Stn 125011 tositumomab therapeutic regimen ttr tositumomab plus i 131 tositumomab
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STN 125011 Tositumomab Therapeutic Regimen (TTR) [tositumomab plus I-131 tositumomab]. Oncologic Drugs Advisory Committee December 17, 2002. Proposed Indication.

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Stn 125011 tositumomab therapeutic regimen ttr tositumomab plus i 131 tositumomab

STN 125011 Tositumomab Therapeutic Regimen (TTR)[tositumomab plus I-131 tositumomab]

Oncologic Drugs Advisory Committee

December 17, 2002


Proposed indication

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 studies efficacy
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 efficacy1
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 efficacy2
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 004 trial design
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 004 analytic plan final
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 final1
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 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
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
Study RIT-II-004 MIRROR-Assessed Response


Study rit ii 004 primary endpoint analysis
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 004 primary endpoint analysis1
Study RIT-II-004Primary Endpoint Analysis


Study rit ii 004 primary endpoint analysis2
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 cp97 012 design
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
Study CP97-012

Population/Subpopulations

  • Registered n = 43

  • Treated n = 40

  • “Indicated” Population

    • follicular NHL

    • Rituximab response duration

      of < 6 mosn = 30


Study cp97 012 registered n 43
Study CP97-012 Registered (n=43)


Study cp97 012 indicated subpopulation n 30
Study CP97-012 “Indicated” subpopulation (n=30)


Study cp97 012 exploratory analysis of efficacy by responsiveness to rituximab
Study CP97-012Exploratory Analysis of efficacy by responsiveness to Rituximab


Supportive studies
Supportive studies

  • RIT-II-002

  • RIT-II-001

  • RIT-II-000


Study rit ii 002 design
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 002 design1
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
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 i 000
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
Study RIT-II-001

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

  • 47 patients enrolled



Pooled subset analyses
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
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
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)


Low grade nhl w transformation
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 transformation1
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
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 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 database2
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





Acute hematologic toxicity
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





Infections fever
Infections/Fever

Fever

  • 37% (84 patients)

  • 19% (43 pts)  study day 14

  • 7-8% (15 pts/3 missing) fever associated with neutropenia




Transfusions support growth factor use
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
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 toxicities1
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
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)




Percent elevated tsh by months censored at the last available tsh value cumulative
Percent Elevated TSH by Months Censored at the Last available TSH Value (Cumulative)


Hama evaluation site or central assay
HAMA Evaluation available TSH Value (Cumulative(Site or Central Assay)


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


Hama evaluation in rit ii 003
HAMA Evaluation in RIT-II-003 at the Last available HAMA Value (Cumulative

  • 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)


Myelodysplasia or acute leukemia mds or aml
MYELODYSPLASIA or ACUTE LEUKEMIA (MDS or AML at the Last available HAMA Value (Cumulative)


Percent of mds aml incidence by year
Percent of MDS/AML Incidence by Year at the Last available HAMA Value (Cumulative


Efficacy summary
Efficacy Summary at the Last available HAMA Value (Cumulative

  • 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 summary1
Efficacy Summary at the Last available HAMA Value (Cumulative

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

  • ORR  60%

  • CR/CCR 30%

  • Median response duration 2 yrs


Efficacy summary2
Efficacy Summary at the Last available HAMA Value (Cumulative

Supportive studies showed

  • ORR from 48% - 63%

  • Median durations of response from 1.0-1.3 years

  • CR/CCR from 27% - 33%


Safety summary1
Safety Summary at the Last available HAMA Value (Cumulative

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 summary2
Safety Summary at the Last available HAMA Value (Cumulative

  • 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 summary3
Safety Summary at the Last available HAMA Value (Cumulative

  • Hypothyroidism-

    • an observed 30% cumulative rate of TSH elevation at 5 years

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


Safety summary4
Safety Summary at the Last available HAMA Value (Cumulative

  • 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–RIT-II-004 (n=61) at the Last available HAMA Value (Cumulative


Rit 004 subset analysis transformed vs non transformed

Response at the Last available HAMA Value (Cumulative

Category

Response Rate in Subset without Transformation

Response Rates in Subset with Transformation

CR

13%

(5/38)

13%

(3/23)

CCR

11%

(4/38)

0 %

(0/23)

PR

37%

(14/38)

8%

(2/23)

ORR

61%

(23/38)

21%

(5/23)

SD

8%

(3/38)

4%

(1/23)

PD

32%

(11/38)

74%

(17/23)

RIT-004 Subset AnalysisTransformed vs Non-transformed


Study cp97 0121
Study CP97‑012 at the Last available HAMA Value (Cumulative

  • 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
Response Rates & Duration CP-97-012 at the Last available HAMA Value (Cumulative


Response rates cp 97 012
Response Rates CP-97-012 at the Last available HAMA Value (Cumulative


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

Prior response to most recent Rituximab regimen at the Last available HAMA Value (Cumulative

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

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


Efficacy results rit i i 002 mirror panel assessed outcomes

Efficacy Endpoint at the Last available HAMA Value (Cumulative

Arm 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

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


Duration of durable response over years
Duration of durable response over years at the Last available HAMA Value (Cumulative


Iss population
ISS Population at the Last available HAMA Value (Cumulative


Grade 3 4 hematologic toxicity
Grade 3-4 Hematologic Toxicity at the Last available HAMA Value (Cumulative


Grade 3 4 hematologic toxicity1
Grade 3-4 Hematologic Toxicity at the Last available HAMA Value (Cumulative


Grade 3 4 hematologic toxicity2
Grade 3-4 Hematologic Toxicity at the Last available HAMA Value (Cumulative


Grade 3 4 hematologic toxicity3
Grade 3-4 Hematologic Toxicity at the Last available HAMA Value (Cumulative


Study cp97 012 treated mitt n 40
Study CP97-012 at the Last available HAMA Value (CumulativeTreated/mITT (n=40)


Long term responders1
Long-term Responders at the Last available HAMA Value (Cumulative

  • 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 transformation2
Low Grade NHL w/Transformation at the Last available HAMA Value (Cumulative

  • 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 toxicity4
Grade 3-4 Hematologic Toxicity at the Last available HAMA Value (Cumulative


Timeline
Timeline at the Last available HAMA Value (Cumulative

  • 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


Timeline1
Timeline at the Last available HAMA Value (Cumulative

  • 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


Timeline2
Timeline at the Last available HAMA Value (Cumulative

  • 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


Timeline3
Timeline at the Last available HAMA Value (Cumulative

  • 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


Timeline4
Timeline at the Last available HAMA Value (Cumulative

  • 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


Timeline5
Timeline at the Last available HAMA Value (Cumulative

  • 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
Study RIT-II-002 - Duration of Response at the Last available HAMA Value (Cumulative


Study rit ii 002 time to progression or death
Study RIT-II-002 – Time to Progression or Death at the Last available HAMA Value (Cumulative


Study rit ii 002 overall survival
Study RIT-II-002 – Overall Survival at the Last available HAMA Value (Cumulative


Study rit ii 004 exploratory subset analysis
Study RIT-II-004 at the Last available HAMA Value (CumulativeExploratory subset analysis


Incidence of aes2
Incidence of AEs at the Last available HAMA Value (Cumulative


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