of molecular response 4.5
(MR4.5) after 12 months of combination therapy
with ruxolitinib plus a TKI (bosutinib, dasatinib or
nilotinib) versus a TKI alone, based on local PCR
testing to measure BCR-ABL transcripts in chronic
phase CML patients with molecular evidence of
disease.
To estimate the frequency and severity of toxicities
of each regimen in this patient population.
To estimate progression-free survival and overall
survival of each regimen in this patient population.
Patient Population Patients must have a diagnosis of chronic phase
chronic myeloid leukemia (CML) without any history
of progression to accelerated or blast phase CML as
defined in the protocol. Patients must have detectable
BCR-ABL transcripts measured by RT-PCR at a
CLIA-approved laboratory as outlined in the
protocol.
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm 1:
Single-agent TKI
Arm 2:
Single-agent TKI
+Ruxolitinib
APRIL 22 - 25, 2020 SWOG LEUKEMIA 26
S1712/II
Patients must have received treatment with one of
bosutinib, dasatinib or nilotinib for a minimum of six
months prior to registration and must be expected to
remain on the same TKI for the next 12 months. If
patients have received more than one TKI, the reason
for changing treatment must have been intolerance to
the prior TKI. Patients must have been receiving TKI
treatment for CML for at least one year and for no
more than 10 years prior to randomization. Prior
malignancy is allowed providing it does not require
concurrent therapy; active hormonal therapy is
allowed.
Patients must have adequate hematologic, hepatic,
renal, and cardiac function. Patients known to be
HIV+ are allowed provided they have undetectable
HIV viral loads on their most recent viral load test
within six months prior to randomization.
Patients must be offered participation in specimen
banking for future research. With patient consent,
specimens must be submitted as outlined in the
protocol.
Stratification/Descriptive Factors Patient randomization will be stratified by the
following factors: (1) time on any TKI therapy prior
to randomization: ≥ 1 and < 4 years vs ≥ 4 and ≤ 10
years; and (2) current TKI: bosutinib vs.dasatinib vs
nilotinib.
Accrual Goals The accrual goal is 84 patients to achieve 74 eligible
patients (37 per arm).
One interim analysis is planned at the time when 12-
month MR4.5 data are available from 19 patients on
each arm.
Summary Statement This study activated on July 20, 2018. As of
December 31, 2019, 16 patients had been
randomized. Two patients (one on each arm) are
ineligible because they changed prior TKI treatment
due to lack of response.
One patient on the TKI+Ruxolitinib arm withdrew
consent after initiating treatment due to extra visits
and associated costs. No patient has experienced a
Grade 3 or higher treatment-related adverse event.
Registration by Institution
Registrations ending December 31, 2019
Institutions
Total
Reg Institutions
Total
Reg
Heartland NCORP 4 Utah, U of 1
Duke Univ Med Ctr 2 ALLIANCE 2
H Lee Moffitt CC 2 NRG 2
Hawaii MU-NCORP 1 ECOG-ACRIN 1
New Mexico MU-NCORP 1 Total (9 Institutions) 16
Registration, Eligibility, and Evaluability
Registrations ending December 31, 2019; Data as of February 14, 2020
TOTAL
Single Agent
TKI
TKI +
Ruxolitinib
NUMBER REGISTERED 16 8 8
INELIGIBLE 2 1 1
ELIGIBLE 14 7 7
Analyzable, Pend. Elig. 1 0 1
ADVERSE EVENT ASSESSMENT
Evaluable 10 7 3
Too Early 4 0 4
APRIL 22 - 25, 2020 SWOG LEUKEMIA 27
S1712/II
Patient Characteristics
Registrations ending December 31, 2019; Data as of February 14, 2020
Single Agent
TKI
(n=7)
TKI +
Ruxolitinib
(n=7)
AGE
Median 61.5 41.5
Minimum 19.7 21.7
Maximum 75.5 71.0
SEX
Males 4 57% 2 29%
Females 3 43% 5 71%
HISPANIC
Yes 1 14% 0 0%
No 5 71% 7 100%
Unknown 1 14% 0 0%
RACE
White 5 71% 7 100%
Black 1 14% 0 0%
Pacific Islander 1 14% 0 0%
TKI TIME
≥ 1 and < 4 years 3 43% 4 57%
≥ 4 and ≤ 10 years 4 57% 3 43%
CURRENT TKI
Dasatinib 3 43% 5 71%
Nilotinib 4 57% 2 29%
Treatment Summary
Registrations ending December 31, 2019; Data as of February 14, 2020
TOTAL
NUMBER ON PROTOCOL TREATMENT 13
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
1
Refusal unrelated to adverse event 1
MAJOR PROTOCOL DEVIATIONS 0
LOST TO FOLLOW-UP 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
1
APRIL 22 - 25, 2020 SWOG LEUKEMIA 28
S1905/II
S1905 Phase II
Coordinating Group: SWOG
A Phase II Study of AKR1C3-Activated Prodrug OBI-3424 in Patients with
Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)
Participants:
SWOG, CTSU
Study Chairs:
A Advani, N Papadantonakis, C Yeung
Statisticians:
M Othus, M Duong
Data Coordinator:
L Highleyman
Objectives To assess the response rate [complete remission (CR)
or CR with incomplete count recovery (CRi)] of
OBI-3424 in patients with relapsed/refractory T-cell
acute lymphoblastic leukemia (TALL).
To estimate the frequency and severity of toxicities
of OBI-3424 in this patient population.
To estimate event-free survival, relapse-free survival,
and overall survival in this patient population.
To estimate minimal/measurable residual disease
(MRD) negativity (among patients who achieve CR
or CRi).
Patient Population Patients must have a diagnosis of relapsed or
refractory T-ALL based on WHO classification.
Patients must have evidence of acute leukemia in
their peripheral blood or bone marrow with at least
5% lymphoblasts in the peripheral blood or bone
marrow. Patients with only extramedullary disease
are not eligible. Patients must be refractory to or have
relapsed following prior standard induction therapy.
Patients must have no evidence of central nervous
system (CNS) disease including a negative lumbar
puncture for patients with clinical signs or symptoms
consistent with CNS involvement.
Patients must have received prior treatment with
nelarabine as described in the protocol. Patients must
not have had chemotherapy within 14 days prior to
registration except for steroids, oral
60mercaptopurine, oral methotrexate, vincristine,
intrathecal chemotherapy, or hydroxyurea. Patients
must not have undergone allogeneic hematopoietic
transplant within 90 days prior to registration.
Patients must be at least 18 years of age, adequate
renal and hepatic functions, and a Zubrod
performance status of 0-3. Patients must not have
uncontrolled systemic fungal, bacterial, viral or other
infection. Patients must have no evidence of Grade 2
or greater acute graft versus host disease (GVHD) or
moderate or severe limited chronic GVHD and must
have no history of extensive GVHD of any severity.
Patients must agree to have bone marrow and blood
specimens submitted for MRD testing and must be
offered the opportunity to participate in specimen
banking.
Accrual Goals The accrual goal is 43 patients to achieve 35
evaluable patients. Enrollment will be paused for
additional toxicity monitoring and to evaluate
response after 10 and then 20 patients are enrolled in
a three-stage design.
APRIL 22 - 25, 2020 SWOG LEUKEMIA 29
S1925/III
S1925 Phase III
Coordinating Group: SWOG
Randomized Phase III Study of Early Intervention with Venetoclax and
Obinutuzumab Versus Delayed Therapy with Venetoclax and Obinutuzumab
in Newly Diagnosed Asymptomatic High-Risk Patients with Chronic
Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL):
EVOLVE CLL/SLL Study
Participants:
SWOG, CTSU (Supported by ECOG-ACRIN)
Study Chairs:
D Stephens, B Hill, J Pagel, A Mato (ECOG-ACRIN)
Statisticians:
A Moseley, M Othus
Data Coordinators:
T Maher, L Kingsbury
SCHEMA
Objectives To evaluate whether early treatment with venetoclax
and obinutuzumab (V-O) extends overall survival
compared with delayed treatment with V-O in high-
risk (chronic lymphocytic leukemia [CLL]
international prognostic indicator [CLL-IPI] ≥4 or
complex cytogenetics), newly diagnosed
asymptomatic CLL/SLL patients.
R
A
N
D
O
M
I
Z
A
T
I
O
N
Early Arm:
Venetoclax + Obinutuzumab
Delayed Arm:
Venetoclax + Obinutuzumab*
*Treatment on Delayed Arm begins when the 2018 International
Workshop on CLL (IWCLL) indication is met.
APRIL 22 - 25, 2020 SWOG LEUKEMIA 30
S1925/III
To compare overall response rates (complete
response [CR] + partial response), CR rates,
progression-free survival, and event-free survival
between arms.
To evaluate safety and tolerability of each arm.
To compare time to second CLL-directed treatment
(from randomization and from response) between
arms.
To compare relapse-free survival and time to second
objective disease progression between arms.
To compare the rates of Richter’s transformation
between arms.
To describe distribution of Cumulative Illness Rating
Scale across the study, in each treatment arm, and to
estimate the interaction between the scale and
treatment arm and OS.
To assess the impact of early intervention with V-O
versus delayed therapy with V-O in CLL patients in
relation to Health-Related Quality of Life (HRQoL)
using the FACT-Leukemia scale.
To assess the impact of the two treatment arms on the
specific domains of the FACT-Leukemia, including
physical, social, emotional, and functional well-being
and leukemia-specific HRQoL.
Patient Population Patients must have a confirmed diagnosis of CLL or
small lymphocytic lymphoma (SLL) (collectively
referred to as CLL) according to the 2018
International Workshop on CLL (IWCLL) within 12
months prior to registration. Patients must not meet
any of the IWCLL specified criteria for active CLL
therapy. Patients must have CLL-IPI Score ≥ 4 or
complex cytogenetics.
Patients must not have received any prior CLL-
directed therapy, and the treating physician must
have the intent of using V-O as initial therapy.
Treatment with high dose corticosteroids or
intravenous immunoglobulin for autoimmune
complications of CLL must be completed at least
four weeks prior to enrollment. Palliative steroids
must be at a dose ≤ 20 mg/day at registration. Prior
therapy with anti CD20 monoclonal antibodies is not
allowed.
Patients must have performance status 0 - 2 and have
adequate hematologic, renal, and hepatic function.
FISH and cytogenetic analyses, IgVH mutational
status, and serum beta-2 microglobulin levels must be
obtained prior to registration according to the timing
in the protocol. Patients must not have current
clinically significant gastrointestinal malabsorption
and must be able to take oral medications. Patients
must not have uncontrolled autoimmune hemolytic
anemia, idiopathic thrombocytopenia purpura,
bleeding disorder, or history of cardiac disease,
stroke, or intracranial hemorrhage per the timing
specified in the protocol. Patients must not have
uncontrolled active infection with hepatitis B or C,
and those with latent hepatitis B must agree to
prophylaxis during and for six months following V-O
therapy. HIV-infected patients on effective anti-
retroviral therapy are allowed provided they have
undetectable HIV viral loads on their most recent
viral load test within six months prior to
randomization. Patients must not require continued
therapy with a strong inhibitor or inducer of
CYP3A4/5.
Patients must be offered participation in specimen
banking for future research. Patients who are able to
complete patient reported outcome forms in English,
Spanish, French, German, Russian, or Mandarin must
agree to participate in the quality of life assessments
as outlined in the protocol.
Stratification/Descriptive Factors Patient randomization will be stratified by CLL-IPI
risk score status: high risk (4-6 points) vs very high
risk (≥ 7 points or complex cytogenetics).
Accrual Goals The accrual goal is 247 patients to achieve 222
eligible patients randomized in a 2:1 ratio (148 on the
Early Arm and 74 on the Delayed Arm).
Formal interim analyses for efficacy and futility are
planned after approximately 40%, 60%, and 80% of
the expected events have occurred across both arms.
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Alliance Study A041501 – A Phase III Trial to Evaluate the Efficacy of the Addition of Inotuzumab ozogamicin (a conjugated anti-CD22 Monoclonal Antibody) to Frontline Therapy in Young Adults
(Ages 16-39 years) with Newly Diagnosed Precursor B-Cell ALL
Data as of 09/16/2019
Committee: Leukemia Study Statisticians: Jun (Vivien) Yin, Ph.D. Gabriela Perez Burbano, M.S Study Chair: Daniel J. DeAngelo, M.D., Ph. D. 1.0 OBJECTIVES Primary
1. To confirm tolerability of the combination regimen with the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of CALGB 10403.
2. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, without censoring for transplant.
Secondary
1. To determine the impact of inotuzumab ozogamicin on disease-free (DFS) and overall survival (OS) in patients who achieve an induction response.
2. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, with censoring for transplant.
3. To determine the impact of inotuzumab ozogamicin on minimal residual disease (MRD) and correlate this with the EFS, DFS and OS.
4. To determine the prognosis based on patients’ LDA gene signature in terms of EFS, DFS, and OS after treatment with or without inotuzumab ozogamicin when added to the C10403 backbone regimen.
5. To evaluate the toxicity and tolerability of the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of CALGB 10403.
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2.0 CURRENT SCHEMA
3.0 ELIGIBILITY CRITERIA Pre-registration Eligibility Criteria (Step 0)
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• Bone marrow submission for LDA Assay
Registration Eligibility Criteria (Step 1) • Newly diagnosed patients with CD-22 positive B-cell acute lymphoblastic leukemia (WHO
criteria). Burkitt type ALL is NOT eligible. Patients who have BCR-ABL fusion transcript determined by FISH or RT-PCR or t(9;22)(q34;q11) by cytogenetics are not eligible for this trial and should be considered for enrollment on studies that incorporate imatinib or other tyrosine kinase inhibitors during induction.
