STN 125011

Tositumomab Therapeutic

Regimen (TTR)[tositumomab plus I-131 tositumomab]

Oncologic Drugs Advisory Committee

December 17, 2002

Proposed Indication

Treatment of Patients with Relapsed or Refractory, Low-Grade, Follicular, or Transformed Low-Grade Non-Hodgkin’s Lymphoma (NHL) including Patients with Rituximab-Refractory Follicular NHL

OVERVIEW OF CLINICAL STUDIESEfficacy

• Study RIT-II-004 - The primary efficacy trial supporting the request for accelerated approval for the treatment of chemotherapy-refractory patients with low grade and follicular NHL, with or without transformation.

OVERVIEW OF CLINICAL STUDIES Efficacy

• Study CP97-012 : The primary efficacy trial supporting standard approval for the treatment of Rituximab-refractory patients with follicular NHL.

OVERVIEW OF CLINICAL STUDIES Efficacy

• Three additional studies provide supportive anti-tumor activity data for the proposed indications.

• RIT-II-002 - controlled Phase 2 study

• RIT-II-000 & 001 are single-arm trials

Study RIT-II-004Trial Design

• multicenter• historically-controlled • single-arm• patients w/ chemotherapy-

refractory low grade or follicular NHL

• with or without transformation

Study RIT-II-004Analytic Plan (Final)

• Primary Efficacy Endpoint –– proportion of patients with longer

duration of response after TTR vs. proportion with longer duration of response after Last Qualifying Chemotherapy (LQC) regimen

– based on MIRROR Panel assessment

Study RIT-II-004 Analytic Plan (Final)

• Secondary Efficacy Endpoints – overall response rate

– complete response rate

– duration of response

– time to progression

– survival

Study RIT-II-004

• Study population consisted of 61 patients enrolled at 8 centers

• FDA analyses include 1 patient who withdrew consent and did not receive either dosimetric or therapeutic dose

RIT-II-004

Among the 61 patients registered:

• 7 (11%) responded to LQC

• 1 (2%) achieved CR/CCR to LQC

• Median duration of response - 4.1 months (range 3.0-5.4 months)

Study RIT-II-004 MIRROR-Assessed Response 

 

Response to TTR

No Response

to TTR

Total

Response to LQC 3 4 7

No Response to LQC

25 29 54

Total 28 33 61

Study RIT-II-004Primary Endpoint Analysis

• Equivalent duration

• Longer duration of response after

TTR (>30 days longer) than after

LQC

• Longer duration of response after

LQC than after TTR

Study RIT-II-004Primary Endpoint Analysis 

 

Response to TTR

No Response

to TTR

Total

Response to LQC 2 TTR

1 LQC4 LQC

2 TTR 5 LQC

No Response to LQC

25 TTR 29 = 54

Total27 TTR

1 LQC33 61

Study RIT-II-004Primary Endpoint Analysis

Response Frequency % of 61 ---------------------------------------------------------------------- Equivalent duration 29 48% Longer response w/ TTR 27 44%

Longer response w/ LQC 5 8%

Significant by McNemar’s and by sign-rank test

Study RIT-II-004

Secondary Endpoints

ORR46%

(28/61)

Median Duration ORR

in months (95% CI)

11.7

(6.9, NR)

CR/CCR20%

(12/61)

Median Duration CR/CCR in months (95% CI)

NR

(12.5, NR)

Study CP97-012Design

• Single‑arm, multicenter• Conducted in patients who had

relapsed after 1 course(s) of Rituximab

• Endpoints: ORR, CR+CCR, response duration, time to progression, time to treatment failure, and survival.

