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Newer Agents And Combinations

in Myelodysplastic Syndromes

Ruben A. Mesa, MD – Mayo Clinic Arizona

David P. Steensma, MD – Dana-Farber Cancer Institute

Clinical TrialsWhat are they?

• Biomedical or health-related related research studies in human beings that follow a pre-determinded protocol (document detailing uniform treatment)

• Two major types

– Interventional-when patients are assigned a treatment

– Observational-when patients are observed

Clinical TrialsWhy participate?

• Patients play an active role in their own health care, they become engaged

• Patients can gain access to new treatments that may not be otherwise available, before formal governmental (FDA) approval

• Patients can help others by contributing to medical research and helping establish new and better treatments for future patients

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Clinical TrialsWho can or should participate?

• Patients with a disease where treatment is not curative

• Clinical trials have inclusion and exclusion criteria to

– Protect the safety of the patient from the new treatment being tested

– Help produce reliable results which will make sure the trial really determines if the new treatment is effective

– Inclusion/exclusion criteria include age, type and stage of disease, prior treatment history, organ function (heart, lung, kidneys) to make sure the treatment is safe

Clinical TrialsInformed consent

• Process of learning the facts of the clinical trial before deciding whether or not to participate

• Details are explained by the treating physician, nurse and other professionals

• Document must be signed which includes purpose of the clinical trial and treatment, duration, required procedures, risks and potential benefits

Clinical TrialsBenefits

• Patients play an active role in their health care

• Patients can gain access to new treatments before they are approved by the government (FDA) and widely available

• Patients can help others by contributing to medical research to identify new and better treatment

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Clinical TrialsRisks

• There may be side effects, some life-threatening

• Treatment under study in the clinical trial may not be effective

• Treatment on the clinical trial may require more time and tests than required by what we call standard (routine or nonprotocol or nonclinical trial) treatment

Clinical TrialsPhases

• Phase I-designed to determine the best and safest dose and identify side effects

• Phase II-designed to determine the effectiveness of the new treatment

• Phase III-designed to compare the effectiveness of the new treatment to the commonly used treatment

• Phase IV-postmarketing (after FDA approval) trial to further refine the risks and benefits and identify new side effects once the new treatment is widely used

Clinical TrialsSponsors and funding (financial

support)

• University medical centers, cancer centers

• Foundations

• Pharmaceutical industry

• Federal agencies such as the National Institutes of Health, Cooperative oncology groups

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Outline

• Combination approaches

– Azacitidine + MS275

– Azacitidine + SAHA (vorinostat)

• Newer agents

– Oral azacitidine

– Oral TLK199 (ezatiostat)

– IV and oral clofarabine

– IV ON01910.Na

– Alemtuzumab (IV)

Combination Approaches

Azacitidine Combination Studies

Combination Patient Population Response

Azacitidine + lenalidomide High-risk MDS

(n = 18)

Overall RR: 67%

CR: 44%

Azacitidine + etanercept MDS (low to high risk)

(n = 18)

CR: 72% (13/18)

Azacitidine + vorinostat MDS, elderly AML

(n = 18)

CR: 50% (9/18)

Azacitidine + MGCD0103 MDS, R/R AML

(n = 52)

CR/CRi: 35%; PR: n = 1

(18/52)

Azacitidine + gemtuzumab AML/high-risk MDS

(n = 15)

CR + CRp: 72%

(11/15)

Azacitidine + romiplostim Low/int-1 MDS

azacitidine or decitabine

Platelet response

CR = complete response, R/R = relapsed/refratory, RR = response rate

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ECOG E1905 study schema

Eligible patients (no prior azacitidine):•MDS (higher risk; if IPSS low/INT-1 risk, then platelets <50 x 109/L or ANC<500)

•CMML with WBC <12 x 109/L•AML with multilineage dysplasia and WBC ≤30 x 109/L for ≥4 weeks

Azacitidine SC 50 mg/m2 x 10 days every 28 days

Primary Endpoint:IWG 2000 responses with hematological normalization

(CR+PR+trilineage HI)

Azacitidine SC 50 mg/m2 x 10 days every 28 days, plusEntinostat (MS-275) 4 mg/m2 PO days 3 and 10 each cycle

Randomize 1:1

E1905 enrolled patients

Number enrolled150 (137 eligible, 136

evaluable)

Median age 72 years

Diagnosis:

MDS n=88

CMML n=5

AML n=43

IPSS Int-2/High 72%

Poor risk

cytogenetics31%

Prebet T et al, ASH 2010, Abstract #601

E1905 study results

Response / AE

Arm A

(azacitidine

monotherapy)

Arm B

(combination therapy)

Complete response (CR) 12% 7%

Partial response (PR) 9% 7%

Trilineage hematological

improvement (tHI)10% 10%

Qualifying Response

(CR+PR+tHI)31% 24% (p=NS)

