Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete

remission

BV301Phase III clinical trial results

Schuster SJ*, Neelapu SS*, Gause BL, Muggia FM, Gockerman JP, Sotomayor EM, Winter JN, Flowers CR, Stergiou AM, Kwak

LW

on behalf of the BV301 Phase III Study Investigators

Author Disclosure Information

AuthorResearch Support / Uncompensated

Consultant / Compensated

S.J. Schuster Biovest International

S.S. Neelapu Biovest International

B.L. Gause None

F.M. Muggia Biovest International

J.P. Gockerman Biovest International

E.M. Sotomayor Biovest International

J.N. Winter Biovest International

C.R. Flowers Biovest International Biovest International

A.M. Stergiou Biovest InternationalAccentia Biopharmaceuticals

L.W. Kwak Biovest International Biovest International

Non-Hodgkin Lymphomas (NHL)

• 6th most common type of cancer in the US 1

• Most common hematological cancer

• 65,980 new cases expected in the US in 2009 2

• 19,500 are expected to die of NHL in 2009 2

• Follicular lymphoma is the second most common subtype of NHL, accounting for ~25% of all NHL diagnoses 3

1 http://www.cancer.gov/cancertopics/commoncancers#12 American Cancer Society. Cancer Facts & Figures 2009. 3 Blood 89: 3909, 1997

Follicular Lymphoma

• B-cell immunophenotype• Clonal surface immunoglobulin (tumor-specific idiotype)• Median survival ranges from 5 to >10 years depending on

prognostic factors 1

• Disease-free and overall survival are improved by combining rituximab with chemotherapy 2,3

• No curative therapy for most patients

1 Solal-Celigny, et al. Blood 104:1258, 2004

2 Marcus, et al. J Clin Oncol 26:4579, 2008

3 Hochster, et al. J Clin Oncol 27:1607, 2009

Id+KLH Protein (BiovaxID)

• The idiotype of the SmIg of a B-cell lymphoma can be used as a tumor-specific immunogen that induces immunity against Id-bearing tumor cells

• Keyhole lympet hemocyanin (KLH) carrier serves as an immune stimulant

• GM-CSF administered concurrently at site of injection as an adjuvant

KLH

(with GM-CSF)

antigen binding site / idiotype

Idiotype Vaccine Production

+

scale-up

affinity purification

KLHconjugation

LN biopsy

myeloma cell

tumor cell

fusion

heterohybridomaId

I

Id-KLH (BiovaxID) Pre-Clinical and Clinical Trials

Biovest TransferIND from NCI (2004)

Start of Phase IIClinical Trial (1993)

1972 1975 1980 1985 1990 1995 2000 2005 2009

1972

Lynch R,Eisen H, et al.

MouseMyelomaIdiotypeStudies

WashingtonUniversity

PNAS 197269(6):

1540–1544

1992

Kwak, Levy et al.studies at Stanfordshow responses inhuman patients.

NEJM 199222;327(17):1209-15.

1997

Hsu, et al.Clinical trialresults reportontumor-specificidiotypevaccines.

Blood. 19971;89(9):3129-35.

1999

Bendandi,Kwak et al. atNCI report onPhase IIresults.

Nat Med. 19995(10):1171-7.

2000Start ofPhase III

Clinical Trial1996

Kwak, et al.studies at NCIdemonstrateadjuvant efficacyof GM-CSF.

PNAS 19961;93(20):10972-7.

2008234 patients

enrolled117 patientscompletedtreatment

NCI Phase II Follicular Lymphoma Idiotype Vaccine Study Results

*HLA class I restriction of cytokine release and cytotoxicity are suggestive of cytotoxic CD8+ T-cell response.

†Molecular remission sustained for >18 mo.

• N=20 in CR > 6 months after PACE received Id-KLH + GM-CSF vaccination

• At median follow-up of 9.2 yrs, 45% (9 / 20 pts) in CR; overall survival 95%

• Anti-Id antibody response (15 / 20 pts)

• Tumor-Specific CD4+ and CD8+ T-cell responses (19 / 20 pts) *

• Conversion to t(14;18) PCR-negative (8 / 11 pts) †

Bendandi et al. Nat Med 5:1171, 1999Santos et al. Blood (ASH Abstract #2441), 2005.