Study CP97-012

Population/Subpopulations• Registered n = 43• Treated n = 40• “Indicated” Population

– follicular NHL – Rituximab response duration

of < 6 mos n = 30

Study CP97-012 Registered (n=43)

Outcome Investigator

Assessment

MIRROR

Assessment

ORR 60% 63%

Median Resp duration

1.9 yrs 1.3 yrs

CR/CCR 33% 31%

Study CP97-012 “Indicated” subpopulation (n=30)

Outcome Investigator

Assessment

MIRROR

Assessment

ORR 60% 63%

Median Resp Duration

NR 2.1 yrs

CR/CCR 37% 26%

Study CP97-012Exploratory Analysis of efficacy by

responsiveness to Rituximab

OutcomeRituximab

Responsive

(n=18)

Rituximab Unresponsive

(n= 25)

ORR61%

(11/18)

64%

(16/25)

Median Response Duration 2.1 yrs 1.3 yrs

Supportive studies

• RIT-II-002

• RIT-II-001

• RIT-II-000

Study RIT-II-002Design

• Two-arm

• Open-label

• Multi-center

• Randomized (not stratified)

• Chemotherapy-relapsed or refractory

• Low-grade, follicular, or transformed low-grade NHL

Study RIT-II-002Design

• Treatment Arms– Arm A –TTR (hot arm)– Arm B – unlabeled Tositumomab

antibody (cold arm)

• Endpoints: – 1 CR/CCR– 2° ORR, response duration, TTP, and

toxicity profile

Study RIT-II-002

• 78 patients enrolled– 42 in arm A– 36 in arm B

• Prognostic variables similar except for– 7% intermed. histology in A vs. 17% B– 10% high IPI in Arm A vs. 3% in Arm B– 52% 5 cm lesions Arm A vs. 34% Arm B

Study RIT-II-002

Outcome Arm A(n=42)

Arm B(n=36)

P-value

CR/CCR 33%(14/42)

8%(3/36)

ORR 55%(23/42)

19%(7/36)

Median resp. duration

NR 2.3 yrs

Median CR duration

NR NR

Median TTP or death

0.52 yrs 0.45 yrs

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0%

Res

pond

ers

0 1 2 3 4 5

Duration of Response (Years) - RIT-II-002

Arm A (Hot)

Arm B (Cold)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0%

No

t P

rogr

essi

ng

0 1 2 3 4 5

Years to Time to Progression - RIT-II-002

Arm A (Hot)

Arm B (Cold)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0%

Sur

vivi

ng

0 1 2 3 4 5

Years to Survival-RIT-II-002

Arm A (Hot)

Arm B (Cold)

Survival in Years RIT-II-002

Study RIT-I-000

• Single-center, dose escalation study • to determine

– the optimal biologic dose of cold antibody

–MTD for TTR in patients with and without prior BMT

• 59 patients were enrolled• 22 patients without prior BMT were

treated at the MTD

Study RIT-II-001

• Multicenter, single arm study to assess reproducibility of dosimetry methods across clinical sites

• 47 patients enrolled

Overview of Study Results

Study004

(n=61)

012

(n=43)

002

(n=42)

001

(n=47)

000

(n=59)Median # prior chemo (range)

4 (2-13) 4 (1-11) 2 (1-4) 4 (1-8) 3 (1-11)

ORR46%

(33%, 59%)

63% (47%, 77%)

55% (39%, 70%)

49% (34%, 64%)

48% (34%, 61%)

CR/CCR 20% 30% 33% 30% 27%

Median Duration response

1.0 yrs 1.3 yrs NR 1.0 yrs 1.2 yrs

Pooled Subset Analyses

• Long-term responders– Submitted by sponsor to show that TTR

provides “a meaningful therapeutic benefit over existing treatments” in support of accelerated approval

• Low-Grade Transformed NHL– Analyses requested by FDA to assess

for differences in activity in transformed vs. non-transformed since results include both types of patients

Long-Term Responders• Defined as responding patients with

TTP 1 year per MIRROR review

• 76/271 (28%) patients identified by MIRROR

• 68/271 who rec’d a single dosimetric and any therapeutic dose

• Patients retrospectively identified across 5 efficacy/activity studies (n=271)

Long-term responders (n=68)

• CR/CCR - 54 of 68 (79%)

• PR - 14 of 68 (21%)

• Median response duration 4.9 years (range from 0.9 to 7.8+ years)

Study entry variable

Long term responders

(n= 68)

Patients w/o long term response

(n=203)

LQC end day to study entry day (yrs; 95% CI)

1.0

(0.8, 1.2)