• Prior Treatment (Section 3.3.3) o No prior therapy for acute leukemia except emergency therapy (corticosteroids or
hydroxyurea for ≤ 7 days) for blast cell crisis, or renal failure due to leukemia infiltration of the kidneys
o Single-dose intrathecal cytarabine is allowed prior to registration (see also Section 7.1.1.2).
o Prior steroid therapy is allowed. • Not pregnant and not nursing. • Age ≥ 18 years and < 40 years. • ECOG Performance Status 0-2 • Patients with Down Syndrome are excluded from this study due to the likelihood of excessive
toxicity. These patients should be treated in consultation with a pediatric oncologist. Randomization Eligibility Criteria (Step 2)
• Completion of remission induction therapy (per Section 7.2). • Patients with M2 marrow or better are eligible. Patients with M3 or M4 marrow (greater than
25% lymphoblasts) will not be eligible to be randomized. • Lab values
o Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 o Platelet Count ≥ 100,000/mm3 o Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients with known
Gilbert’s syndrome o AST ≤ 8 x upper limit of normal (ULN)
4.0 TREATMENT SCHEDULE Table 4a. Safety Run-in: Course I and Inotuzumab
Induction Inotuzumab Course I (Remission Induction) Arm 3: Cycle1 Arm 3: Cycle 2
Allopurinol 300 mg PO daily until peripheral
blasts and extramedullary disease are reduced.
-
-
IT-Ara-C 70 mg IT on Day 1. - -
Dexamethasone 5mg/m2 PO or IV BID on Days 1-7 and 15-21
-
-
Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8, 15, and 22
-
-
Daunorubicin -25 mg/m2 IV on Days 1, 8, 15, and 22
- -
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PEG-asparaginase 2000 IU/m2 IV x 1 dose on Day 4 (OR Day 5 OR Day 6). (cap dose
at 3750 IU) *
-
-
IT Methotrexate
15 mg IT on Day 8 and Day 29. For patients with CNS3 disease, IT-MTX is also administered on
Day 15 and 22.
-
-
Bone marrow aspirate and biopsy
specimen Day 29
Day 28
Day 28
Inotuzumab - 0.5 mg/m2/day IV
on Day 1, 8 and 15 of a 28-day cycle. *
0.5 mg/m2/day IV on Day 1, 8 and 15 of a 28-day cycle. *
Table 4b. Safety Run-in: Course II-V
Course II: Remission
Consolidation Course III: Interim
Maintenance Course IV: Delayed
Intensification Course V:
Maintenance Therapy Cyclophosphamide 1000 mg/m2 IV on Day 1
and 29 -
1000 mg/m2 IV on
Day 29 -
Cytarabine
75 mg/m2 IV or SC on Days 1-4, 8-11, 29-32,
and 36-39
-
75 mg/m2 IV or SC on Days 29-32 and 36-39
-
6-Mercaptopurine 60 mg/m2 PO on Days 1-14 and 29-42. **
- - 75 mg/m2/day PO on Days 1-84. **
IT Methotrexate
15 mg IT (addition of 50 mg of hydrocortisone
optional per institutional guidelines) on Days 1, 8, 15, and 22 [omit dose on Day 15 and 22 for CNS3
patients].
15 mg IT on Days 1 and 31
15 mg IT (addition of 50 mg of
hydrocortisone optional per
institutional guidelines) on Days 1, 29, and 36
15 mg IT (addition of 50 mg of
hydrocortisone optional per
institutional guidelines) on Day 1. IT
methotrexate also is given on Day 29 of the
first 4 courses of maintenance therapy
PO Methotrexate
-
-
-
20 mg/m2 PO weekly on Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,
and 78. Round to nearest 2.5 mg dose. PO methotrexate is
held on Day 29 of the first 4 courses of
maintenance therapy (when IT methotrexate
is given).
IV Methotrexate
-
100 mg/m2 IV (escalate by 50 mg/m2/dose) on
Days 1, 11, 21, 31, and 41.
-
-
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Rituximab for CD20+ patients only *
375 mg/m2 IV on Days 1 and 8 and then again on
Days 29 and 36. *
375 mg/m2 IV on Days 1 and 11. *
375 mg/m2 IV on Days 1 and 8. *
-
Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 15, 22,
43, and 50.
1.5 mg/m2 (maximum 2 mg) IV push on Days 1, 11,
21, 31, and 41.
1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8,
15, 43, and 50.
1.5 mg/m2 (maximum dose 2 mg) IV on
Days 1, 29, and 57
PEG-Asparaginase
2000 IU/m2 IV on Days 15 and 43. (cap dose at
3750 IU) *
2000 IU/m2 IV on Days 2 and 22. Cap dose at 3750 IU. *
2000 IU/m2 IV on Day 4 (OR Day 5 OR Day 6) AND Day 43. (cap
dose at 3750 IU) *
-
Bone marrow aspirate and biopsy specimen
Day 56
-
One week after completion of Course
IV
-
Dexamethasone
-
-
5 mg/m2 PO or IV BID on Days 1-7 and 15-
21
6 mg/m2/day PO or IV divided BID every 4 weeks on Days 1-5,
29-33, and 57-61 Doxorubicin - - 25 mg/m2 IV on Days
1, 8, and 15 -
Thioguanine
-
-
60 mg/m2/day PO on Days 29-42, at least 1 hour after the evening
meal.
-
*Premedicate with 650 mg acetaminophen, 100 mg hydrocortisone and 25-50 mg diphenhydramine (or equivalent) prior to PEG-asparaginase ** Not to be taken with milk or citrus products Table 4c. Phase III: Course I, Randomization, and Inotuzumab
Induction Randomization: M0, M1, M2 <=25% blasts Course I (Remission
Induction) Arm 1 Arm 2: Cycle1 Arm 2: Cycle 2
Allopurinol
300 mg PO daily until peripheral blasts and
extramedullary disease are reduced.
-
-
-
IT-Ara-C 70 mg IT on Day 1. - - -
Dexamethasone 5mg/m2 PO or IV BID on Days 1-7 and 15-21
-
-
-
Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8, 15, and 22
-
-
-
Daunorubicin -25 mg/m2 IV on Days 1, 8, 15, and 22
- - -
PEG-asparaginase 2000 IU/m2 IV x 1 dose on Day 4 (OR Day 5 OR Day 6). (cap dose at 3750 IU) *
-
-
-
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IT Methotrexate
15 mg IT on Day 8 and Day 29. For patients with CNS3
disease, IT-MTX is also administered on Day 15 and
22.
-
-
-
Bone marrow aspirate and biopsy specimen Day 29
Day 28
Day 28
Inotuzumab - -
0.5 mg/m2/day IV on Day 1, 8 and 15 of a
28-day cycle. *
0.5 mg/m2/day IV on Day 1, 8 and 15 of a
28-day cycle. * Table 4d. Phase III: Course II-V
Course II: Remission Consolidation
Course III: Interim Maintenance
Course IV: Delayed Intensification
Course V: Maintenance Therapy
Cyclophosphamide 1000 mg/m2 IV on Day 1 and 29
-
1000 mg/m2 IV on Day 29
-
Cytarabine
75 mg/m2 IV or SC on Days 1-4, 8-11, 29-32,
and 36-39
-
75 mg/m2 IV or SC on Days 29-32 and 36-39
-
6-Mercaptopurine 60 mg/m2 PO on Days 1-14 and 29-42. **
- - 75 mg/m2/day PO on Days 1-84. **
IT Methotrexate
15 mg IT (addition of 50 mg of hydrocortisone
optional per institutional guidelines) on Days 1, 8, 15, and 22 [omit dose on Day 15 and 22 for CNS3
patients].
15 mg IT on Days 1 and 31
15 mg IT (addition of 50 mg of
hydrocortisone optional per
institutional guidelines) on Days 1, 29, and 36
15 mg IT (addition of 50 mg of
hydrocortisone optional per
institutional guidelines) on Day 1. IT
methotrexate also is given on Day 29 of the
first 4 courses of maintenance therapy
PO Methotrexate
-
-
-
20 mg/m2 PO weekly on Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,
and 78. Round to nearest 2.5 mg dose. PO methotrexate is
held on Day 29 of the first 4 courses of
maintenance therapy (when IT methotrexate
is given).
IV Methotrexate
-
100 mg/m2 IV (escalate by 50 mg/m2/dose) on
Days 1, 11, 21, 31, and 41.
-
-
Rituximab for CD20+ patients only *
375 mg/m2 IV on Days 1 and 8 and then again on
Days 29 and 36. *
375 mg/m2 IV on Days 1 and 11. *
375 mg/m2 IV on Days 1 and 8. *
-
Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 15, 22,
43, and 50.
1.5 mg/m2 (maximum 2 mg) IV push on Days 1, 11,
21, 31, and 41.
1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8,
15, 43, and 50.
1.5 mg/m2 (maximum dose 2 mg) IV on
Days 1, 29, and 57
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PEG-Asparaginase
2000 IU/m2 IV on Days 15 and 43. (cap dose at
3750 IU) *
2000 IU/m2 IV on Days 2 and 22. Cap dose at 3750 IU. *
2000 IU/m2 IV on Day 4 (OR Day 5 OR Day 6) AND Day 43. (cap
dose at 3750 IU) *
-
Bone marrow aspirate and biopsy specimen
Day 56
-
One week after completion of Course
IV
-
Dexamethasone
-
-
5 mg/m2 PO or IV BID on Days 1-7 and 15-
21
6 mg/m2/day PO or IV divided BID every 4 weeks on Days 1-5,
29-33, and 57-61 Doxorubicin - - 25 mg/m2 IV on Days
1, 8, and 15 -
Thioguanine
-
-
60 mg/m2/day PO on Days 29-42, at least 1 hour after the evening
meal.
-
*Premedicate with 650 mg acetaminophen, 100 mg hydrocortisone and 25-50 mg diphenhydramine (or equivalent) prior to PEG-asparaginase ** Not to be taken with milk or citrus products 5.0 STUDY DESIGN 5.1 Study Phase/Type of Design/Stratification Factors This study has two separate components: an upfront tolerability confirmation portion and then a full phase III evaluation of the two treatment regimens. Randomization will be stratified on the following stratification factors: LDA gene signature (BCR-ABL1-like versus not), age (≤25 vs >25), CD20+ status (CD20+ or not) and BM Response (M0/M1 vs. M2). Patients will be randomized to receive one of the two treatment regimens with equal allocation using a dynamic allocation method to balance the stratification factors. 5.2 Primary Endpoint The primary endpoint in this phase III trial is event-free survival (EFS) in those who achieve an induction response. Event-free survival will be defined as the time from induction response to the time of progressive-disease, secondary malignancy, or death. Those who have not experienced one of these defined events of interest at their last evaluation will be censored at that time point. All randomized patients meeting the eligibility criteria will be evaluable for the primary endpoint (EFS) analysis based on an intention to treat. The trial endpoint of EFS begins at the time of randomization, so patients that die during induction or fail to achieve an induction response are not randomized. We estimate that ~95% of patients who start induction will achieve an M2 marrow or better and will be randomized. Based on the transplant rates reported in C10403 (8 transplants overall reported out of the 296 evaluable patients), and the fact that we are using C10403 trial EFS estimates (not censored for transplant) as the basis for sample size calculations for this trial, we will perform the primary analysis without censoring patients at the time of transplant. Thus, our primary analysis will include all information regardless of transplant, assuming rates and timing of transplant will be similar across arms. This study has two separate components: an upfront tolerability assessment portion (run-in phase) followed by a full phase III evaluation of the two treatment regimens. The primary component of this trial will include patients who achieve a response to the induction therapy (estimated to be about 95% of the patients).