Other hematological

improvement12% 19%

Any response 43% 44%

Grade IV

thrombocytopenia44% 63% (p=0.07)

Grade III/IV fatigue 13% 23% (p=0.13)

Comparator -- CALGB 9221 study: CR + PR + trilineage HI rate = 15%

Prebet T et al, ASH 2010, Abstract #601

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Phase II Study of

5-azacytidine and vorinostat in patients with newly

diagnosed MDS or AML not eligible for clinical trials

because poor performance or presence of other

comorbidities

Guillermo Garcia-Manero, Elihu Estey, Elias Jabbour, Tapan Kadia,

Zeev Estrov, Jorge Cortes, Ross Levine, Hui Yang, Pat Boone and

Hagop Kantarjian

Department of Leukemia, University of Texas MD Anderson Cancer

Center; Fred Hutchinson Cancer Research Center, and Memorial Sloan

Kettering Cancer Center

ASH 2010 Abstract #604

AZA + SAHA: Patient eligibility

• Untreated MDS (≥ Int-1) or AML

• And any of the following:

• Total bilirubin ≥ 2 mg/dL

• Creatinine ≥ 2 mg/dL

• ECOG performance status > 2

• Excluded from any other clinical trial

Dose and schedule:

AZA 75 mg/m2 IV QD days 1 to 5

SAHA 200 mg PO TID days 1 to 5

Cycles repeated every 28 days

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AZA+ SAHA: Patient Characteristics

Characteristic Total N=27

Median age (range)

Median % BM blasts (range)

69 (44-83)

20 (2-62)

Diagnosis (%)

AML

MDS

9 (33)

18 (66)

Median (range)

Total bilirubin

Creatinine

1.1 (0.1-4.2)

1.2 (0.5-2.9)

WBC 14 (1.4-123)

Cytogenetics (%)

Diploid

Unfavorable

N eligible for “creatinine”

N eligible for “Total Bili”

N eligible for “malignancy”*

N eligible other*

7 (25)

20 (75)

4 (14)

3 (11)

10 (37)

10 (37)

*Metastatic sarcoma, met ovarian, met breast ca (3), prostate ca, CLL(2),

NHL (2), GBM, liver cirrhosis (2), CHF (2), COPD, bone dx

AZA + SAHA

Non-Hematological Toxicity(N=24, courses= 48)

Toxicity

(Any Grade)Course 1 Course 2

Diarrhea 7 3

Nausea/Vomiting 6 4

Constipation 4

Fatigue 3 2

Hepatic 3

Rash 1

No Pts

AZA+ SAHA: Complete Responses

N CR OR %

Median Courses

to Response

(range)

Evaluated: 15 7 46 2 (1-9)

Stopping rule for CR: 4 CR in 30 achieved by patient # 8

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Novel Agents

Evaluation of Oral Azacitidine

Using Extended Treatment

Schedules: A Phase I Study

(Abstract 603)

G. Garcia-Manero, S.D. Gore, C.R. Cogle, E.J. Jabbour, M.R. Ward, K.J. MacBeth, E. Laille, H.

Giordano, H.M. Kantarjian, and B.S. Skikne

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Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA;

The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA;

University of Florida, Gainesville, FL, USA; Celgene Corporation, Summit, NJ, USA

Extended dosing oral azacitidine in MDS:

phase I

Design and patients

Eligibility:

Age ≥18 with MDS, CMML, or AML

Hb ≤9 g/dL or platelets <50 x 109/L

No prior azanucleoside therapy

Garcia-Manero et al, ASH 2010 Abstract #603

Starting dose: 300 mg QD or 200 mg BID for 14/28 or 21/28 days

Cohorts of 6, DLT assessment after Cycle 1

Enrolled patients thus far: 25 (14 M : 11 F), median age 68 (range 44-87)

MDS (n=13)

AML (de novo, n=7; post-MDS, n=3)

CMM: (n=2)

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Extended dosing oral azacitidine in MDS:

phase I

Results

Garcia-Manero et al, ASH 2010 Abstract #603

Adverse events:

2 DLTs (grade 3 N/V) in patients on 14 days QD dosing

No DLTs yet on 21 days QD, 14 day BID, 21 day BID

No dose escalation/MTD definition yet

Rate of febrile neutropenia highest with 21-day QD cohort

PK: mean first/last day drug exposure 26-58% of historically expected SC drug

exposure (AUC)

Updated response data at meeting on 15 MDS patients:

CR in 2/15 (IWG 2006 criteria)

Any HI in 6/14

RBC transfusion freedom in 3/5

Townsend DM et al Oncogene 2003;

Steensma D Hem/Onc Clin N America 2010

Phase I/II Study of Intravenous

Liposomal TLK199 in MDS

• n=54

• Responses:

– Trilineage responses in 4/16 pts (25%) with

pancytopenia

– HI-E in 9/38 (24%) anemic pts

– HI-N in 11/26 (42%) neutropenic pts

– HI-P in 12/24 (50%) thrombocytopenic pts

• Adverse events:

– Most mild & attributable to liposomal preparation (e.g.

back pain, chills, nausea, bone pain, and diarrhea)

Raza A et al J Hematol Oncol 2:20, 2009

Liposome

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Phase I Study of Oral TLK199

(Ezatiostat) in MDS• n=45, IPSS Low to INT-2, median age 71

• Starting dose 200 mg

• Up to 6,000 mg/day ezatiostat divided into 2 doses days 1-7 out of 21-day cycle was tolerated, without a DLT

• 17/45 (38%) had His by IWG 2000, most (11) at higher end of dose range (≥4 g/day)– 6/29 HI-E, 4/19 HI-N, 7/21 HI-P

• Adverse events (all grade ½):– nausea (65%)

– diarrhea (43%)

– vomiting (31%)

– constipation (13%)

– abdominal pain (9%)

Raza A et al Blood 113:6533, 2009

Ongoing Phase II TLK199 Study

• n=86, 36 participating centers

• Eligible: De novo IPSS Low/Int-1 MDS

• Endpoint: HI-E (primary)

• Schedule 1: Ezatiostat 4500 mg/day in 2 divided doses PO for 2 weeks on, 1 week off

• Schedule 2: Ezatiostat 4500 mg/day in 2 divided doses PO for 3 weeks on, 1 week off

• Clinicaltrials.gov identifier NCT00700206

Phase 2 Randomized Multicenter Study of

Extended Dosing Schedules of Oral Ezatiostat

HCl (Telintra), a Glutathione Analog Prodrug

GSTP1-1 Inhibitor, In Low to Intermediate-1

Risk Myelodysplastic Syndrome (MDS)

(Abstract 2910a)

Azra Raza, Naomi Galili, Scott Smith, John E. Godwin, Ralph Boccia, Han Myint, Daruka Mahadevan, Deborah Mulford, Mark Rarick, Mary Ann Allison, Ostap Melnyk,

Lisa Meng, Marsha Jones, Gail Brown, Shelby A Young, and Mikkael A. Sekeres

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Phase 2 Oral Ezatiostat

Response Type

3000 mg/day

2 wks on/1

wk off

(n=30)

2000 mg/day

3 wks on/1

wk off

(n=31)

Total

(n=61)

HI–E (%) (95% CI) 7 (24) (10–44) 6 (19) (8–38) 13 (22) (12–34)

HI–N (%) (95% CI) 1 (10) (0–45) 3 (27) (6–61) 4 (19) (5–42)

HI–P (%) (95% CI) 1 (7) (0–34) 0 (0) (0–25) 1 (4) (0–19)

Bilineage (HI-E and HI-N) (%) (95% CI) 1 (11) (0–48) 3 (27) (6–61) 4 (20) (6–44)

Trilineage (HI-E, HI-N, and HI-P) (%) (95% CI) 1 (17) (0–64) 0 (0) (0–52) 1 (9) (0–41)

Median Time (Weeks) to HI-E Response (Range) 8 (8–10) 8 (8–11) 8 (8–11)

Median Duration (Weeks) of HI-E Response

(Range)

18 (2–51) 46 (2–63) 34 (2–63)

# of RBC Transfusion Dependent Patients (%) 20 (69) 18 (58) 38 (63)

RBC Transfusions Reduced by 4U/8wks (%) (95%

CI)6 (30) (12–54) 5 (28) (10–54) 11 (29) (15–46)

RBC Transfusion Independence (%) (95% CI) 1 (5) (0–25) 3 (17) (4–41) 4 (11) (3–25)

Raza et al. Blood 2010;116:2910a

Steensma HemOncClin NA 2010

IV Clofarabine MDS Study

• Eligible: MDS or CMML with either >5% blasts or IPSS Int-2/High risk

• Treatment: Clofarabine, either 15 or 30 mg/m2/day IV for 5 consecutive days, repeat every 4-6 wks

• Patients: 58 patients enrolled– 40% >70 years old

– 74% with IPSS Int-2/High risk disease

– 60% had tried azacitidine or decitabine or both

– 26% had a prior malignancy

– 1 RA, 15 RAEB-1, 26 RAEB-2, 9 CMML,7 RAEB-t

Jabbour E et al ASCO 2010; abstract 6504

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IV Clofarabine in MDS: Results

Jabbour E et al ASCO 2010; abstract 6504

Overall

(n=58)

15 mg/m2

dose

(n=37)

30 mg/m2

dose

(n=21)

Any

response21 (36%) 15 (41%) 6 (29%)

CR (%) 15 (26%) 10 (27%) 5 (24%)