0.4

(0.4, 0.6)

Response to LQC• CR + CCR• PR

23 (34%)

25 (37%)

30 (15%)

62 (31%)

Duration of response to LQC (yrs; 95% CI)

0.6

(0.5, 0.9)

0.4

(0.3, 0.5)

Tumor Grade:• Low• Intermediate

58 (85%)

10 (15%)

130 (64%)

68 (33%)

Low Grade NHL w/Transformation

• 71 of 271 (26%) patients across 5 efficacy studies with evidence of transformed histology

• FDA reviewed and confirmed sufficient info to document transformation in 40 of the 59 (remaining 12 under review)

Low Grade NHL w/Transformation

• ORR 40% (16/40)

• CR/CCR 26% (11/40)

• Median response duration 1.6 years (range 0.1+ to 4.9 years)

Safety Summary

• Hematologic-acute– Neutropenia/lymphopenia: Infections– Thrombocytopenia: Hemorrhagic events

• Infusional reactions• Gastrointestinal toxicity• Immune responses to murine protein• Delayed toxicity due to irradiation

– Hypothyroidism– Secondary leukemias, myelodysplasia,

other cancers

Safety Database

• Safety data provided for 620 patients • 229 patients enrolled in 5

efficacy/activity studies (RIT‑I‑000, RIT-II-001, RIT‑II‑002, RIT‑II‑004 and CP‑97‑012)

• 391 patients treated under expanded access experience in Protocol CP-98-020 and 4 sponsor-investigator INDs

Safety DatabaseProtocol # Enrolled # ISS-A # ISS-B

RIT-I-000 59 22 0

RIT-II-001 47 47 0

RIT-II-002 42+36 (19) 42+19 0

RIT-II-004 61 59 0

CP-97-012 43 40 0

CP-98-020 464 0 387

Single Pt 6 0 4

RIT-II-003 77 0 0

Total 854 229 391

Safety Database

• Safety profile in 5 efficacy/activity studies (n=229, ISS-A) showed a higher incidence for adverse events in the first 13 weeks vs. expanded access (n=391, ISS-B)

• Less comprehensive collection of data in expanded access and no monitoring

• Underreporting of AEs in expanded access confirmed during inspection

Incidence of AEsPreferred

Term

ISS-A Any Grade

ISS-B Any Grade

ISS-A Gr 3-4

ISS-B Gr 3-4

Asthenia 46% 24% 2% 3%Fever 37% 13% 2% 2%

Nausea 35% 19% 3% 1% Cough 21% 6% < 1% < 1%Infection 21% 5% < 1% 1%

Pain 19% 11% 1% 2%Chills 18% 9% 1% < 1%

Rash 17% 8% < 1% 0%

Incidence of AEs

Preferred Term

ISS-A Any

Grade

ISS-B Any

Grade

ISS-A Gr 3-4

ISS-B Gr 3-4

Headache 16% 7% 0% < 1%

Abdominal Pain

15% 6% 3% 1%

Vomiting 15% 8% 1% < 1%

Anorexia 14% 6% 0% < 1%

Myalgia 13% 7% < 1% < 1%

Diarrhea 12% 7% 0% < 1%

Incidence of SAE

Preferred Term ISS-A (n=229)

ISS-B (n=391)

Myeloproliferative Disorder

17 (7%) 1 (<1%)

Fever 9 (4%) 1 (<1%)

Sepsis 7 (3%) 1 (<1%)

Pneumonia 6 (3%) 1 (<1%)

Dyspnea 5 (2%) 1 (<1%)

Pleural Effusion 5 (2%) 1 (<1%)

Acute Hematologic Toxicity

• Complete blood counts were to be collected at least weekly beginning at week 3 until – recovery from nadir – removal from study

• Patients with missing data during the period of expected nadir (weeks 5-9) or at recovery (week 13) were assigned worst toxicity in “Worst case scenario” analyses

Acute Hematologic Toxicity

ANC

n=229

Platelets

n=229

Hgb

n=229

Gr 3-4 toxicity 51% 42% 15%

Gr 3-4 toxicity worst case

64% 54% 29%

Gr 4 toxicity 21% 18% 4%

Gr 4 toxicity

worst case25% 22% 4%

Acute Hematologic Toxicity

ANC

n=229

Platelets

n=229

Hgb

n=229

Median days to nadir (gr 3-4)

