FC RIIIa Receptor Polymorphisms Do Not Influence the Outcome of Treatment with Rituximab Followed by Active Immunotherapy with Mitumprotimut-T David

FCRIIIa Receptor Polymorphisms Do Not Influence the Outcome of Treatment

with Rituximab Followed by ActiveImmunotherapy with Mitumprotimut-T

David G. Maloney, Barbara Pender, Erin McCarthy, and Daniel P. Gold

Presented December 10, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia

FCRIIIa Receptor Polymorphisms Do Not Influence the Outcome of Treatment with Rituximab Followed by

Active Immunotherapy with Mitumprotimut-T

• Patient specific active idiotype immunotherapy with immunoglobulin idiotype is a promising new therapy for follicular non-Hodgkin's Lymphoma (NHL).

• Response to therapy may include both humoral and cellular anti-idiotypic immunity, but it is not clear which is most important.

Background

Maloney DG et al. Abstract #3416. Presented December 10, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.



• Prior studies have suggested that immunoglobulin FCgammaRIIIa (FCRIIIa ) polymorphisms at position 158 valine (V) or phenylalanine (F) affect the response to treatment with rituximab as well as outcomes from idiotype immunotherapy following objective response to chemotherapy.

Background




Polymorphisms in FCgRIIIA (CD16) Influence PFS following Single Agent Rituximab• CD16 Amino Acid 158 encodes valine (V) or phenylalanine (F)

- V/V phenotype associated with higher affinity interaction with human IgG1

- F/F phenotype associated with lower affinity interaction and poorer outcome to rituximab

• Initial therapy of low-tumor burden follicular NHL patients treated with rituximab 375 mg/m2 x 4 weeks (Cartron G, Blood

99:754, 2002)- Treatment of patients with relapsed follicular NHL (Weng and

Levy, JCO 21:3940, 2003)- Also observed in Waldenstrom’s but not in CLL (Treon S, ASH

2003, Farag S, Blood 103:1472, 2004)

Background: FCRIIIA




• Mitumprotimut-T is a patient-specific and B-cell tumor-specific idiotype (Id) protein chemically conjugated to keyhole limpet hemocyanin (KLH), a potent non-specific immunogenic protein

• Mitumprotimut-T induces a cellular and humoral immune response to the Id protein expressed by the patient’s own tumor, leading to active immunization against the tumor while sparing normal B-cells

Background




• Mitumprotimut-T is co-administered with granulocyte-macrophage colony-stimulating factor (GM-CSF) to further enhance immune anti-Id immune responses

• The Id protein is produced by proprietary recombinant technology; ~8 weeks from biopsy to final product

Background




• To assess the correlation between long term progression free survival (PFS) following combined rituximab + mitumprotimut-T (Id-KLH) treatment and FCRIIIa (CD16) polymorphism expression

• To assess the correlation of FCRIIIa polymorphisms and outcomes from idiotype immunotherapy following treatment with rituximab

Objective




• Key Inclusion Criteria:– Histologically confirmed Grade 1 or 2 follicular

B-cell lymphoma (WHO classification)

– Treatment-naïve, relapsed/refractory to chemotherapy, or relapsed following prior ≥ 6-month response to rituximab

– ≥8 weeks between completion of any prior lymphoma therapy and start of rituximab on study

– Measurable disease (≥2 cm) following node biopsy

– Performance status (ECOG) of 0, 1 or 2

Methods




• Key Exclusion Criteria:– >3 prior chemotherapy or anti-CD20 regimens

– Prior fludarabine

– Concurrent immunosuppressive therapy (e.g., high-dose steroids)

Methods




• PCR primers were designed to specifically amplify the regions of interest in FCRIIIa

• The FCRIIIa genotypes of 55 rituximab-naïve patients treated on a Phase II trial of mitumprotimut-T were determined using a SSCP method with genomic DNA