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Based on the C10403 study, we expect an accrual of about 8 patients/month with induction response AYA B-cell ALL patients. With 140 induction response patients per treatment arm (280 total number of randomized patients), we will have 90% power to detect a significant improvement in EFS with the addition of inotuzumab assuming that the true EFS distributions correspond to 3-year EFS rates of 65% vs. 80% using a one-sided log-rank test to specifically test an significance level of 0.025. Assuming that at least 95% of patients will achieve some response to induction therapy in this protocol, and another 5% of patients otherwise non-evaluable (ineligible, drop out etc.), 310 total patients (155 per arm) will need to be enrolled to this trial. The final analysis will be conducted after 100 events have been observed without censoring for transplant. 5.3 Target Accrual The target accrual for this study is 324 patients, 162 per arm, using a 1:1 randomization. The target accrual rate is 8 patients per month. 6.0 CURRENT ACCRUAL
Study Activation Date 06/01/2017 Target Accrual (n) 324 Patients Screened or Pre-registered (n) 93 Current Accrual (n) 70 Expected Accrual Rate 8/month Accrual Rate – Safety Run-In .67/month Accrual Rate – Phase III 4.00/month
Safety-Run In
Phase III
0 0 01 0 0
1 0
31
Jun17 Jul17 Aug17 Sep17 Oct17 Nov17 Dec17 Jan18 Feb18 Mar18
Month
0
5
10
15
20
25
30
35
40
Total
Num
ber o
f Pati
ents
Expected Accrual 324 PatientsActual Accrual
A041501 Cumulative Accrual: Actual Versus ExpectedNumbers on the Accrual Line are M onthly Accrual
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7.0 CURRENT STUDY STATUS This study opened on 06/01/2017 and has accrued 93 patients to pre-registration. A total of 70 patients were fully enrolled (Safety Run-in: 6, Phase III cohort: 64) with twenty-two screen failures and one patient who has not been fully registered yet. Study temporarily closed for the safety run-in for the first 6 evaluable patients, no patients received a Dose-Limiting Toxicity (DLT). The study reopened on 06/15/2018 for the Phase III portion of the trial. There are currently 64 patients on study. Of these, 46 achieved an M0/M1 marrow after Course I and were randomized, 7 went off treatment, 8 are waiting to be randomized and 3 failed to achieve an M0/M1/M2 and hence were not randomized. 8.0 PATIENT CHARACTERISTICS Table 8a. Demographics
Phase III Patients Randomized
(N=46)
Phase III Patients Not Randomized
(N=18) Safety Run-in
(N=6) Total
(N=70) Age
N 46 18 6 70 Mean (SD) 26.7 (6.36) 26.2 (5.26) 21.8 (2.79) 26.2 (5.97) Median 27.0 25.0 22.5 25.0 Q1, Q3 21.0, 32.0 22.0, 29.0 19.0, 24.0 21.0, 31.0 Range 18.0, 39.0 19.0, 37.0 18.0, 25.0 18.0, 39.0
Race
White 31 (67.4%) 12 (66.7%) 5 (83.3%) 48 (68.6%) Black or African American 2 (4.3%) 1 (5.6%) 0 (0.0%) 3 (4.3%) Asian 2 (4.3%) 0 (0.0%) 0 (0.0%) 2 (2.9%) Not reported: patient refused or
not available 6 (13.0%) 2 (11.1%) 1 (16.7%) 9 (12.9%)
02
53
33
54
2
5
5
54
8
73
Jun18 Aug18 Oct18 Dec18 Feb19 Apr19 Jun19 Aug19
Month
05
101520253035404550556065707580
Tota
l Num
ber o
f Pat
ients
Expected Accrual 324 PatientsActual Accrual
A041501 Cumulative Accrual: Actual Versus ExpectedNumbers on the Accrual Line are M onthly Accrual
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Phase III Patients Randomized
(N=46)
Phase III Patients Not Randomized
(N=18) Safety Run-in
(N=6) Total
(N=70) Unknown: Patient unsure 5 (10.9%) 3 (16.7%) 0 (0.0%) 8 (11.4%)
Gender
f 16 (34.8%) 8 (44.4%) 3 (50.0%) 27 (38.6%) m 30 (65.2%) 10 (55.6%) 3 (50.0%) 43 (61.4%)
Table 8b. Stratification Factors
Patients Randomized
(N=46) Total
(N=46) Age Group <=25 23 (50.0%) 23 (50.0%) >25 23 (50.0%) 23 (50.0%) CD20 status CD20+ 22 (47.8%) 22 (47.8%) Not CD20+ 24 (52.2%) 24 (52.2%) BM Response M0/M1 43 (93.5%) 43 (93.5%) M2 3 (6.5%) 3 (6.5%)
9.0 ADVERSE EVENTS
Adverse events (AEs) are reported using CTCAE version 5.0. 57 patients are evaluable for adverse events (AE) analyses (Arm 1: 38.60%, Arm 2: 35.09%, Arm 3: 15.79%, Arm 4: 10.53%). Commonly occurring grade 3+ AE include Lymphopenia (18%, Arm 1; 25%, Arm2; 22%, Arm 3; 51%, Arm 4), Neutrophils (96%, Arm 1; 90%, Arm 2; 100%, Arm 3; 100%, Arm 4), Platelets (87%, Arm 1; 95%, Arm 2; 89%, Arm 3; 100%, Arm 4), Anemia (32%, Arm 1; 50%, Arm 2; 11%, Arm 3; 50%, Arm 4), and White blood cell decreased (27%, Arm 1; 35%, Arm 2; 55%, Arm 3; 67%, Arm 4). There have been 2 deaths on treatment (one death (Prior to randomization) was due to a probably related Stroke, and one death (Arm 2: Initial agents with Ino (exp)) due to an unlikely related lung infection.) and two deaths off treatment (one patient (Arm 1: Initial agents w/o Ino (control)) from ALL (Disease) after withdrawing from protocol therapy, and one patient (Prior to Randomization) from HHV6 after going off treatment for other complicating disease). See below for a summary of adverse events by arm regardless of attribution.
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Summary of Grade 3+ Adverse Events Regardless of Attribution
Number of Evaluable Patients: Initial agents w/o Ino (control) (Arm 1)=22
Initial agents with Ino (exp) (Arm 2)=20 Prior to Randomization (Arm 3)=9
Safety Run-in (Arm 4)=6 Patients with a maximum: Arm n (%) Total
Grade 3 Event 1 0 (0.0%)
2 2 (10.0%)
3 1 (11.1%)
4 0 (0.0%)
Grade 4 Event 1 22 (100.0%)
2 17 (85.0%)
3 7 (77.8%)
4 6 (100.0%)
Grade 5 Event 1 0 (0.0%)
2 1 (5.0%)
3 1 (11.1%)
4 0 (0.0%)
Hematologic Adverse Events
Grade 3 Event 1 0 (0.0%)
2 1 (5.0%)
3 1 (11.1%)
4 0 (0.0%)
Grade 4 Event 1 22 (100.0%)
2 18 (90.0%)
3 8 (88.9%)
4 6 (100.0%)
Grade 5 Event 1 0 (0.0%)
2 0 (0.0%)
3 0 (0.0%)
4 0 (0.0%)
Non-Hematologic Adverse Events
Grade 3 Event 1 12 (54.5%)
2 10 (50.0%)
3 3 (33.3%)
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Summary of Grade 3+ Adverse Events Regardless of Attribution
Number of Evaluable Patients: Initial agents w/o Ino (control) (Arm 1)=22
Initial agents with Ino (exp) (Arm 2)=20 Prior to Randomization (Arm 3)=9
Safety Run-in (Arm 4)=6 Patients with a maximum: Arm n (%)
4 3 (50.0%)
Grade 4 Event 1 7 (31.8%)
2 5 (25.0%)
3 5 (55.6%)
4 3 (50.0%)
Grade 5 Event 1 0 (0.0%)
2 1 (5.0%)
3 1 (11.1%)
4 0 (0.0%)
Note: Summaries are based on available patient data
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Regardless of Attribution Number of Evaluable Patients:
Initial agents w/o Ino (control) (Arm 1)=22 Initial agents with Ino (exp) (Arm 2)=20
Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Hematologic Adverse Events Blood/Bone Marrow Anemia 1 6 ( 27%) 1 ( 5%) 0 ( 0%) 2 10 ( 50%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 3 ( 50%) 0 ( 0%) 0 ( 0%) Hemoglobin increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 2 ( 22%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphopenia 1 2 ( 9%) 2 ( 9%) 0 ( 0%) 2 2 ( 10%) 3 ( 15%) 0 ( 0%)
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 3 0 ( 0%) 2 ( 22%) 0 ( 0%) 4 2 ( 33%) 1 ( 17%) 0 ( 0%) Neutrophils/granulocytes (ANC/AGC) 1 1 ( 5%) 20 ( 91%) 0 ( 0%) 2 1 ( 5%) 17 ( 85%) 0 ( 0%) 3 3 ( 33%) 6 ( 67%) 0 ( 0%) 4 0 ( 0%) 6 (100%) 0 ( 0%) Platelets 1 5 ( 23%) 14 ( 64%) 0 ( 0%) 2 3 ( 15%) 16 ( 80%) 0 ( 0%) 3 3 ( 33%) 5 ( 56%) 0 ( 0%) 4 0 ( 0%) 6 (100%) 0 ( 0%) White blood cell decreased 1 0 ( 0%) 6 ( 27%) 0 ( 0%) 2 1 ( 5%) 6 ( 30%) 0 ( 0%) 3 2 ( 22%) 3 ( 33%) 0 ( 0%) 4 0 ( 0%) 4 ( 67%) 0 ( 0%) Non-Hematologic Adverse Events ** Acute kidney injury 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 10%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspareunia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Hepatobiliary disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 2 ( 33%) 0 ( 0%) 0 ( 0%)
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Infusion related reaction 1 0 ( 0%) 1 ( 5%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 1 ( 5%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Nervous system disorders - Oth spec 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Pulmonary edema 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Respiratory failure 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 11%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Stroke 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 11%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 0 ( 0%) 1 ( 5%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Urine output decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 1 ( 5%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Vasovagal reaction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 5%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Cardiovascular Hypertension 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypotension 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 15%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Coagulation Disseminated intravascular coagulation 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 11%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Fibrinogen 1 7 ( 32%) 0 ( 0%) 0 ( 0%) 2 5 ( 25%) 3 ( 15%) 0 ( 0%) 3 4 ( 44%) 1 ( 11%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) PTT (Partial Thromboplastin Time) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal Colitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Diarrhea 1 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 2 3 ( 15%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Dysphagia (difficulty swallowing) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis/stomatitis (func/symp) 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Nausea 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Pancreatitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Typhlitis (cecal inflammation) 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Vomiting 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Hemorrhage Hematoma 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Hepatic ALT, SGPT 1 4 ( 18%) 0 ( 0%) 0 ( 0%) 2 3 ( 15%) 0 ( 0%) 0 ( 0%) 3 3 ( 33%) 0 ( 0%) 0 ( 0%) 4 4 ( 67%) 0 ( 0%) 0 ( 0%) AST, SGOT 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 5 ( 25%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Albumin, serum-low (hypoalbuminemia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Alkaline phosphatase 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 1 ( 17%) 0 ( 0%) Bilirubin (hyperbilirubinemia) 1 2 ( 9%) 1 ( 5%) 0 ( 0%) 2 2 ( 10%) 1 ( 5%) 0 ( 0%) 3 3 ( 33%) 1 ( 11%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Infection/Febrile Neutropenia Febrile neutropenia 1 4 ( 18%) 0 ( 0%) 0 ( 0%) 2 11 ( 55%) 0 ( 0%) 0 ( 0%) 3 2 ( 22%) 0 ( 0%) 0 ( 0%) 4 4 ( 67%) 1 ( 17%) 0 ( 0%) Infection w/ normal or Grade 1/2 ANC 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection with unknown ANC 1 0 ( 0%) 1 ( 5%) 0 ( 0%) 2 5 ( 25%) 2 ( 10%) 0 ( 0%)
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 3 0 ( 0%) 2 ( 22%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphatics Edema:limb 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Metabolic/Laboratory Calcium, serum-low (hypocalcemia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Glucose, serum-high (hyperglycemia) 1 6 ( 27%) 1 ( 5%) 0 ( 0%) 2 3 ( 15%) 1 ( 5%) 0 ( 0%) 3 2 ( 22%) 0 ( 0%) 0 ( 0%) 4 2 ( 33%) 0 ( 0%) 0 ( 0%) Lipase 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Phosphate, serum-low (hypophosphatemia)
1 0 ( 0%) 0 ( 0%) 0 ( 0%)
2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Potassium, serum-low (hypokalemia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Sodium, serum-low (hyponatremia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%)
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Triglyceride, serum-high 1 2 ( 9%) 3 ( 14%) 0 ( 0%) 2 1 ( 5%) 2 ( 10%) 0 ( 0%) 3 2 ( 22%) 1 ( 11%) 0 ( 0%) 4 4 ( 67%) 1 ( 17%) 0 ( 0%) Neurology Depressed level of consciousness 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 5%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Encephalopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Mood alteration 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Neuropathy: sensory 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Syncope (fainting) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Pain Pain 1 4 ( 18%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 2 ( 33%) 0 ( 0%) 0 ( 0%) Pulmonary
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Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6
Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Adult Respiratory Distress Syndrome 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 10%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspnea (shortness of breath) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypoxia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 10%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal /Genitourinary Creatinine 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Syndromes Tumor lysis syndrome 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%)
10.0 IMBEDDED CORRELATIVES A041501: Low Density Array (LDA) Assay and EFS Participation to imbedded correlative A041501 was required for all patient registered to A041501. There are currently 93 patients enrolled on this study. A041501: Minimal Residual Disease (MRD) Detection and EFS Participation to imbedded correlative A041501 was required for all patient registered to A041501. There are currently 93 patients enrolled on this study. A041501-LC1: Molecular Genetics of AYA ALL
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Participation to imbedded correlative A041501-LC1 was optional for all patient registered to A041501. There are currently 79 patients enrolled on this study. A041501-PP1: Pharmacogenomic Determinants of toxicity Participation to imbedded correlative A041501-PP1 was optional for all patient registered to A041501. There are currently 79 patients enrolled on this study. A041501-PP2: Asparaginase Pharmacokinetics in AYA Participation to imbedded correlative A041501-PP2 was optional for all patient registered to A041501. There are currently 78 patients enrolled on this study. A041501-HO1: Health Outcomes: Adherence to Oral Chemotherapy and Outcomes in Adolescents and Young Adults (AYAs) with Acute Lymphoblastic Leukemia (ALL) Participation to imbedded correlative A041501-HO1 was optional for all patient registered to A041501. There are currently 74 patients enrolled on this study.
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Alliance Study A041701 – A Randomized Phase II/III Study of Conventional Chemotherapy +/- Uproleselan (GMI-1271) in Older Adults with Acute Myeloid Leukemia Receiving Intensive Induction
Chemotherapy
Data as of 09/10/2019 Committee: Leukemia Study Statisticians: Jun (Vivien) Yin, Ph.D. Study Chair: Geoffrey L. Uy, MD Luke Huebner, M.S. 1.0 OBJECTIVES Primary: Phase II
Compare the event-free survival (EFS) of daunorubicin, cytarabine plus uproleselan versus daunorubicin and cytarabine in subjects ≥ age 60 with previously untreated acute myeloid leukemia
Primary: Phase III Compare the overall survival (OS) of the daunorubicin, cytarabine plus uproleselan to daunorubicin and cytarabine in this patient population.