43 34 47

Median days of

Gr 3-4 (Q1; Q3)30 (22; 43)

30 (22; 51)

19 (14; 34)

90th percentile 62 days102

days40

days

Maximum observed

383+ 211 78

Lymphopenia in RIT-001 & 003

CD20 (cells/l)

Wk 0 (n=125)

Wk 7 (n=111)

Wk 13 (n=74)

M 6 (n=57)

M 12 (n=14)

25th Quartile

63 0 0 19 42

Median 118 2 13 49 101

75th Quartile

196 14 38 100 177

Infections/Fever

Fever

• 37% (84 patients)• 19% (43 pts) study day 14• 7-8% (15 pts/3 missing) fever

associated with neutropenia

Infectious Events

Pooled preferred terms Per-patient incidence

# of events

Infection pharyngitis

Pneumonia bronchitis

H. Zoster UTI

Sepsis sinusitis

H. simplex cellulitis

fungal dermatitis periodontal abscess

(43%)

98/229

149

Hemorrhagic Events

Pooled preferred terms

Per-patient incidence

# of events

Epistaxis Ecchymosis

Melena GI hemorrhage

Hemoptysis Gum hemorrhage

Lung hemorrhage

12%

(28/229)

31

Transfusions Support & Growth Factor Use

ISS-A

• 16% (36/229) rec’d RBC transfusions

• 15% (35/229) rec’d platelet transfusions

• 12% (28/229) rec’d G-CSF/GM-CSF– Median duration of use 16 days (Q1=9; Q3=34)

• 7% (16/229) rec’d Epoetin alfa– Median duration of use 52 days (Q1=32; Q3=123)

Infusional Toxicities

• “Symptom-complex” primarily consisting of fever, asthenia, nausea/vomiting and/or diarrhea, chills, pain & headache, pharyngitis, rhinitis & cough, hypotension, myalgias/arthralgias, and rash

Infusional Toxicities

• Dosimetric dose (day 0-7)– 55% (125/229) patients with 1 AE– 309 events reported

• Therapeutic dose (day 8-14)– 46% (105/229) patients with 1 AE– 222 events reported

Gastrointestinal Toxicities

• Biodistribution studies demonstrated uptake in Waldeyer’s ring & GI tract due to binding to normal CD20+ cells

• Both acute (per-infusional) and delayed toxicities throughout the GI tract were reported

• Acute toxicities were also observed with unlabeled antibody (Arm B in RIT-II-002)

Gastrointestinal Toxicities

Pooled preferred termsIncidence

# of events

UGINauseaVomitinggastrointestinal disorderintestinal obstruction

38%

(86/229)136

LGI Diarrheaabdominal painabnormal stoolsGastroenteritisintestinal perforationulcerative colitis & colitis

24%

(55/229)78

Thyroid (TSH) Evaluation ISS Population N = 620

Available TSH value after treatment

362

Elevated TSH after treatment 34

Median Time to TSH Elevation (months)

10.9

95% CI on Median (months) 6.0, 13.6

Range (Months) 1.8, 76.3

Percent Elevated TSH by Months Censored at the Last available TSH Value (Cumulative)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

Cum

ulat

ive

Perc

ent E

leva

ted

TSH

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84 87 90 93 96

Months for the Last TSH Value or first elevated TSH from dosimetric dose

95% UCI

95% LCL

% Elevated

HAMA Evaluation(Site or Central Assay)

ISS Population N = 620

HAMA negative at baseline 604

At least one f/u assessment 515

HAMA positive 51

Median time to HAMA + (Days) 96

Range (Days) 5 - 446

Percent HAMA positive (Site or Central) by Months Censored at the Last available HAMA Value (Cumulative)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Perc

ent C

um

ula

tive H

AM

A Incid

ences

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Months from Dosimetric Dose to any (Site or Central) HAMA positivity