HI (%) 6 (10%) 5 (14%) 1 (5%)

Died by 8

weeks11 (19%) 5 (14%) 6 (29%)

Alive at one

year37% 37% 38%

IV Clofarabine in MDS: Adverse

Effects

• Common:

– Nausea/vomiting

– Diarrhea

– Skin rash

– Liver test abnormalities

• Serious (grade 3 or 4):

– Infections (45%, more common with higher dose)

– Renal failure (6 patients, 4 with higher dose)

Preliminary Results of Fixed-Dose Oral Clofarabine (CLO)

In Patients Who Have Failed Hypomethylating Agents for

the Treatment of Myelodysplastic Syndromes (MDS)

(Abstract 1869)

Mikkael A. Sekeres, Gail J. Roboz, Olatoyosi Odenike, Edward Agura, Bayard L. Powell,

Reginald Ewesuedo, Michael J. Vasconcelles, Stefan Faderl, and Hagop Kantarjian

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Oral Clo for Patients Failing Hypomethylating

Agents

Sekeres et al. Blood 2010;116:1869a.

Oral Clo for Patients Failing

Hypomethylating Agents

Sekeres et al. Blood 2010;116:1869a.

ON 01910.Na - Multikinase Inhibitor

ON 01910.Na

Multikinase inhibitor

Polo-like kinase 1 modulator?

PI3K/Akt/ERK pathway inhibitor

Induces Bim, inhibits Mcl-1

activation

Reduces cyclin D1 levels

Barr F et al Nature Reviews Molecular Cell Biology 2004; 5: 429-441

Cell-cycle functions and localizations of Plk1

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ON 01910.Na Development History

Source: http://www.onconova.com/on01910na.shtml

= Ongoing MDS/AML study recruiting pts per clinicaltrials.gov

“ON 01910.Na Suppresses Cyclin D1 Accumulation in trisomy 8 Myelodysplastic Syndromes Patients

While Decreasing Bone Marrow CD34+ Blast Counts

and Aneuploid Clone Size”

• Ongoing studies – NIH (9) and St Vincents (6)

• 15 pts with treatment-refractory IPSS Int-1 to High risk MDS or AML (2 AML; 7 with trisomy 8)

• (13 pts at St Vincents reported in another abstract)

• Escalating doses: – 800 mg/m2/day over 48 hours continuous IV 3 weeks out of 4 up to

– 1500 mg/m2/day over 48 hours continuous IV 3 weeks out of 4

• Most common AEs: cytopenias, nausea, fatigue

• Responses:– StV: One patient RBC transfusion-independent x 14 mos, one

patient with neutrophil response; 2/6 pts with increased blasts reduced (2 progressed, 2 stable)

– NIH: 1 HI-E, 2 HI-N, 2 bilineage responses

Sloand E et al ASH 2009 Abstract #120

Raza A et al ASH 2009 Abstract #3815

Aneuploidy During ON 01910.Na

Treatment

80

10

50

1917

4

15 1310

562

510

10

20

30

40

50

60

70

80

90

Baseline After 4-8 weeks of

treatment

% a

neu

plo

idy

Blast Proportion During ON

01910.Na Treatment

1 2

13

2

30 30

3 333 2

25

11

35

9

5

10

2

15

20

0

5

10

15

20

25

30

35

40

Baseline After 4-8 weeks of

treatment

% a

neu

plo

idy

Sloand E et al ASH 2009 Abstract #120

Raza A et al ASH 2009 Abstract #3815

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Predicted Probability of Response (PPR)

to Immunosuppressive Therapy in MDS

HLA DRB15 - HLA DRB15 + PPR

>57 >71 Low (0-40%)

≤57 ≤71 High (41-100%)

Age of the patient (years) +

Duration of transfusion dependence (months)

PPR Total Response No Response

Low (0-40%) 14 1 (7%) 13 (93%)

High (41-100%) 9 6 (67%) 3 (33%)

Validation Cohort (n=23)

Saunthararajah Y et al Blood 2003 102(8):3025-7

Phase II: Alemtuzumab in

IPSS Int-1/Int-2 MDS With High PPR For

Immunosuppressive Therapy

Sloand EM et al Abstract #116 - ASH 2009

Key Eligibility (goal n=39):

•De novo MDS with cytopenias and <5% blasts

•High likelihood (PPR) of IST response (using 2003 formula)

•No prior ATG/CSA

Regimen:

•Alemtuzumab (anti-CD52) test dose, then 10 mg IV/day x 10 days

•TMP/SMX and valgancyclovir prophylaxis

Results:

•Enrolled patients younger (median ~53 years old) and more hypocellular (45%)

than a typical MDS population

•IWG responses in 15/16 (93%) with Int-1 MDS, 2/5 (40%) with Int-2

•Cytogenetic remission in 5/7

•Transient EBV positivity in 4/22