BV301 Phase III Follicular Lymphoma Idiotype Vaccine Study Objectives

• Primary Objective: – To determine whether Id-KLH (BiovaxID) + GM-CSF

prolongs disease free survival (DFS) compared to KLH + GM-CSF (control vaccine) in patients with follicular lymphoma in CR/CRu after PACE

• Secondary Objectives:– Evaluate safety of Id-KLH (BiovaxID) + GM-CSF

– Compare overall survival of subjects in both treatment arms

– Evaluate immunologic and molecular responses

BV301 Phase III Follicular Lymphoma Idiotype Vaccine Study Design

Id-KLH + GM-CSF

KLH + GM-CSFLNBx

Assign CR

Stratify for IPI1, cycles of PACE2

2:1 Randomization

PACE Chemo

Timeline

• Primary endpoint: disease-free survival• 14 sites enrolled patients from 2000-2007

1low, low-intermediate or high-intermediate, high groups2 < 8 or > 8 cycles

6 - 12 months 6 months6 - 8 months

Inclusion Criteria

• Follicular lymphoma with monoclonal surface IgM or IgG

• Follicular lymphoma histology, grades 1, 2, or 3a

• Stage III or IV lymphoma (including Stage IIX )

• Chemotherapy naïve

• 2 sites previous radiation treatment

• > 2cm single lymph node accessible for biopsy

Day 1 Day 8 Day 29

Cyclophosphamide

650 mg/m2 per dose IV

X X Next cycle begins

Doxorubicin

25 mg/m2 per dose IV

X X

Etoposide

120 mg/m2 per dose IV

X X

Prednisone 40 mg/m2 orally once daily Days 1 to 14

Induction Chemotherapy (PACE)

Statistical Design: Sample Size

• Assumed 2/3 CR/CRu response to PACE– required 563 pts for 2:1 randomization of 375 pts to

either Id-KLH (BiovaxID) arm (250) or control arm (125)

• 80% power to detect a difference between DFS curves with an initial hazard ratio of 1.0 and an intended hazard ratio of 0.5 after the first 8 months

Statistical Design: Two Prospective Efficacy Analyses

• Intent-to-Treat Analysis (ITT) compared DFS in treatment arms for all randomized pts

• Modified Intent-to-Treat Analysis (mITT) compared DFS in treatment arms for randomized pts who remained in CR/CRu and received either Id-KLH (BiovaxID) or control

Study Concluded Based on DMC Recommendation

• Recommendation of DMC:– Review of trial objectives and results– Impact on accrual related to change in

standard of care to include rituximab – No safety concerns for Id-KLH (BiovaxID)

• Independent Data Monitoring Committee (DMC)– G. Messerschmidt, M.D. (Chairman)– Prof. V. Diehl, M.D., Ph.D. (Member)– H. Parise, Sc.D. (Member, Statistician)

Assessed for eligibility (n=234)

Excluded from Randomization (n=57)

Did not receive induction therapy (n=6)Achieved CR (n=2)

Achieved CRu (n=2)Achieved PD (n=11)Achieved SD (n=31)

Unknown/Not assessed (n=5)

Randomized (n=177)

Allocated to Id-KLH (BiovaxID) (n=118)

Allocated to KLH(Control) (n=59)

Failed to Maintain CR/CRu (n=18)

Failed to Maintain CR/CRu (n=42)

Vaccinated with Id-KLH + GM-CSF (n=76)

Rec’d 5 immunizations (n=72)Rec’d 4 immunizations (n=2)Rec’d 3 immunization (n=2)

Vaccinated with KLH + GM-CSF (n=41)

Rec’d 5 immunizations (n=39)Rec’d 4 immunizations (n=1)Rec’d 2 immunization (n=1)

PD, no vax(n=60)

Enrollment

Stratify / Randomize

Post-InductionRecoveryPeriod(6-12 months)

Vaccination

Results

modifiedITT

(n=117)

ITT(n=177)

Results: DFS for All Randomized Patients

(ITT)

• For all randomized pts, no statistically significant difference in DFS was observed between pts allocated to Id-KLH (BiovaxID) or control arms.