Secondary
1. Determine the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), complete remission with incomplete hematopoietic recovery (CRh) and cytogenetic complete remission (CCyR) for each chemotherapy regimen.
2. Determine the overall survival (OS), and remission duration of patients for each chemotherapy regimen.
3. Describe the frequency and severity of adverse events for patients for each chemotherapy regimen
4. Describe the interaction of pretreatment disease and patient characteristics including morphology, cytogenetics, molecular genetic features, WBC count and hemogram, and performance status on clinical outcomes.
2.0 CURRENT SCHEMA
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3.0 ELIGIBILITY CRITERIA
• Diagnosis of AML based on 2017 WHO criteria excluding acute promyelocytic leukemia with PMLRARA
• No activating mutation in Fms-like tyrosine kinase-3 (FLT3) • No evidence of CNS involvement of AML • No prior chemotherapy for MDS or AML including hypomethylating agents or lenalidomide (see
section 3.3.2 for exceptions) • Age ≥ 60 years • Total Bilirubin ≤ 3 x upper limit of normal (ULN) • Creatinine ≤ 3 x upper limit of normal (ULN) or Creatinine Clearance ≥ 30 mL/min/1.73m2
4.0 TREATMENT SCHEDULE
Arm 1 Treatment Remission Induction Second Remission
Induction (if required) Consolidation (up to 3 cycles)
Daunorubicin 60 mg m2/day IV Days 1-3 (total dose 180 mg/m2)
60 mg/m2/day IV Days 1-2 (total dose 120 mg/m2)
Cytarabine 100 mg/m2/day CIVI Days 1-7 (168 hour infusion, total dose 700 mg/m2)
100 mg/m2/day CIVI Days 1-5 (120 hour infusion, total dose 500 mg/m2)
2 g/m2/day by IV infusion over 3 hours on Days 1-5 (total dose 10 gms/m2)
Bone marrow Day 14 (+3 days)
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examination (aspirate and biopsy)
Arm 2 Treatment Remission Induction Second Remission
Induction (if required) Consolidation (up to 3 cycles)
Uproleselan 800 mg IV, once a day on Day 1, and q12 hours on Days 2-10
800 mg IV, once on Day 1, and q12 hours on Days 2-8
Daunorubicin 60 mg m2/day IV Days 2-4 (total dose 180 mg/m2)
60 mg/m2/day IV Days 2-3 (total dose 120 mg/m2)
800 mg IV, once on Day 1, and q12 hours on Days 2-8
Cytarabine 100 mg/m2/day CIVI Days 2-8 (168 hour infusion, total dose 700 mg/m2)
100 mg/m2/day CIVI Days 2-6 (120 hour infusion, total dose 500 mg/m2)
2 g/m2/day by IV infusion over 3 hours on Days 2-6 (total dose 10 gms/m2)
Bone marrow examination (aspirate and biopsy)
Day 14 (+3 days)
5.0 STUDY DESIGN
5.1 Study Phase/Type of Design/Stratification Factors This is an open-label, randomized phase II/III study. The primary objective of the Phase II study is to determine based on the event-free survival (EFS) whether the combination of uproleselan plus daunorubicin/cytarabine should be tested further against standard of care: daunorubicin/cytarabine in the phase III component of this trial. The primary objective of the Phase III study is to compare the OS between uproleselan plus daunorubicin/cytarabine versus the control arm (daunorubicin/cytarabine). Patients accrued during the Phase II portion of the trial will be used in the Phase III analysis. Randomization will be stratified on the following stratification factors: age (60-69 vs. 70 and older), performance status (0-1 vs. 2-3), de novo vs. secondary/therapy related AML. Patients will be randomized to receive one of the two treatment regimens with equal allocation using a permutated block method to balance the stratification factors. 5.2 Primary Endpoint Phase II component: Event-free survival (EFS). EFS is defined as the time from the date of registration/randomization to the first of failure to achieve a CR during induction, relapse, or death due to any cause, with patients last known to be alive and event-free censored at the date of last contact. Patients who are removed from protocol treatment for allogeneic HCT will not be censored for EFS. Patients who receive other non-protocol therapy without relapse or CR during induction will be censored at the time they discontinue the treatment. All randomized patients meeting the eligibility criteria will be evaluable for the primary endpoint (EFS) analysis based on an intention to treat.
Patients will be randomized to receive daunorubicin and cytarabine or the novel regimen with equal allocation using a dynamic allocation method. E2906 study6 reported a 1-year EFS of 29%. Therefore, we estimate that the 1-year EFS in the daunorubicin and cytarabine arm will be 30%. We are interested in testing the alternative hypothesis that the 1-year EFS in the novel experimental arm will be at least 47% (a 17% improvement in the 1-year EFS). This translates to an improvement
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in the median EFS from 7 to 11 months (HR = 0.64), assuming exponential distributions of EFS in both control and experimental arm. A sample size of 131 evaluable patients per arm (262 total) provides 96% power to detect an improvement in median EFS from 7 months to 11 months (a hazard ratio of 0.64), using a one-sided log-rank test at a significance level of 10%. Phase III component: Overall survival (OS) – measured from the date of registration/randomization to death from any cause, with patients last known to be alive censored at the date of last contact. All randomized patients will be evaluable for this endpoint. A median OS of 12 months is anticipated on the control arm.6 We are interested in testing the alternative hypothesis that the median OS in the novel experimental arm will be at least 16 months (a 33% improvement in the median OS, for a HR of 0.75). This translates into an improvement in the 1-year OS from 50% to 60%, assuming exponential survival. A randomized trial comparing the novel agents passing the Phase II component against the standard arm (daunorubicin and cytarabine) will be conducted using a 1:1 randomization scheme. A sample size of 335 evaluable patients per arm (670 total) provides 90% power to detect an improvement in median OS from 12 months to 16 months (a hazard ratio of 0.75), using a one-sided log-rank test at a significance level of 2.5%. The overall power for the phase II/III design is 81% (=0.9*0.9). The total sample size for the Phase III component will include the patients rolled over from the Phase II component.
5.3 Target Accrual The anticipated accrual rate is approximately 5 pts/month in the first year, 10 pts/month second year, and 14 patients per month afterwards. The phase II component is expected to accrue in 30 months after trial activation. Accrual will be suspended between the phase II and phase III component for primary endpoint analysis from phase II; the suspension between the Phase II and Phase III is expected to be 12 months to allow for follow-up on the last phase II patients and completion of the primary analysis for phase II. The phase III component is expected to accrue in approximately 59 months. Including the suspension between Phase II and III, the total study duration is expected to be approximately 83 months, or until the last Phase III patient accrued has been observed for at least 12 months.
6.0 CURRENT ACCRUAL
Study Activation Date 01/15/2019 Target Accrual (n) 670 Patients Screened/Pre-registered (n) 52/43 Current Accrual (n) 32 Expected Accrual Rate, 1st year 5/month Accrual Rate – Since activation 3.5/month Accrual Rate – Past 6 months 5.3/month
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7.0 CURRENT STUDY STATUS
The study opened on 01/15/2019 and has screened 52 patients, pre-registered 43 patients (the study protocol was amended to add pre-registration step post activation) and accrued 32 patients as of the beginning of September. There have been four deaths; two on treatment (Both were due to Tumor) and two off treatment (one was due to Tumor and one was due to disease progression). One patient went off treatment due to an adverse event of ejection fraction decreased.
8.0 PATIENT CHARACTERISTICS Table 8a. Demographics
Active Treatment (Daunorubicin +
Cytarabine) (N=15)
Active Treatment (Uproleselan + Daunorubicin +
Cytarabine) (N=17)
Total (N=32)
Age N 15 17 32 Mean (SD) 67.6 (4.3) 68.5 (6.1) 68.0 (5.3) Median 67.5 67.6 67.6
0 0
3
62
6
5
9 1
Jan19 Feb19 Mar19 Apr19 May19 Jun19 Jul19 Aug19 Sep19
Month
0
5
10
15
20
25
30
35
40
45
50To
tal N
umbe
r of P
atien
tsExpected Accrual 670 PatientsActual Accrual
A041701 Cumulative Accrual: Actual Versus ExpectedNumbers on the Accrual Line are M onthly Accrual
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Active Treatment (Daunorubicin +
Cytarabine) (N=15)
Active Treatment (Uproleselan + Daunorubicin +
Cytarabine) (N=17)
Total (N=32)
Q1, Q3 63.4, 69.9 63.3, 73.9 63.4, 71.1 Range (61.6-75.6) (61.5-77.9) (61.5-77.9) Race White 2 (13.3%) 1 (5.9%) 3 (9.4%) Black or African American 0 (0.0%) 3 (17.6%) 3 (9.4%) 13 (86.7%) 13 (76.5%) 26 (81.3%) Gender Male 6 (40.0%) 6 (35.3%) 12 (37.5%) Female 9 (60.0%) 11 (64.7%) 20 (62.5%)
Table 8b. Stratification Factors
Active Treatment (Daunorubicin + Cytarabine)
(N=15)
Active Treatment (Uproleselan + Daunorubicin +
Cytarabine) (N=17)
Total (N=32)
Age Group
60-69 12 (80.0%) 12 (70.6%) 24 (75.0%)
70 and older 3 (20.0%) 5 (29.4%) 8 (25.0%)
ECOG Performance status
0-1 13 (86.7%) 13 (76.5%) 26 (81.3%)
2-3 2 (13.3%) 4 (23.5%) 6 (18.8%)
ONSET AML
de novo 14 (93.3%) 17 (100.0%) 31 (96.9%)
Secondary/therapy related
1 (6.7%) 0 (0.0%) 1 (3.1%)
9.0 ADVERSE EVENTS
9.1 Adverse Event Summary Eighteen patients were evaluable for adverse events; fourteen patients have no AE data submitted. All 18 have reported a grade 3 or higher adverse event. Commonly occurring grade 4+ AE include Neutrophils/granulocytes (Arm A: 5 (56%); Arm B: 2 (22%)), Platelets (Arm A: 6
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(67%); Arm B: 4 (44%)), and White blood cell decreased (Arm A: 6 (67%); Arm B: 4 (44%)). There have been four deaths; two on treatment (Both were due to Tumor) and two off treatment (one was due to Tumor and one was due to disease progression). One patient went off treatment due to an adverse event of grade 4 ejection fraction decreased. See Appendix F for a detailed list of adverse events by arm regardless of attribution. Note: Arm A = Daunorubicin + Cytarabine, Arm B = Uproleselan + Daunorubicin + Cytarabine.
Summary of Grade 3+ Adverse Events Regardless of Attribution
Number of Evaluable Patients: Arm A =9 Arm B =9
Patients with a maximum: Arm n (%) Total
Grade 3 Event A 1 (11.1%)
B 3 (33.3%)
Grade 4 Event A 8 (88.9%)
B 4 (44.4%)
Grade 5 Event A 0 (0.0%)
B 2 (22.2%)
Hematologic Adverse Events
Grade 3 Event A 0 (0.0%)
B 0 (0.0%)
Grade 4 Event A 0 (0.0%)
B 0 (0.0%)
Grade 5 Event A 0 (0.0%)
B 0 (0.0%)
Non-Hematologic Adverse Events
Grade 3 Event A 1 (11.1%)
B 3 (33.3%)
Grade 4 Event A 8 (88.9%)
B 4 (44.4%)
Grade 5 Event A 0 (0.0%)
B 2 (22.2%)
Note: Summaries are based on available patient data
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Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event
Regardless of Attribution Number of Evaluable Patients:
Arm A=9 Arm B=9 Grade of AdverseEvent
Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)
Non-Hematologic Adverse Events
ALT, SGPT A 2 ( 22%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) AST, SGOT A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) Albumin, serum-low (hypoalbuminemia)
A 3 ( 33%) 0 ( 0%) 0 ( 0%)
B 0 ( 0%) 0 ( 0%) 0 ( 0%) Anemia A 6 ( 67%) 1 ( 11%) 0 ( 0%) B 4 ( 44%) 0 ( 0%) 0 ( 0%) Anorexia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Bilirubin (hyperbilirubinemia) A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Death not associated with CTCAE term
A 0 ( 0%) 0 ( 0%) 0 ( 0%)
B 0 ( 0%) 0 ( 0%) 1 ( 11%) Dyspnea (shortness of breath) A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) Ejection fraction decreased A 0 ( 0%) 1 ( 11%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Febrile neutropenia A 6 ( 67%) 0 ( 0%) 0 ( 0%) B 3 ( 33%) 0 ( 0%) 0 ( 0%) Glucose, serum-high (hyperglycemia)
A 1 ( 11%) 0 ( 0%) 0 ( 0%)
B 1 ( 11%) 0 ( 0%) 0 ( 0%) Heart failure A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection w/ normal or Grade 1/2 ANC
A 1 ( 11%) 0 ( 0%) 0 ( 0%)
B 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection with unknown ANC A 3 ( 33%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 1 ( 11%) 1 ( 11%) Infections and infestations - Oth spec
A 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event
Regardless of Attribution Number of Evaluable Patients:
Arm A=9 Arm B=9 Grade of AdverseEvent
Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)
B 1 ( 11%) 0 ( 0%) 0 ( 0%) Lung infection A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Lymphopenia A 2 ( 22%) 2 ( 22%) 0 ( 0%) B 1 ( 11%) 2 ( 22%) 0 ( 0%) Magnesium, serum-high (hypermagnesemia)
A 1 ( 11%) 0 ( 0%) 0 ( 0%)
B 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis/stomatitis (func/symp) A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Neutrophils/granulocytes (ANC/AGC)
A 0 ( 0%) 5 ( 56%) 0 ( 0%)
B 1 ( 11%) 2 ( 22%) 0 ( 0%) Pain A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Pericardial effusion (non-malignant)
A 0 ( 0%) 0 ( 0%) 0 ( 0%)
B 1 ( 11%) 0 ( 0%) 0 ( 0%) Pericarditis A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) Phosphate, serum-low (hypophosphatemia)
A 1 ( 11%) 0 ( 0%) 0 ( 0%)
B 1 ( 11%) 0 ( 0%) 0 ( 0%) Platelets A 1 ( 11%) 6 ( 67%) 0 ( 0%) B 0 ( 0%) 4 ( 44%) 0 ( 0%) Potassium, serum-high (hyperkalemia)
A 0 ( 0%) 0 ( 0%) 0 ( 0%)
B 1 ( 11%) 0 ( 0%) 0 ( 0%) Potassium, serum-low (hypokalemia)
A 1 ( 11%) 0 ( 0%) 0 ( 0%)
B 0 ( 0%) 0 ( 0%) 0 ( 0%) Respiratory failure A 0 ( 0%) 1 ( 11%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Sodium, serum-low (hyponatremia) A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event
Regardless of Attribution Number of Evaluable Patients:
Arm A=9 Arm B=9 Grade of AdverseEvent
Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)
Supraventricular and nodal arrhythmia
A 0 ( 0%) 0 ( 0%) 0 ( 0%)
B 1 ( 11%) 0 ( 0%) 0 ( 0%) White blood cell decreased A 1 ( 11%) 6 ( 67%) 0 ( 0%) B 0 ( 0%) 4 ( 44%) 0 ( 0%)
10.0 IMBEDDED CORRELATIVES Not Applicable
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Alliance - A041702 – A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (≥ 70 Years of Age) with
Chronic Lymphocytic Leukemia (CLL)
Data as of 09/06/2019
Committee: Leukemia Study Statisticians: Amy Ruppert Stark, PhD Study Chair: Jennifer Woyach, MD Gabriela Perez, MS 1.0 OBJECTIVES Primary
To compare the progression-free survival (PFS) between control treatment and experimental treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.