• Bands were sequenced to confirm the presence of the polymorphism

Methods


SSCP Analysis for FCRIIIa Polymorphism at position 158


H2O V/V V/F F/F V/V V/F F/F

200 bp100 bp

PCR SSCP



• Rituximab: 375 mg/m2 weekly infusion x 4 weeks. Subjects with stable disease (SD) or an objective response (CR or PR) to rituximab were eligible for mitumprotimut-T

• Mitumprotimut-T: 1 mg sc on Day 1 of each course. Courses administered monthly x6, bimonthly x6, and then every 3 months until disease progression or significant toxicity

• GM-CSF: 250 mcg/day sc on Days 1-4 of each course; same injection site as mitumprotimut-T

• CT scans: Obtained every 3 months; read by an independent radiologist blinded to clinical data

• Response assessment: Central review using modified IWG response criteria (Cheson et al, J Clin Oncol 1999;17:1244-1253)

Study Schema And Treatment Regimen


Study Schema and Treatment Regimen


0 3 6 9 12 15 18 21 24Months

CT Scans

Mitumprotimut-T+ GM-CSF

Rituximab

Mitumprotimut-TProduction

Biopsy

Cytoreduction Induction Maintenance



• DNA was isolated from all 55 patients and successfully analyzed by SSCP for polymorphisms at position 158 of FCRIIIa:– V/V: 9 (16%)

– 27 (49%)

– V/F 19 (35%)

Results




• 95 patients received rituximab and were evaluable.• 38 Treatment-naïve (T-N) patients• 57 Relapsed/Refractory (R/R) patients

- 25 of the 57 R/R pts were rituximab-naïve- 32 of the 57 R/R pts had previously received rituximab

± chemotherapy• 6 of 95 patients were progressive disease (PD) following

rituximab and were ineligible to receive mitumprotimut-T (IdKLH)

• 89 patients received mitumprotimut-T following rituximab

Patient Enrollment:




• 4 patients who progressed following rituximab and therefore did not receive mitumprotimut-T were excluded from this analysis

• All 55 patients in this analysis had follicular NHL with a median age of 55 years

• 35 patients were treatment naïve and 20 had relapsed following prior chemotherapy

Treatment




• 4 patients who progressed following rituximab and therefore did not receive mitumprotimut-T were excluded from this analysis

• All 55 patients in this analysis had follicular NHL with a median age of 55 years

• 35 patients were treatment naïve and 20 had relapsed following prior chemotherapy

DNA Sample Availability


FCRIIIa Polymorphism at Position 158: Distribution Among Evaluable Subjects

T-N = treatment-naïve, R/R = relapse-refractory.Maloney DG et al. Abstract #3416. Presented December 10, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Group N V/V V/F F/F

All 84 12 (14%) 34 (41%) 38 (45%)

R/R 46 7 (15%) 18 (39%) 21 (46%)

T-N 38 5 (13%) 16 (42%) 17 (45%)

Rituximab naïve 61 (38T-N, 23R/R)

10 (16%) 21 (34%) 30 (49%)

Results



• The 3 month response (post rituximab) was: – V/V: 5/9 (56%)

– V/F: 9/19 (47%)

– F/F: 17/27 (63%)

• The best response was:– V/V: 6/9 (67%)

– V/F: 12/19 (63%)

– F/F: 21/27 (78%)

Results


Initial Overall Response Rate to Single Agent Rituximab Therapy, Among Rituximab-Naïve Patients According to FCRIIIa Polymorphism at Position 158

The overall response rate is equal to the incidence of complete response and partial response: ORR = CR + PR.Maloney DG et al. Abstract #3416. Presented December 10, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Group N Rituximab ORR

All 61 54%

V/V 10 50%

V/F 21 52%

F/F 30 57%

Any V 31 52%

Any F 51 55%

ORR = CR+PR

Best ORR Achieved, TTP, and PFS with Combined Rituximab + Mitumprotimut-T Among Rituximab-Naïve Patients According to FCRIIIa Polymorphism at Position 158

ORR = overall response rate; TTP = time to progression; PFS = progression free survivalMaloney DG et al. Abstract #3416. Presented December 10, 2007, at the 49th ASH Annual Meeting in Atlanta, Georgia.