95% UCL

95% LCL

% HAMA +

HAMA Evaluation in RIT-II-003

• 77 patients with previously untreated low grade NHL enrolled

• At baseline

– 73 negative, 3 positive, 1 no data

• After treatment - 54 (70%) patients were HAMA seropositive

• Median time to seropositivity for HAMA 27 days (95% CI 23; 202 days)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0%

HA

MA

+

0 1 2 3 4 5

Years to HAMA+ RIT-II-003

95% UCL

95% LCL

MYELODYSPLASIA or ACUTE LEUKEMIA (MDS or AML)

Study N # MDS/ AML

% MDS/ AML

Median Yrs to MDS/AML

RIT-I-000 22 5 23% 3.9

RIT-II-001 47 5 11% 1.8

RIT-II-002 61 3 4.9% 1.2

RIT-II-004 59 4 6.8% 2.7

CP-97-012 40 1 2.5%

CP-98-020 387 1 0.3%

Total 620 19 3.1% 2.1

Percent of MDS/AML Incidence by Year

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

% R

epor

ted

Inci

denc

e

.0 .5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5

Years to MDS/AML

95% UCL

95% LCL

Efficacy Summary

• Primary efficacy trial in 61 chemo-refractory patients demonstrated significantly higher proportion of patients with longer duration of response following the TTR as compared to last chemotherapy

• ORR 46% • CR/CCR 20%• Median response duration 11.7 months

Efficacy Summary

• Primary efficacy trial in 30 Rituximab refractory patients with follicular NHL demonstrated

• ORR 60%

• CR/CCR 30%

• Median response duration 2 yrs

Efficacy Summary

Supportive studies showed

• ORR from 48% - 63%

• Median durations of response from 1.0-1.3 years

• CR/CCR from 27% - 33%

Safety Summary

Hematologic toxicity – 60-71% incidence of any grade 3-4

hematologic toxicity, median duration 30 days

– Profound and prolonged B-cell lymphopenia

– 43% incidence of infectious events– 12% incidence hemorrhagic events

Safety Summary

• Symptom complex of infusional toxicities, comprised of fever, chills, nausea, asthenia, rash in 50% of patients

• Clinical and serologic immune responses – 20% cumulative incidence of HAMA at 18

months in heavily pretreated patients 70% cumulative incidence of HAMA in

chemotherapy -naïve patients at 18 mos– Clinical sequelae (anaphylactoid reactions and

serum sickness infrequently observed)

Safety Summary

• Hypothyroidism- – an observed 30% cumulative rate

of TSH elevation at 5 years

– an observed 45%cumulative rate of TSH elevation at 7 years

Safety Summary

• Leukemias and myelodysplasia observed with increasing cumulative incidence (23% in study with longest follow-up)

• Across all studies, incidence is 3% with median time to MDS/AML of 2.1 yrs

Response–RIT-II-004 (n=61)

Response Category LQC Investigator

LQC MIRROR

I-131 MIRROR

Complete Response (CR) 1 1 7

Complete Clinical Response (CCR)

1 0 5

Partial Response (PR) 15 6 16

Stable Disease (SD) 23 5 4

Progressive Disease (PD) 21 49 29

RIT-004 Subset AnalysisTransformed vs Non-

transformedResponse Category

Response Rate in Subset without Transformation

Response Rates in Subset with

Transformation

CR13% (5/38)

13%(3/23)

CCR11% (4/38)

0 %(0/23)

PR37%

(14/38) 8%

(2/23)

ORR61%

(23/38)21% (5/23)

SD8%

(3/38)4%

(1/23)

PD32%

(11/38)74%

(17/23)

Study CP97‑012

• Analyses of time to progression, time to treatment failure, and survival are not provided by FDA, because these data cannot be interpreted in a study that does not contain an internal control population.

Response Rates & Duration CP-97-012

IIT-Inves

N=43

IIT-MIR.

N=43

Treat

Inves

N=40

Treat

MIR

N=40

Indic-

Inves

N=30

Indic-

MIR

N=30

ORR

(%)

60 63 65 68 60 63

Median Duration

(Years) 1.9 1.3 1.0 1.3 NR 2.1

Response Rates CP-97-012

IIT-Inves

N=43

IIT-MIR.