Secondary
1. To compare BM MRD- CR rates, MRD rates, and depth of response at Cycle 15 Day 1 between patients treated with IO versus IVO.
2. To compare overall survival (OS) between the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.
3. To compare the 5-year PFS and OS for the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.
4. To describe the toxicity profile for each of the treatment strategies and by each treatment course.
5. To determine whether baseline cytogenetic abnormalities by FISH and stimulated karyotype or IGHV mutational status correlates with BM MRD- CR status and PFS of each treatment strategy.
6. To determine whether mutations in TP53, NOTCH1, SF3B1, XPO1, PLCG2, and BRAF correlate with BM MRD- CR status or PFS of each treatment strategy and determine how the frequency of these mutations change over time.
7. To determine how frequencies of DNA mutations change during the course of therapy and whether these changes are different between IO versus IVO treatment.
8. To compare MRD status between blood and bone marrow at the end of induction treatment/Cycle 15 Day 1 to determine whether blood MRD can be used as a surrogate to bone marrow MRD with these treatment regimens.
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RE-REGISTRATION (Step 2)
2.0 CURRENT SCHEMA Schema
1 Cycle = 28 Days
Patients will be followed for 10 years from study registration (Step 1) or until death, whichever comes first.
PRE-REGISTRATION (STEP 0)
REGISTRATION/RANDOMIZATION (STEP 1)
Central specimen submission for FISH (see Sec 6.2), Local assessment of Rai Stage (see Sec 3.3), & confirmation of
eligibility (see Sec 3.3)
Arm 1 Ibrutinib 420 mg PO daily days 1-28 for 15 cycles Obinutuzumab 100 mg IV 100 mg on C1D1, 900 mg on C1D2, 1000 mg on Cycle1D8 & C1D15, C2-6D1
Arm 2 Ibrutinib 420 mg PO daily days 1-28 for 15 cycles Obinutuzumab 100 mg IV 100 mg on C1D1, 900 mg on C1D2, 1000 mg on C1D8 & C1D15, C2-6D1 Venetoclax 20 mg daily PO beginning C3D1, dose escalated weekly to a final dose of 400 mg on C4D1, then 400 mg daily PO C4D1-C14D28
Any response except BM MRD- CR
(BM MRD+ CR, PR, PRL, SD)
BM MRD - CR
Observation q3 cycles for 6 years from registration (step 1), then q6 cycles until progression
Ibrutinib 420 mg PO daily days 1-28 until progression or unacceptable adverse events
Ibrutinib 420 mg PO daily days 1-28 until progression or unacceptable adverse events
C15D1 Response Assessment Specimen submission for central BM MRD & local response assessment &
labs performed per Sec 5.0.,
At the same time, Continue Ibrutinib 420 mg PO daily C15D1-D28.
C15D1 Response Assessment Specimen submission for central BM MRD & local response assessment &
labs performed per Sec 5.0.
At the same time, Continue Ibrutinib 420 mg PO daily C15 D1-D28.
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3.0 ELIGIBILITY CRITERIA -Diagnosis with CLL in accordance with 2018 IWCLL criteria
-Intermediate or high-risk Rai stage CLL -Criteria met for treatment as defined by 2018 IWCLL guidelines -No prior therapy for CLL (except palliative steroids or treatment of autoimmune complications per Section 3.3.3) -Age ≥ 70 years -ECOG performance status 0-2 -No comorbid conditions or other active diseases per Section 3.3.7 -Not taking concomitant medications as outlined in Section 3.3.8 -No known allergy to mannitol -No prior significant hypersensitivity to rituximab
-No major surgery within 10 days or minor surgery within 7 days 4.0 TREATMENT SCHEDULE Arm 1 Ibrutinib Obinutuzumab
Cycle 1 D1-28 C2
C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15
Day 1 D2 D8 D15 D1 D1 D1 D1 D1
Ibrutinib 420 mg daily
Obinutuzumab
100 mg
900 mg
1000 mg
1000 mg
1000 mg
1000 mg
1000 mg
1000 mg
1000 mg
Arm 2 Ibrutinib, Venetoclax, and Obinutuzumab Cycle 1 D1-28 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15
Day 1 D2 D8 D15
Ibrutinib PO
420 mg daily
Obinutuzumab IV
100 mg
900 mg
1000 mg
1000mg
Day 1 1000 mg
D1 1000 mg
D1 1000 mg
D1 1000 mg
D1 1000 mg
Venetoclax PO
20 mg daily,
400 mg daily
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dose escalated weekly*
* Arm 2 Venetoclax Dose Escalation
Cycle 3 Cycle 4 Day 1 – 7 D8 - 14 D15-21 D22 - 28 D1 - 7
20 mg 50 mg 100 mg 200 mg 400 mg
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5.0 STUDY DESIGN
5.1 Study Phase/Type of Design/Stratification Factors Patients will be randomized using dynamic allocation procedures in a 1:1 manner to the two treatment arms: (Arm 1: Ibrutinib, Obinutuzumab vs. Arm 2: Ibrutinib, Venetoclax, and Obinutuzumab). Randomization will be stratified on Rai stage (intermediate vs. high) and high-risk FISH abnormality del(17p13.1) (present vs. absent).
5.2 Primary Endpoint The primary endpoint in this phase III trial is progression-free survival (PFS), which will be defined from randomization date until the earlier of disease progression or death from any cause, censoring patients alive and progression-free at the date of last known clinical assessment.
The primary goal of this phase III trial is to determine whether the experimental treatment strategy of IVO followed by IM for patients without BM MRD- CR and IM discontinuation for patients with BM MRD- CR has superior PFS compared to the control treatment strategy of IO followed by IM for all patients. We will test the null hypothesis that the hazard ratio is equal to 1.0 versus the alternative hypothesis that the hazard ratio is equal to 0.55 in favor of the experimental treatment strategy. Assuming exponential parameters for control and experimental treatment strategy groups are 0.071 and 0.039, respectively, this corresponds to a median PFS of 9.717 years vs. 17.667 years and is equivalent to 5-year PFS rates of 70% vs. 82.187%. Based on design assumptions, the 70% PFS rate at 5 years assumed for the control treatment strategy group corresponds with data available from a randomized phase III trial, in which previously untreated patients aged 65 years or older received ibrutinib until disease progression or unacceptable toxic effects and had a PFS estimate at 18 months of 90% (Burger et al, 2015).
There is 90% power for this one-sided log-rank test of superiority with the experimental treatment strategy versus the control treatment strategy using a group sequential design and constraining the one-sided type I error to 0.025 (i.e., two-sided error of 0.05). This design requires 128 events and translates to 431 total evaluable patients when assuming uniform accrual over 3 years and a minimum follow-up of 5 years.
5.3 Target Accrual The target accrual for this study is 454 patients using a 1:1 randomization. The target accrual rate is 13 patients per month.
6.0 CURRENT ACCRUAL
Study Activation Date 01/04/2019 Target Accrual (n) 454 Patients screened or pre-registered (n) 81 Current Accrual (n) 63 Expected Accrual Rate 13/month Accrual Rate – Since activation 8/month Accrual Rate – Past 6 months (if applicable) 10/month
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Jan19 Feb19 Mar19 Apr19 May19 Jun19 Jul19 Aug19 Sep19
Month
0
50
100
150
200
250
300
350
400
450To
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atien
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A041702 Cumulative Accrual: Actual Versus ExpectedNumbers on the Accrual Line are M onthly Accrual
7.0 CURRENT STUDY STATUS
This study opened on January 4, 2019. As of September 6, 2019, 63 patients have been randomized. 60 patients (95%) are alive and remain on active treatment.
8.0 PATIENT CHARACTERISTICS
All randomized participants are included in the table.
Table 8a. Demographics
Arm 1 (IO) (N=32)
Arm 2 (IVO) (N=31)
Total (N=63)
Age N 32 31 63 Mean (SD) 74.5 (3.6) 75.2 (3.5) 74.8 (3.5) Median 74.0 75.0 74.0 Q1, Q3 71.0, 78.0 72.0, 78.0 72.0, 78.0 Range (70.0-83.0) (70.0-82.0) (70.0-83.0) Race White 31 (96.9%) 28 (90.3%) 59 (93.7%) Not reported 0 (0.0%) 2 (6.5%) 2 (3.2%) Unknown 1 (3.1%) 1 (3.2%) 2 (3.2%) Gender Female 12 (37.5%) 7 (22.6%) 19 (30.2%) Male 20 (62.5%) 24 (77.4%) 44 (69.8%)
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Table 8b. Stratification Factors Arm 1 (IO)
(N=32) Arm 2 (IVO) (N=31)
Total (N=63)
Rai stage classification category Intermediate (Stage I/II) 13 (40.6%) 12 (38.7%) 25 (39.7%) High (Stage III/IV) 19 (59.4%) 19 (61.3%) 38 (60.3%) High-risk FISH abnormality del(17p13.1)
Absent 27 (84.4%) 27 (87.1%) 54 (85.7%) Present 5 (15.6%) 4 (12.9%) 9 (14.3%)
9.0 ADVERSE EVENTS
9.1 Adverse Event Summary 37 patients are evaluable for adverse events (AE) analyses (Arm 1: 19, Arm 2: 18). Commonly occurring grade 3+ AE include anemia (16% Arm 1), leukocytosis (11% Arm 1), Lymphocyte count increased (16% Arm 1, 11% Arm 2), Neutrophils/granulocytes (ANC/AGC) (26% Arm 1, 28% Arm 2), platelets (22% Arm 1, 11% Arm 2), and hypertension (11% Arm 1, 11% Arm 2). There have been 0 deaths on treatment. See below for a summary of adverse events by arm regardless of attribution.
Summary of Grade 3+ Adverse Events
Regardless of Attribution Number of Evaluable Patients:
Arm 1=19 Arm 2=18 Patients with a maximum: Arm n (%) Total
Grade 3 Event 1 9 (47.4%)
2 13 (72.2%)
Grade 4 Event 1 2 (10.5%)
2 0 (0.0%)
Grade 5 Event 1 0 (0.0%)
2 0 (0.0%)
Hematologic Adverse Events
Grade 3 Event 1 7 (36.8%)
2 10 (55.6%)
Grade 4 Event 1 2 (10.5%)
2 0 (0.0%)
Grade 5 Event 1 0 (0.0%)
2 0 (0.0%)
Non-Hematologic Adverse Events
Grade 3 Event 1 5 (26.3%)
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Summary of Grade 3+ Adverse Events Regardless of Attribution
Number of Evaluable Patients: Arm 1=19 Arm 2=18
Patients with a maximum: Arm n (%)
2 4 (22.2%)
Grade 4 Event 1 0 (0.0%)
2 0 (0.0%)
Grade 5 Event 1 0 (0.0%)
2 0 (0.0%)
Note: Summaries are based on available patient data
Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event
Regardless of Attribution Number of Evaluable Patients:
Arm 1=19 Arm 2=18 Grade of AdverseEvent
Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)
Hematologic Adverse Events Blood/Bone Marrow
Anemia 1 3 ( 16%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%) Leukocytosis 1 2 ( 11%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%) Lymphocyte count increased 1 3 ( 16%) 0 ( 0%) 0 ( 0%) 2 2 ( 11%) 0 ( 0%) 0 ( 0%) Lymphopenia 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Neutrophils/granulocytes (ANC/AGC)
1 4 ( 21%) 1 ( 5%) 0 ( 0%)
2 5 ( 28%) 0 ( 0%) 0 ( 0%) Platelets 1 2 ( 11%) 2 ( 11%) 0 ( 0%) 2 2 ( 11%) 0 ( 0%) 0 ( 0%)
Non-Hematologic Adverse Events **
Infections and infestations - Oth spec
1 1 ( 5%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) Pulmonary edema 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%)
Cardiovascular
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Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event
Regardless of Attribution Number of Evaluable Patients:
Arm 1=19 Arm 2=18 Grade of AdverseEvent
Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)
Hypertension 1 2 ( 11%) 0 ( 0%) 0 ( 0%) 2 2 ( 11%) 0 ( 0%) 0 ( 0%) Supraventricular and nodal arrhythmia
1 1 ( 5%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal
Diarrhea 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)
Hepatic Albumin, serum-low (hypoalbuminemia)
1 1 ( 5%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection/Febrile Neutropenia
Infection with unknown ANC 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)
Lymphatics Edema:limb 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%)
Metabolic/Laboratory Sodium, serum-low (hyponatremia) 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)
Pulmonary Pneumonitis/pulmonary infiltrates 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)
10.0 IMBEDDED CORRELATIVES Laboratory Correlative Studies: There will be one sub-study and all patients are required to
participate. The correlative science objectives are to compare MRD status between blood and bone marrow at the end of induction treatment/Cycle 15 Day 1 to determine whether blood MRD can be used as a surrogate to bone marrow MRD with these treatment regimens.
