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%