N=43

Treat

Inves

N=40

Treat

MIR

N=40

Indic-

Inves

N=30

Indic-

MIR

N=30

CR (%) 14 26 15 28 17 23

CCR (%) 19 5 20 5 20 3

PR (%) 28 33 30 35 23 37

Response rate to I-131 in subsets of based on prior response to rituximab

 Prior response to most recent Rituximab regimen

Response to the I-

131 regimen 

Median Duration of

response to I-131

Rituximab-responsive (CR, CCR, or PR)

11/18 (61%)

2.1 years

Rituximab non-responsive(PD OR SD)

16/25 (64%)

1.3 years

Efficacy Results - RIT‑II‑002 -- MIRROR Panel–Assessed Outcomes

Efficacy EndpointArm A(N = 42)

Arm B(N = 36) P‑value

     

Complete response (CR+CCR)

14/42 (33%)

3/36 (8%)

0.01

Secondary endpoints      

Overall Response 23/42(55%)

7/36 (19%)

0.001

Median duration (yrs) of response (95% CI)

NR (0.5–NR)

2.3 (0.4, NR )

0.9

Median duration (yrs) of CR (95% CI)

NR (NR, NR)

NR (2.3, NR)

0.4

Median time to progression or death (yrs) (95% CI)

0.52 (0.35, NR)

0.45 (0.24, 0.5)

0.031

Duration of durable response over years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Perc

ent D

ura

ble

Response

1 2 3 4 5 6 7 8

Duration of Response in Years for Durable Responders (n=78)

95% UCI

95% LCI

Median = 4.9 Years

ISS PopulationProtocol # Enrolled # ISE # ISS-A # ISS-B

RIT-I-000 59 59 22 0

RIT-II-001 47 47 47 0

RIT-II-002 42+36+19 42+19 42+19 0

RIT-II-003 77 0 0 0

RIT-II-004 61 61 59 0

CP-97-012 43 43 40 0

CP-98-020 464 0 0 387

Single Pt 6 0 0 4

Total 854 271 229 391

Grade 3-4 Hematologic Toxicity

Neutropenia ISS-A (n=229)

ISS-B (n=391)

% Documented Grade 3-4 toxicity

51% 37%

Median days to nadir

(95% CI)

43

(42, 46)

42

(42, 43)

25th and 75th percentiles for days to nadir

39 ; 49 37; 50

Median duration of documented Grade 3-4 toxicity

30

(22, 43)

30

(24, 36)

25th and 75th percentiles for duration of toxicity (days)

21; 49 19; 54

Grade 3-4 Hematologic ToxicityThrombocytopenia ISS-A

(n=229)ISS-B (n=391)

% Documented Grade 3-4 toxicity

42% 33%

Median days to nadir

(95% CI)

34

(33, 35)

33

(31, 34)

25th and 75th percentiles for days to nadir

29; 40 28, 36

Median duration of documented Grade 3-4 toxicity

30

(28, 36)

29

(24, 29)

25th and 75th percentiles for duration of toxicity (days)

22; 51 22; 47

Grade 3-4 Hematologic Toxicity

Anemia ISS-A (n=229)

ISS-B (n=391)

% Documented Grade 3-4 toxicity

15% 9%

Median days to nadir

(95% CI)

47

(45, 49)

46

(43, 48)

25th and 75th percentiles for days to nadir

39; 60 35, 57

Median duration of documented Grade 3-4 toxicity

19

(15, 22)

17

(15, 31)

25th and 75th percentiles for duration of toxicity (days)

14; 34 15; 35

Grade 3-4 Hematologic Toxicity

Neutropenia &/or Thrombocytopenia

ISS-A (n=229)

ISS-B (n=391)

% Documented Grade 3-4 toxicity

59% 47%

% Grade 3-4 toxicity (worst case scenario accounting for missing values)

70% 61%

% Documented Grade 4 toxicity 26% 26%

% Grade 4 toxicity (worst case scenario accounting for missing values)

30% 30%

Study CP97-012 Treated/mITT (n=40)