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E1910 A PHASE III RANDOMIZED TRIAL OF BLINATUMOMAB FOR NEWLY DIAGNOSED BCR-ABL NEGATIVE B ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS
Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Mark Litzow Statistician Dr. Zhuoxin Sun Data Specialist Henry Baptista Phase of Study III Type of Study Therapeutic Committee Leukemia Accrual Objective 488 Patients Participating Groups ECOG-ACRIN, CTSU NSC# 740, 3590, 10023, 14575, 26271, 34521, 63878,
67574, 141540, 624239, 697732, 765986 Clinicaltrials.gov Study ID NCT02003222 Study Status Open to Accrual Date Proposed June 26, 2012 Date Activated December 17, 2013 Schema
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Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1 Step 2 Step 3 Step 4 Beaumont NCORP 0 0 0 0 Beth Israel Deaconess Medical Center 3 3 3 1 Cancer Research Consortium of West Michigan NCORP 1 2 2 0 Dartmouth Hitchcock Medical Center 2 0 0 0 Dayton NCORP 1 1 0 0 Emory University/Winship Cancer Institute 2 1 1 1 Froedtert and the Medical College of Wisconsin 17 11 9 3 Geisinger Cancer Institute NCORP 0 0 0 0 Georgia NCORP 7 2 2 0 Gulf South MU NCORP 1 0 0 0 Heartland Cancer Research NCORP 1 0 0 0 Johns Hopkins Univ/Sidney Kimmel Cancer Center 33 27 23 9 Loyola University Medical Center 1 1 1 0 Mayo Clinic 10 5 2 0 Memorial Sloan Kettering Cancer Center 1 0 0 0 Montana Cancer Consortium NCORP 2 1 0 0 NorthShore Univ HealthSystem-Evanston Hospital 2 1 1 0 Northwestern University 24 12 11 3 Ochsner NCORP 2 1 1 1 Pacific Cancer Research Consortium NCORP 0 1 0 1 Penn State Milton S Hershey Medical Center 1 0 0 0 Rutgers Cancer Institute of New Jersey 7 3 3 1 Stanford Cancer Institute Palo Alto 1 0 0 0 Stony Brook University Medical Center 0 0 0 0 Thomas Jefferson University Hospital 4 2 2 0 UT Southwestern/Simmons Cancer Center-Dallas 5 3 3 1 University of Alabama at Birmingham Cancer Center 1 1 1 1 University of Kansas Cancer Center 4 1 1 0 University of North Carolina at Chapel Hill 1 0 0 0 University of Pennsylvania/Abramson Cancer Center 25 15 10 5 University of Wisconsin Hospital and Clinics 10 5 5 3 VCU Massey Cancer Center MU NCORP 13 9 6 2 Washington University School of Medicine 4 1 1 0 Wichita NCORP 5 3 3 1 Wisconsin NCORP 3 1 1 0 Yale University 0 1 0 0 Total 194 114 92 33
Table 1b. Accrual by Group
Step 1 Step 2 Step 3 Step 4
ECOG-ACRIN 194 114 92 33 CCTG 16 7 6 2 SWOG 115 74 61 24 ALLIANCE 111 66 56 26 NRG 18 16 14 6 Total 454 277 229 91
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Table 1c. Projected Accrual
Step 1 Step 2 Step 3 Step 4
Accrual goal 488 Planned accrual rate 72/yr Accrual to date 454 277 229 91 Annual accrual rate Overall 81/yr 50/yr 41/yr 16/yr Last 6 months 124/yr 66/yr 68/yr 38/yr Projected date of closure October 2019
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Table 2. Patient Status as of July 17, 2019
Step 1 Step 2 Step 3 Step 4 Cases Entered 454 277 229 91 Ineligible 6 6 5 0 Never Started Assigned Therapy 7 2 8 0
Reason for ineligibility Step 1:
Patient was BCR/ABL+ (19004, 19063, 19193, 19259). Bone Marrow pathology report was not done (19155). Pre-study bone marrow biopsy not obtained within 1 week of registration (19392).
Reason for not starting assigned therapy Step 1: Patient withdrawal/refusal (19066, 19260). Patient ineligible (19155, 19193, 19322, 19547); medical
decision (19523). Reason for ineligibility Step 2:
CR/CRi not confirmed (19037, 19053, 19139). ECOG Performance Status reported as 3, and also neurological complications (19194). Lab values not obtained <= 48 hours prior to registration (19120, 19239)
Reason for not starting assigned therapy Step 2: Neurological complications (19194). Decrease blood counts (19392).
Reason for ineligibility Step 3: Baseline labs (bilirubin, creatinine, anc, blasts, platelets) not done before randomization (19040). Serum Creatinine and Bilirubin were not obtained within 48 of step 3 registration in order to confirm eligibility (19051, 19053, 19504), Blast % in Blood not reported at Baseline (19218)
Reason for not starting assigned therapy Step 3:
Patient withdrawal/refusal (19093, 19221). Disease progression (19223, 19044, 19352, 19370, 19424). PI discretion (19156)
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Table 3a. Demographics --Step 1
Variable Level Arm A
(n=454) Sex Male 236 (52.0)
Female 218 (48.0) Race White 372 (90.7)
African-American 20 (4.9) Asian 8 (2.0) Native Hawaiian 1 (0.2) Native American 7 (1.7) Multirace 2 (0.5) Unknown/Unreported 44
Ethnicity Hispanic 65 (15.3) Non-Hispanic 361 (84.7) Unknown/Missing 28
Age Median 51 Minimum 30 Maximum 70
Table 3b. Demographics --Step 2
Variable Level Arm B
(n=277) Sex Male 137 (49.5)
Female 140 (50.5) Race White 228 (90.8)
African-American 12 (4.8) Asian 6 (2.4) Native Hawaiian 1 (0.4) Native American 3 (1.2) Multirace 1 (0.4) Unknown/Unreported 26
Ethnicity Hispanic 33 (12.5) Non-Hispanic 230 (87.5) Unknown/Missing 14
Age Median 52 Minimum 30 Maximum 70
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Table 3c. Demographics --Step 3
Variable Level Arm C
(n=118) Arm D
(n=111) Total
(n=229) Sex Male 53 (44.9) 58 (52.3) 111 (48.5)
Female 65 (55.1) 53 (47.7) 118 (51.5) Race White 94 (88.7) 94 (94.0) 188 (91.3)
African-American 9 (8.5) 3 (3.0) 12 (5.8) Asian 1 (0.9) 2 (2.0) 3 (1.5) Native Hawaiian 1 (0.9) 0 (0.0) 1 (0.5) Native American 1 (0.9) 1 (1.0) 2 (1.0) Unknown/Unreported 12 11 23
Ethnicity Hispanic 18 (15.7) 13 (12.7) 31 (14.3) Non-Hispanic 97 (84.3) 89 (87.3) 186 (85.7) Unknown/Missing 3 9 12
Age Median 52 52 52 Minimum 30 30 30 Maximum 70 70 70
Table 3d. Demographics --Step 4
Variable Level Arm E (n=91)
Sex Male 45 (49.5) Female 46 (50.5)
Race White 74 (92.5) African-American 2 (2.5) Asian 1 (1.3) Native Hawaiian 1 (1.3) Native American 2 (2.5) Unknown/Unreported 11
Ethnicity Hispanic 13 (15.1) Non-Hispanic 73 (84.9) Unknown/Missing 5
Age Median 50 Minimum 30 Maximum 69
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Table 4. Record Status
Form Name Forms Due
Forms Received %
Adverse Event Form 2156 2105 97.6% Baseline Hematology/Chemistry 1028 1022 99.4% Disease Follow-up Status 3088 3062 99.2% Follow-Up Hematology/Chemistry 19724 19686 99.8% Late Adverse Event Form 47 47 100.0% Off Treatment 94 91 96.8% Off-Treatment with Intent to Reg Next Step 775 774 99.9% Other Adverse Event Form 1082 1075 99.4% Patient Characteristics 3182 3156 99.2% Report Period and Vital Status Form 3351 3304 98.6% Treatment Agent: 6 Mercaptopurine 790 780 98.7% Treatment Agent: Blinatumomab 292 288 98.6% Treatment Agent: Cyclophosphamide (1d) 109 108 99.1% Treatment Agent: Cyclophosphamide (2d) 358 357 99.7% Treatment Agent: Cytarabine (16d) 357 356 99.7% Treatment Agent: Cytarabine (1d) 432 424 98.1% Treatment Agent: Cytarabine (5d) 361 355 98.3% Treatment Agent: Cytarabine (8d) 108 107 99.1% Treatment Agent: Daunorubicin (4d) 538 529 98.3% Treatment Agent: Dexamethasone 536 527 98.3% Treatment Agent: Etoposide (5d) 362 356 98.3% Treatment Agent: Leucovorin 265 265 100.0% Treatment Agent: Methotrexate (13d) 331 322 97.3% Treatment Agent: Methotrexate (1d) 901 887 98.4% Treatment Agent: Methotrexate (2d) 266 266 100.0% Treatment Agent: Methotrexate (4d) 357 356 99.7% Treatment Agent: Methotrexate IT (1d) 268 264 98.5% Treatment Agent: Pegaspargase 1196 1181 98.7% Treatment Agent: Prednisone 331 323 97.6% Treatment Agent: Rituximab (1d) 198 194 98.0% Treatment Agent: Rituximab (2d) 327 327 100.0% Treatment Agent: Vincristine (1d) 337 334 99.1% Treatment Agent: Vincristine (4d) 538 529 98.3%
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Table 5a. Reasons Off Treatment - Step 1 For Patients Not Registered To Subsequent Steps (Includes all patients who
started treatment and for whom off-treatment data have been received)
Reasons N % Adverse event/side effects/complications 9 7.0 Alternative therapy 11 8.6 Death on study 12 9.4 Disease progression- relapse during active treatment 26 20.3 Other 37 28.9 Patient off-treatment for other complicating disease 2 1.6 Patient withdrawal/refusal after beginning protocol therapy 13 10.2 Treatment completed per protocol criteria 18 14.1 Total off treatment 128 100.0
Table 5b. Reasons Off Treatment - Step 2 For Patients Not Registered To Subsequent Steps (Includes all patients who
started treatment and for whom off-treatment data have been received)
Reasons N % Adverse event/side effects/complications 1 2.5 Alternative therapy 1 2.5 Disease progression- relapse during active treatment 11 27.5 Other 5 12.5 Patient withdrawal/refusal after beginning protocol therapy 2 5.0 Treatment completed per protocol criteria 20 50.0 Total off treatment 40 100.0
Table 5c. Reasons Off Treatment - Step 3 For Patients Not Registered To Subsequent Steps (Includes all patients who
started treatment and for whom off-treatment data have been received)
Reasons N % Adverse event/side effects/complications 5 5.3 Alternative therapy 7 7.4 Death on study 3 3.2 Disease progression- relapse during active treatment 16 17.0 Other 8 8.5 Patient withdrawal/refusal after beginning protocol therapy 8 8.5 Treatment completed per protocol criteria 47 50.0 Total off treatment 94 100.0
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Table 5d. Reasons Off Treatment - Step 4
(Includes all patients who started treatment and for whom off-treatment data have been received)
Reasons N %
Adverse event/side effects/complications 2 3.8 Alternative therapy 1 1.9 Death on study 1 1.9 Disease progression- relapse during active treatment 8 15.1 Other 4 7.5 Patient withdrawal/refusal after beginning protocol therapy 7 13.2 Treatment completed per protocol criteria 29 54.7 Total off treatment 52 98.1
Table 6. Toxicity Incidence (Treatment-Related)
Step 1 (Arm A)
Toxicity Type
Treatment Arm A (n=404)
Grade 3 4 5
(n) (n) (n) Anemia 184 24 - Blood and lymphatic system disorders - Other, specify 2 4 - Disseminated intravascular coagulation 1 - - Febrile neutropenia 95 3 - Leukocytosis 1 - - Cardiac disorders - Other, specify - 1 - Chest pain - cardiac 1 - - Myocardial infarction - - 1 Pericarditis 1 - - Sinus bradycardia 1 - - Sinus tachycardia 1 - - Retinopathy 1 - - Abdominal pain 11 - - Colitis 1 - - Constipation 2 - - Diarrhea 7 - - Gastric hemorrhage 1 - - Gastritis 1 - - Gastrointestinal disorders - Other, specify 3 - - Mucositis oral 5 - - Nausea 15 - - Oral hemorrhage 1 - - Pancreatitis 6 1 - Proctitis 1 - - Rectal pain 2 - - Small intestinal obstruction - 1 -
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Toxicity Type
Treatment Arm A (n=404)
Grade 3 4 5
(n) (n) (n) Typhlitis 2 - - Vomiting 15 1 - Fatigue 26 - - Fever 3 - - General disorders and administration site conditions - Other, specify 1 - - Pain 1 - - Edema limbs 1 - - Infusion related reaction 2 1 - Hepatic failure - 2 1 Hepatobiliary disorders - Other, specify - 1 - Allergic reaction 2 - - Anaphylaxis 1 - - Catheter related infection 8 - - Eye infection 1 - - Infections and infestations - Other, specify 13 1 - Otitis externa 1 - - Sepsis - 14 1 Sinusitis 3 - - Skin infection 5 - - Upper respiratory infection 1 - - Urinary tract infection 9 - - Pancreas infection 1 - - Abdominal infection 1 - - Enterocolitis infectious 3 - - Bone infection 1 - - Lung infection 10 1 - Vascular access complication 1 - - Activated partial thromboplastin time prolonged 2 - - Alanine aminotransferase increased 35 5 - Alkaline phosphatase increased 11 1 - Aspartate aminotransferase increased 21 1 - Blood bilirubin increased 23 12 - Cholesterol high - 1 - Fibrinogen decreased 10 5 - Investigations - Other, specify 1 1 - Lipase increased 1 3 - Lymphocyte count decreased 16 92 - Lymphocyte count increased 1 - - Neutrophil count decreased 14 300 - Platelet count decreased 26 257 - Weight loss 1 - - White blood cell decreased 6 196 - GGT increased 3 2 - Anorexia 7 - - Dehydration 7 - - Hypercalcemia 1 - -