Group N*

Best ORR to combined rituximab+ Id-KLH treatment

Med. TTP(months) 1 Yr. PFS 4 Yr. PFS

All 57 70% 17.7 59% 30%

V/V 9 67% 19.6 55% 29%

V/F 21 62% 20.8 58% 34%

F/F 27 78% 17.7 62% 28%

Any V 30 63% 19.6 57% 33%

Any F 48 76% 17.7 60% 30%

* 4 Patients ( 3 FF & 1 VV) who were PD post rituximab did not qualify for mitumprotimut-T Id-KLH treatment and are excluded from the analysis for the combined treatment



• Median TTP was:– V/V: 19.5 months

– V/F: 22.3 months

– F/F 18 months

• The PFS at 1 year post initiation of rituximab was: – V/V: 57%

– V/F: 61%

– F/F: 68%

Results




• At the median follow-up of 3.5 years the PFS was: – V/V: 31%

– V/F: 42%

– F/F: 31%

Results


PFS for V/V vs. V/F vs. F/F FCRIIIa at Position 158


0 10 20 30 40 50 600

10

20

30

40

50

60

70

80

90

100

V/F

V/V

F/F

Months

Pro

gre

ssio

n F

ree

%

PFS for V/V vs. V/F vs. F/F FCRIIIa at Position 158


0 10 20 30 40 50 600

10

20

30

40

50

60

70

80

90

100

Any F

Any V

Months

Pro

gre

ssio

n F

ree

%

Antibody Responses to KLH and Id Among Long Term (> 3 years) Progression Free Survivors* (n=13)

positive (+) negative (-)


PatientFCRIIIa

Genotype KLH Id

1 V/V + –

2 V/V + +

3 V/F + +

4 V/F + +

5 V/F + +

6 V/F + –

7 V/F + –

PatientFCRIIIa

Genotype KLH Id

8 F/F + –

9 F/F – –

10 F/F + +

11 F/F + –

12 F/F + –

13 F/F + –

*As measured by ELISA



• FCRIIIa polymorphisms were not associated with response rate or time to progression following a treatment program consisting of single agent rituximab followed by idiotype vaccination with mitumprotimut-T in rituximab- naive patients

• Results from an ongoing randomized Phase III study will assess the efficacy of this combined therapy, but these data suggest that long term PFS in patients receiving an idiotype vaccine following rituximab may rely more on a cell mediated immune response rather than a humoral response to idiotype

Conclusions




• The distribution of FCRIIIA polymorphisms at Position 158 in this study population is comparable to

previously published data among FL patients.

• In the population of Rituximab Naïve FL patients (23 R/R and 38 T-N), there is no correlation with

FCRIIIA polymorphisms at Position 158 and initial response to 4 course Rituximab therapy nor with

time to progression following idiotype immunotherapy with mitumprotimut-T +GM-CSF.

Summary




Long term progression free survival (> 3 years) following combined Rituximab plus mitumprotimut-T (Specifid™, Id-KLH, FavId®) therapy does not correlate with production of anti-idiotypic antibody suggesting long term PFS may rely more on a cell mediated immune response.

Summary




• Lack of correlation with FCRIIIA polymorphisms and long term PFS may suggest that if such an association does occur with Rituximab monotherapy, the addition of idiotype vaccine overrides the FCRIIIA advantage.

• Results from an ongoing randomized PIII study due to be reported in July 2008 will assess the efficacy of this combined therapy and any potential role for FCRIIIA polymorphisms.

Summary


Documents

FC RIIIa Receptor Polymorphisms Do Not Influence the Outcome of Treatment with Rituximab Followed by Active Immunotherapy with Mitumprotimut-T David