Outcome Investigator

Assessment

MIRROR

Assessment

ORR 65% 68%

Median Resp duration

1.0 yrs 1.3 yrs

CR/CCR 35% 33%

Long-term Responders• Logistic regression analysis in 271 patients• Variables correlated with achieving a long-

term response:– Low grade histology at study entry – Objective response to LQC – Longer duration of response to LQC– Longer time between LQC & Study entry– Fewer prior prior chemotherapy regimens

Low Grade NHL w/Transformation

• Logistic regression analysis in 271 patients

• Variables correlated with confirmed histologic dx of transformation– Intermediate/high tumor grade at study entry – Shorter time between LQC and Study entry– Greater number of prior chemotherapy

regimens– Higher Ann Arbor Stage at study entry

Grade 3-4 Hematologic Toxicity

Neutropenia, Anemia &/or Thrombocytopenia

ISS-A (n=229)

ISS-B (n=391)

% Grade 3-4 toxicity 60% 48%

% Grade 3-4 toxicity (worst case scenario)

71% 62%

% Grade 4 toxicity 26% 23%

% Grade 4 toxicity (worst case scenario)

30% 26%

Timeline

• Sept 14, 2000- Original BLA– RIT-II-004- interim study report dated

5/31/2000– RIT-II-000 and 001- final study reports– RIT-II-002 and 003-interim study reports– ISS - 286 subjects

• Dec 14, 2000– CP98-020 interim study report– ISS - 308 subjects

Timeline

• August 27, 2001– RIT-II-003 second interim report through

12/20/2000– ISS update – 309 patients

• Sept 7, 2001– Final study report CP97-012– Amended study report RIT-II-002 -

MIRROR panel review, data cut-off Jan. 2001

Timeline

• Dec 11, 2001– RIT-II-004- amended final study report,

data cutoff Jan 2001, MIRROR panel review Sept 2001

– ISS update – 620 patients (includes 387 from expanded access)

– Long-term responders- various studies- MIRROR panel review

– Additional info for CP98-020

Timeline

• March 5, 2002– ISS update – 620 patients – additional

hematology data collected from audit at clinical study sites

• July 2, 2002– Case report forms and report

tabulations for long-term responder subpopulation

Timeline

• July 11, 2002– Revised proposed indication– Requested accelerated approval for

chemo-refractory and standard approval for Rituximab-refractory pts

– Amendment 1 to final study report for CP97-012

Timeline

• October 4, 2002– Amendment 2 to final study report for CP97-

012

• October 30, 2002– Independent review for additional patients with

transformed histology in CP 97-012

• December 10, 2002– Responses to BiMo inspectional findings

Study RIT-II-002 - Duration of Response

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Per

cent

Res

pond

ers

0 1 2 3 4 5

Bexaar MIRROR Assessed Duration of Response (Years) for RIT-II-002 Study

Arm A (Hot)

Arm B (Cold)

Study RIT-II-002 – Time to Progression or Death

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

% P

rogr

essi

ng

0 1 2 3 4 5

I-131 Anti-B1 Antibody Time to Progression or death in Years

Arm A (Hot)

Arm B (Cold)

Study RIT-II-002 – Overall Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Per

cent

Sur

vivi

ng

0 1 2 3 4 5

Survival in Years form Dosemetric Dose for RIT-II-002 Study (n=78)

Arm A (Hot)

Arm B (Cold)

Study RIT-II-004Exploratory subset analysis

Outcome without transformation

(n=38)

with transformation

(n=23)

ORR 60%

(23/38)

22%

(5/23)

CR/CCR 24%

(9/38)

13%

(3/23)

Incidence of AEsPreferred Term

AEISS-A Any

Grade (n=229)ISS-A Grade 3-4 (n=229)

ISS-B Any Grade (n=391)

ISS-B Grade 3-4 (n=391)

Headache 16% 0% 7% < 1%

Abdominal Pain

15% 3% 6% 1%

Vomiting 15% 1% 8% < 1%

Anorexia 14% 0% 6% < 1%

Myalgia 13% < 1% 7% < 1%

Diarrhea 12% 0% 7% < 1%