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Toxicity Type
Treatment Arm A (n=404)
Grade 3 4 5
(n) (n) (n) Hyperglycemia 28 1 - Hyperkalemia 2 - - Hypertriglyceridemia 2 13 - Hyperuricemia - 1 - Hypoalbuminemia 8 - - Hypocalcemia 3 - - Hypokalemia 1 - - Hyponatremia 17 1 - Hypophosphatemia 7 - - Tumor lysis syndrome 21 - - Glucose intolerance 3 - - Arthralgia 2 - - Back pain 1 - - Generalized muscle weakness 6 - - Muscle weakness lower limb 1 - - Cerebrospinal fluid leakage 1 - - Cognitive disturbance 1 - - Dizziness 2 - - Encephalopathy 2 1 - Headache 19 - - Intracranial hemorrhage 1 1 - Paresthesia 1 - - Peripheral motor neuropathy 2 - - Seizure 1 - - Somnolence 1 - - Stroke 1 1 1 Syncope 3 - - Vasovagal reaction 2 - - Confusion 3 - - Delirium 1 - - Insomnia 1 - - Personality change 1 - - Restlessness 1 - - Acute kidney injury 2 2 - Adult respiratory distress syndrome - - 1 Dyspnea 3 - - Epistaxis 2 - - Hiccups 1 - - Hypoxia 2 - - Pneumonitis 3 - - Respiratory, thoracic and mediastinal disorders - Other, specify 1 - - Sore throat 1 - - Wheezing 1 - - Bronchopulmonary hemorrhage - 1 - Rash maculo-papular 1 - - Urticaria 1 - -
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Toxicity Type
Treatment Arm A (n=404)
Grade 3 4 5
(n) (n) (n) Hematoma 1 - - Hypertension 15 - - Hypotension 7 1 - Thromboembolic event 8 6 - WORST DEGREE (NON-HEMATOLOGIC) 180 67 5
Step 2 (Arm B)
Toxicity Type
Treatment Arm B (n=252)
Grade 3 4 5
(n) (n) (n) Anemia 44 1 - Febrile neutropenia 1 - - Abdominal pain 3 - - Colitis 1 - - Diarrhea 3 - - Gastrointestinal disorders - Other, specify 1 - - Mucositis oral 1 - - Nausea 3 - - Pancreatitis 3 - - Fatigue 4 - - Hepatic failure 1 - - Anaphylaxis - 1 - Catheter related infection 2 - - Sepsis - 3 - Skin infection 1 - - Lung infection 1 - - Activated partial thromboplastin time prolonged 1 - - Alanine aminotransferase increased 12 - - Alkaline phosphatase increased 3 - - Aspartate aminotransferase increased 9 - - Blood bilirubin increased 3 1 - Creatinine increased 1 - - Fibrinogen decreased 2 - - Investigations - Other, specify 1 - - Lipase increased 3 1 - Lymphocyte count decreased 16 16 - Neutrophil count decreased 38 29 - Platelet count decreased 15 14 - Weight loss 1 - - White blood cell decreased 11 7 - GGT increased 1 - - Alkalosis 1 - -
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Toxicity Type
Treatment Arm B (n=252)
Grade 3 4 5
(n) (n) (n) Dehydration 1 - - Hyperglycemia 9 2 - Hypertriglyceridemia - 3 - Hypocalcemia 1 - - Hypokalemia 3 - - Hyponatremia 1 - - Hypophosphatemia 1 - - Tumor lysis syndrome 1 - - Glucose intolerance 1 - - Myalgia 1 - - Pain in extremity 1 - - Generalized muscle weakness 1 - - Headache 1 - - Hyperhidrosis 1 - - Rash maculo-papular 1 - - Hypertension 3 - - Hypotension 1 - - Thromboembolic event 1 - - WORST DEGREE (NON-HEMATOLOGIC) 50 11 -
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Step 3 Arm C
Toxicity Type
Treatment Arm Treatment Arm C (n=107) C (n=107)
Blinitumomab Consolidation Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6 Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade
3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)
Anemia 6 - - - - - 6 - - 4 - - 16 1 - 11 - - 2 - - 5 - - 1 - - 17 1 - Blood and lymphatic system disorders - Other, specify - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - Febrile neutropenia - - - 1 - - 1 - - 4 2 - 2 - - 5 - - 1 - - 2 - - - - - 11 2 - Chest pain - cardiac - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Sinus tachycardia 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Ear pain 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Abdominal pain - - - - - - - - - 1 - - - - - 1 - - - - - - - - - - - 2 - - Diarrhea - - - - - - - - - - - - - - - 1 - - - - - 1 - - - - - 2 - - Nausea - - - - - - - - - 2 - - - - - - - - - - - 1 - - - - - 3 - - Vomiting - - - - - - - - - - - - 1 - - 1 - - - - - 1 - - - - - 3 - - Fatigue - - - 1 - - 1 - - - - - - - - - - - - - - 1 - - - - - 1 - - Fever - - - - - - - - - - - - - - - 1 - - - - - 1 - - - - - 2 - - Gait disturbance 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Hepatobiliary disorders - Other, specify 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Cytokine release syndrome 2 1 - - - - 2 1 - - - - - - - - - - - - - - - - - - - - - - Appendicitis perforated - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Catheter related infection 2 - - 1 - - 3 - - - - - - - - 1 - - - - - - - - - - - 1 - - Device related infection - - - - - - - - - - - - - - - - - - - - - 1 - - - - - 1 - - Enterocolitis infectious - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Infections and infestations - Other, specify 2 - - - - - 2 - - - - - - - - - - - 1 - - - - - - - - 1 - - Lung infection - - - - - - - - - - 1 - - - - 1 - - - - - - - - - - - 1 1 - Sepsis - - - - 1 - - 1 - - 3 - - - - - - - - - 1 - 2 - - - - - 5 1 Sinusitis - - - 1 - - 1 - - - - - - - - - - - - - - - - - - - - - - - Urinary tract infection - - - 1 - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - -
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Toxicity Type
Treatment Arm Treatment Arm C (n=107) C (n=107)
Blinitumomab Consolidation Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6 Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade
3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)
Activated partial thromboplastin time prolonged - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Alanine aminotransferase increased 1 1 - - - - 1 1 - 1 - - 1 - - - - - - - - - - - - - - 1 - - Alkaline phosphatase increased - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Aspartate aminotransferase increased 1 1 - - - - 1 1 - - - - 1 - - - - - - - - - - - - - - 1 - - Blood bilirubin increased - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Cholesterol high - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - Fibrinogen decreased - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Investigations - Other, specify 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Lymphocyte count decreased 2 13 - 1 2 - 2 14 - 2 1 - 2 1 - 3 3 - 2 1 - 1 - - 2 - - 3 6 - Neutrophil count decreased 12 10 - 6 5 - 13 14 - - 37 - 3 25 - 3 33 - 3 3 - - 27 - 2 2 - 1 46 - Platelet count decreased 2 2 - - 1 - 2 3 - 4 19 - 4 12 - 4 26 - - 1 - 3 17 - - - - 5 34 - Weight gain - - - - - - - - - - - - - - - - - - 1 - - - - - 1 - - 2 - - White blood cell decreased - 1 - 1 - - 1 1 - 3 9 - 2 3 - 3 10 - - 1 - - 4 - - - - 5 18 - Dehydration 1 - - - - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - - Hyperglycemia 1 - - - - - 1 - - 1 1 - 1 - - 5 - - - - - - - - 1 - - 4 1 - Hypertriglyceridemia - - - - - - - - - - 2 - - 2 - - 2 - 1 - - 1 - - - - - - 4 - Hypocalcemia - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - Hyponatremia 1 - - - - - 1 - - 1 - - - - - 1 - - - - - - - - - - - 1 - - Hypophosphatemia - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Avascular necrosis 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Bone pain - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - - Ataxia 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Cognitive disturbance 2 - - - - - 2 - - - - - - - - - - - - - - - - - - - - - - - Concentration impairment 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Depressed level of consciousness 2 - - - - - 2 - - - - - - - - - - - - - - - - - - - - - - - Dysarthria 1 - - 1 - - 2 - - - - - - - - - - - - - - - - - - - - - - -
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Toxicity Type
Treatment Arm Treatment Arm C (n=107) C (n=107)
Blinitumomab Consolidation Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6 Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade
3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)
Dysphasia 3 - - 1 - - 4 - - - - - - - - - - - - - - - - - - - - - - - Encephalopathy 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - - Headache - - - - - - - - - 1 - - 1 - - 1 - - - - - - - - - - - 3 - - Intracranial hemorrhage - - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - Seizure 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - - Syncope - - - - - - - - - 1 - - - - - 1 - - - - - 1 - - - - - 3 - - Tremor 3 - - - - - 3 - - - - - - - - - - - - - - - - - - - - - - - Confusion 3 - - - - - 3 - - - - - - - - - - - 1 - - - - - - - - 1 - - Acute kidney injury - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Epistaxis - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Capillary leak syndrome 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Hypertension - 1 - - - - - 1 - - - - - - - 1 - - - - - - - - - - - 1 - - Hypotension - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Thromboembolic event - - - - - - - - - 2 - - 1 - - 1 - - 1 - - 1 - - 1 - - 2 - - WORST DEGREE (NON-HEMATOLO - - - 4 1 - - - - - - - - - - 15 2 - - - - 4 2 - 3 - - - - - WORST DEGREE (NON-HEMATOLOGIC) 23 2 1 - - - 25 3 1 9 8 - 7 2 - - - - 5 - 1 - - - - - - 23 10 1
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Step 3 Arm D
Toxicity Type
Treatment Arm D (n=96)
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycles
1-4 Grade Grade Grade Grade Grade
3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)
Anemia 16 1 - 15 1 - 13 - - 7 1 - 35 2 - Febrile neutropenia 7 1 - 6 - - 4 - - 2 - - 16 1 - Abdominal pain - - - - - - 1 - - - - - 1 - - Nausea 1 - - - - - - - - - - - 1 - - Vomiting 3 - - - - - - - - - - - 3 - - Fatigue 3 - - 1 - - - - - - - - 4 - - General disorders and administration site conditions - Other, specify 1 - - - - - - - - - - - 1 - - Allergic reaction 1 - - - - - - - - - - - 1 - - Catheter related infection 3 1 - - 1 - 1 - - - - - 4 1 - Infections and infestations - Other, specify 2 - - - - - 1 - - - - - 3 - - Lung infection - 1 - - - - - - - - - - - 1 - Meningitis - - - - - - 1 - - - - - 1 - - Sepsis - 5 - - 2 - - - - - - - - 6 - Sinusitis - - - - - - 1 - - - - - 1 - - Upper respiratory infection 1 - - - - - - - - - - - 1 - - Urinary tract infection - - - - - - 1 - - - - - 1 - - Alanine aminotransferase increased 2 - - 1 - - 3 1 - 1 - - 6 1 - Alkaline phosphatase increased 1 - - - - - - - - - - - 1 - - Aspartate aminotransferase increased - - - - - - - 1 - 1 - - 1 1 - Lymphocyte count decreased 3 4 - 1 5 - 2 9 - 3 2 - 5 12 - Neutrophil count decreased 5 58 - 1 38 - 2 25 - 2 22 - 4 66 - Platelet count decreased 9 30 - 4 19 - 3 21 - 2 8 - 8 46 - Weight loss - - - 1 - - - - - - - - 1 - - White blood cell decreased 3 21 - 1 11 - 2 13 - 2 6 - 2 32 - Hyperglycemia - - - - - - 3 2 - - - - 3 2 - Hypertriglyceridemia 1 2 - - - - - - - - - - 1 2 - Hyponatremia 1 - - - - - - - - - - - 1 - - Hypophosphatemia 2 - - 1 - - 1 - - - - - 3 - - Iron overload 1 - - 1 - - - - - - - - 1 - - Myalgia - - - - - - 1 - - - - - 1 - - Neck pain - - - - - - 1 - - - - - 1 - - Headache 2 - - 3 - - 2 - - 1 - - 5 - - Peripheral sensory neuropathy 1 - - 1 - - 1 - - - - - 1 - - Depression 1 - - - - - - - - - - - 1 - - Pneumonitis 1 - - - - - - - - - - - 1 - - Hypertension 1 - - - - - - - - - - - 1 - - WORST DEGREE (NON-HEMATOLOGIC) 14 8 - 11 2 - 14 3 - 4 - - 25 12 -
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Step 3 Transplant
Toxicity Type
Treatment Arm C (n=19) D (n=19)
Grade Grade 3 4 5 3 4 5
(n) (n) (n) (n) (n) (n) Anemia 6 - - 6 - - Febrile neutropenia 4 1 - 5 - - Atrial fibrillation 1 - - - - - Anal mucositis - - - 1 - - Colitis 2 - - - - - Diarrhea 3 - - 1 - - Dry mouth - - - 1 - - Dysphagia - - - 1 - - Esophagitis 1 - - - - - Gastrointestinal disorders - Other, specify 1 - - - - - Mucositis oral 2 - - 3 1 - Nausea 1 - - 1 - - Oral pain - - - 1 - - Rectal mucositis 1 - - - - - Small intestinal mucositis 1 - - - - - Typhlitis - - - 1 - - Chills - - - 1 - - Fatigue 1 - - 1 - - Pain - - - 1 - - Infections and infestations - Other, specify 2 - - - - - Lung infection 1 - - 1 - - Lymphocyte count decreased - 4 - - 7 - Neutrophil count decreased - 9 - 1 11 - Platelet count decreased 1 10 - - 10 - White blood cell decreased - 9 - - 7 - Anorexia 2 - - 3 - - Hyperglycemia 1 - - - - - Hypokalemia 1 - - - - - Iron overload - - - 1 - - Back pain - - - 1 - - Trismus - - - 1 - - Headache 1 - - - - - Hematuria - - - 1 - - Dyspnea - - - 1 - - Epistaxis - - - 1 - - Pulmonary edema - - - 1 - - Sore throat - - - 1 - - Dry skin - - - 1 - - Rash acneiform 1 - - - - - WORST DEGREE (NON-HEMATOLOGIC) 6 1 - 6 1 -
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Step 4 Maintenance
Toxicity Type
Treatment Arm C (n=37) D (n=38)
Grade Grade 3 4 5 3 4 5
(n) (n) (n) (n) (n) (n) Anemia 4 - - 2 - - Febrile neutropenia 2 - - - - - Abdominal pain 1 - - - - - Mucositis oral 2 - - 1 - - Nausea 1 - - - - - Pancreatitis - 1 - - - - Vomiting 2 - - - - - Fatigue 1 - - - - - Hepatic failure - - - 1 - - Infections and infestations - Other, specify 1 - - - - - Upper respiratory infection 1 - - - - - Urinary tract infection 1 - - - - - Lung infection 1 - - - - - Alanine aminotransferase increased 5 - - 9 - - Aspartate aminotransferase increased 1 - - 3 - - Blood bilirubin increased 2 - - 3 4 - Investigations - Other, specify 1 - - - - - Lipase increased - 1 - - - - Lymphocyte count decreased - 3 - 4 2 - Neutrophil count decreased 1 19 - 3 10 - Platelet count decreased 3 8 - 2 4 - Serum amylase increased - 1 - - - - White blood cell decreased 1 7 - 1 6 - Dehydration 1 - - - - - Hyperglycemia 1 - - 1 - - Hypertriglyceridemia - 1 - - - - Hyponatremia 1 - - - - - Metabolism and nutrition disorders - Other, specify - 1 - - - - Back pain - - - 1 - - Avascular necrosis 2 - - - - - Treatment related secondary malignancy - - 1 - - - Headache - - - 1 - - Peripheral sensory neuropathy - - - 2 - - Psychiatric disorders - Other, specify 1 - - - - - Hypertension - - - 1 - - Thromboembolic event 1 - - - - - WORST DEGREE (NON-HEMATOLOGIC) 13 1 1 14 4 -
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Table 7. Lethal Adverse Events
Case Arm Description of Event 19001 A Death NOS 19126 A Intracranial hemorrhage 19215 A Sudden death NOS 19220 A Febrile neutropenia 19243 A Sepsis 19299 A Sepsis 19305 A Infections and infestations - Other 19345 A Adult respiratory distress syndrome 19378 A Hepatic failure 19452 A Sepsis 19456 A Myocardial infarction 19514 A Stroke 19521 A Cardiac arrest 19540 A Hepatic failure 19685 A Intracranial hemorrhage 19119 C Intracranial hemorrhage 19327 C Sepsis 19088 D Cardiac arrest 19047 E Cardiac arrest
Table 8. Second Primary Cancers (By arm during which event was reported)
Site Arm A Arm B Arm E
Acute Non-Lymphocytic Leukemia - ANLL, AML 1 - - Leukemia, Type Not Specified - - 1 Melanoma 1 - - Non-Small Cell Lung 1 - - Pancreas 1 - - Skin Cancer Not Melanoma - 1 -
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EA9161 A RANDOMIZED PHASE III STUDY OF THE ADDITION OF VENETOCLAX TO IBRUTINIB AND OBINUTUZUMAB VERSUS IBRUTINIB AND OBINUTUZUMAB IN UNTREATED YOUNGER PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Sponsor(s)
Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Tait Shanafelt Statistician Dr. Xin Victoria Wang Data Specialist Elene Assefa Phase of Study III Type of Study Therapeutic Committee Leukemia Accrual Objective 720 Patients Participating Groups ECOG-ACRIN, SWOG, ALLIANCE, NRG NSC# 748645, 766270, 793436 Clinicaltrials.gov Study ID NCT03701282 Study Status Open to Accrual Date Activated January 3, 2019 Schema
ECOG-ACRIN Cancer Research Group EA9161 Study Progress and Safety Report Fall 2019
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Purpose of Study EA9161 Primary Objective: To compare the progression free survival (PFS) of the time limited administration of the three-drug combination Ibrutinib-Obinutuzumab-Venetoclax (IOV) to Ibrutinib-Obinutuzumab (IO) in CLL patients younger than 70 years of age. Secondary Objectives: (1) Evaluate overall survival (OS) of patients based on treatment arm. (2) Monitor and assess toxicity of treatment based on treatment arm. (3) Compare minimal residual disease (MRD) status as assessed by flow cytometry after 12, 18, 24, and 30 months of treatment of the two treatment arms. (4) To compare quality of life (QOL) in CLL patients during the first 12 months of treatment among patients on each treatment arm. (5) To compare QOL over the long-term in CLL patients receiving continuous therapy using Ibrutinib to that of CLL patients who completed time limited therapy. (6) Determine the effect of pretreatment clinical and biological characteristics (e.g. disease stage, IGHV mutation status, FISH) on clinical outcomes (e.g. complete response, PFS) of the different arms. (7) Compare the genetic abnormalities and dynamics of intra-clonal architecture of CLL patients before and after treatment on each treatment arm and explore relationships with treatment resistance. (8) Explore the effects of each treatment arm on T-cell immune function. (9) Evaluate the ability of prognostic model that incorporates clinical and biologic characters to predict a response to therapy and clinical outcome (PFS, OS). (10) Evaluate signaling networks downstream of the B-cell receptor in patients receiving Ibrutinib-based therapy. Collect relapse samples to study mechanisms of resistance for patients on both treatment arms. (11) Conduct cost effectiveness analysis of treatment for patients in each treatment arm. Study Population Previously untreated CLL patients between 18 and 70 years of age requiring therapy. ECOG PS 0-2. Excludes patients with deletion 17p13. Summary of Study Design Because we expect the IOV arm to have moderate improvement in PFS and, at the same time, the duration of therapy for the IOV arm is 19 cycles whereas patients on IO need to be on therapy indefinitely, a hybrid non-inferiority design is used. We assume the median PFS for the IO arm to be 78 months. The null hypothesis is that the hazard ratio of IOV over IO is 1.18 or larger, corresponding to a 12-month reduction in median PFS to 66 months for the IOV arm. The alternative hypothesis is that this hazard ratio is less than 1.18, meaning that the IOV arm is non-inferior to the IO arm. We design the study to have 80% power to detect an improvement in hazard ratio to 0.83 or less, corresponding to median of 94 months or more for the IOV arm, with one-sided alpha of 0.025. Assuming an accrual rate of 20 patients per month, with one interim analysis and one final analysis, this design requires 720 patients accrued over 36 months and an additional follow-up of 37.2 months to reach the full information of 258 events. Progress to Date This study was activated on January 3, 2019. As of July 17, 2019, 120 patients have been accrued. Accruals by ECOG-ACRIN institutions and by group are shown in Table 1a and 1b. Projected accruals are shown in Table 1c and Figure 1. Table 2 summarizes patient status. Table 3 shows patient demographic information by treatment arm. Record status by form is presented in Table 4. Treatment-related toxicity data are available for 69 patients and are summarized in Table 5. A summary of the collection of quality of life data is presented in Table 6. There have been no report of patients not starting assigned protocol therapy or off treatment. No treatment-related lethal adverse events or second primary cancers have been reported.
ECOG-ACRIN Cancer Research Group EA9161 Study Progress and Safety Report Fall 2019
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Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1 Catholic Health Initiatives NCORP 5 Colorado Cancer Research Program NCORP 2 Heartland Cancer Research NCORP 5 Holy Cross Hospital 1 Mayo Clinic 22 Metro Minnesota Community Oncology Res Consortium 4 Michigan Ca Res Consortium NCORP 2 Montana Cancer Consortium NCORP 3 Ochsner NCORP 2 Pacific Cancer Research Consortium NCORP 4 Penn State Milton S Hershey Medical Center 1 Rutgers Cancer Institute of New Jersey 1 UT Southwestern/Simmons Cancer Center-Dallas 3 University of Kansas Cancer Center 1 University of Oklahoma Health Sciences Center 1 University of Wisconsin Hospital and Clinics 1 Wichita NCORP 2 Wisconsin NCORP 2 Yale University 2 Total 64
Table 1b. Accrual by Group ECOG-ACRIN 64 SWOG 30 ALLIANCE 21 NRG 5 Total 120
Table 1c. Projected Accrual Accrual goal 720 Planned accrual rate 240/yr Accrual to date 120 Annual accrual rate Overall 225/yr
Projected date of closure January 2022
ECOG-ACRIN Cancer Research Group EA9161 Study Progress and Safety Report Fall 2019
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Figure 1. EA9161 Cumulative Accrual
Table 2. Patient Status as of July 17, 2019
Cases Entered 120 Ineligible 0 Never Started Assigned Therapy 0
020
4060
8010
012
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Num
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Jan 2019 Mar 2019 May 2019 Jul 2019
TargetActual
ECOG-ACRIN Cancer Research Group EA9161 Study Progress and Safety Report Fall 2019
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Table 3. Demographics
Variable Level Arm A (n=60)
Arm B (n=60)
Total (n=120)
Sex Male 41 (68.3) 41 (68.3) 82 (68.3) Female 19 (31.7) 19 (31.7) 38 (31.7)
Race White 53 (94.6) 52 (98.1) 105 (96.3) African-American 2 (3.6) 1 (1.9) 3 (2.8) Asian 1 (1.8) 0 (0.0) 1 (0.9) Unknown/Unreported 4 7 11
Ethnicity Hispanic 3 (5.1) 1 (1.8) 4 (3.4) Non-Hispanic 56 (94.9) 56 (98.2) 112 (96.6) Unknown/Missing 1 3 4
Age Median 61 60 60 Minimum 40 31 31 Maximum 69 69 69
Table 4. Record Status
Form Name Forms Due
Forms Received %
Adverse Events 156 148 94.9% Disease Description at Study Entry 113 112 99.1% Disease Follow-Up Status 174 160 92.0% Follow-Up Hematology/Chemistry 495 479 96.8% Hematology/Chemistry 112 109 97.3% Patient Characteristics 293 282 96.2% Report Period and Vital Status Form 181 170 93.9% Treatment Agent: Ibrutinib 168 150 89.3% Treatment Agent: Obinituzumab 161 158 98.1% Treatment Agent: Venetoclax 16 15 93.8%
ECOG-ACRIN Cancer Research Group EA9161 Study Progress and Safety Report Fall 2019
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Table 5. Grade 3 and Above Treatment-related Toxicity Incidence
Toxicity Type
Treatment Arm A (n=33) B (n=36)
Grade Grade 3 4 5 3 4 5
(n) (n) (n) (n) (n) (n) Anemia 1 - - - - - Blood and lymphatic system disorders - Other, specify - - - 1 - - Leukocytosis 2 - - 1 - - Atrial fibrillation - - - 1 - - Diarrhea - - - 1 - - Chills 1 - - - - - Allergic reaction 1 - - - - - Infusion related reaction 5 1 - 3 - - Lymphocyte count decreased 2 - - 2 - - Lymphocyte count increased 2 - - 2 - - Neutrophil count decreased 2 3 - 2 3 - Platelet count decreased 1 - - 3 1 - White blood cell decreased 1 - - 1 - - Hyperkalemia - 1 - - - - Hypoxia 1 - - - - - Rash maculo-papular - - - 1 - - Flushing 1 - - - - - Hypotension 1 - - - - - WORST DEGREE 12 5 - 8 4 -
Table 6. QOL Table
QOL Timepoint
Patients Reaching
Timepoint % Forms
Completed Baseline 78 92.3 Cycle 3 13 100.0 Cycle 7 0 Cycle 15 0 End of Cycle 19 0 6 months after treatment 0 12 months after treatment 0 18 months after treatment 0 24 months after treatment 0 48 months after registration 0