• The intent of the protocol was to compare DFS in pts vaccinated in CR/CRu with either Id-KLH or control vaccine.

• The ITT analysis compares DFS in all randomized pts, including pts not vaccinated.

Characteristics of Patients Relapsing After Randomization and Before Vaccination (n=60)

Id-KLH N (%) Control N (%) Id-KLH N (%) Control N (%)

Sex Age

Female 21 (50%) 11 (61%) Mean (SD) 49.1 (10.4) 46.1 (10.8)

Male 21 (50%) 7 (39%)

Histology

Race Follicular, grade 2 22 (52%) 10 (56%)

Am Indian or AK Native 1 (2%) 0 (0%) Follicular, grade 1 20 (48%) 8 (44%)

Asian 1 (2%) 0 (0%)

Black 3 (7%) 2 (11%) IPI

Caucasian 37 (88%) 14 (78%) High-int or high 6 (14%) 2 (11%)

Hispanic or Latino 0 (0%) 1 (6%) Low or low-int 36 (86%) 16 (89%)

Other 0 (0%) 1 (6%)

Cycles of PACE

ECOG PS < 8 22 (52%) 7 (39%)

0 30 (71%) 16 (89%) > 8 20 (48%) 11 (61%)

1 11 (26%) 1 (6%)

2 1 (2%) 1 (6%) LDH

Mean (SD) 428.4 (301.9) 304.8 (173.6)

No statistically significant (p < 0.05) differencesbetween the two arms for any patient characteristics

control vaccine arm

DFS for Patients Relapsing After Randomization and Before Vaccination (n = 60)

DFS from Time of Randomization (mo)

n events median

95% CI

Id-KLH (BiovaxID)

42

38 6.08 [5.59,7.49]

Control 18

17 5.98 [5.45,9.43]

Cox Proportional Hazards Model

HR = 0.92 [95% CI: 0.51,1.65] (p=0.78)

Months from Randomization

Pro

bab

ility

Id-KLH (BiovaxID) arm

Characteristics of Patients Receiving Id-KLH (BiovaxID) vs. Control Vaccine (mITT, n=117)

Id-KLH N(%) Control N(%) Id-KLH N(%) Control N(%)

Sex Age

Female 37 (49%) 13 (32%) Mean (SD) 49.2 (9.7) 51.1 (9.1)

Male 39 (51%) 28 (68%)

Histology

Race Follicular, grade 2 42 (55%) 24 (59%)

Asian 3 (4%) 0 (0%) Follicular, grade 1 34 (45%) 17 (41%)

Black 2 (3%) 3 (7%)

Caucasian 67 (88%) 38 (93%) IPI

Hispanic or Latino 4 (5%) 0 (0%) High-int or high 7 (9%) 4 (10%)

Low or low-int 69 (91%) 37 (90%)

ECOG PS

0 64 (84%) 30 (73%) Cycles of PACE

1 12 (16%) 11 (27%) < 8 38 (50%) 22 (54%)

> 8 38 (50%) 19 (46%)

LDH

Mean (SD) 277.6 (178.3) 293.3 (219.8)

No statistically significant (p < 0.05) differencesbetween the two arms for any patient characteristics

Overall Survival from Randomization for Id-KLH (BiovaxID) vs. Control Arms (mITT)

Id-KLH (BiovaxID) arm

control vaccine arm

Median OS

not yet reached at median follow-up 56.6 months

Overall SurvivalId-KLH (BiovaxID) =

95.4%Control vaccine =

91.2%

N = 117 Id-KLH (BiovaxID) N = 76Control vaccine N = 41

Events Id-KLH (BiovaxID) = 3Control vaccine = 2

Cox PH ModelHR = 0.7 (p=0.7)

Disease Free Survival from Randomization for Id-KLH (BiovaxID) vs. Control Arms (mITT)

log-rank p=0.045

Median Follow-up 56.6 mo (range 12.6 – 89.3)

Median DFSId-KLH (BiovaxID) = 44.2

moControl vaccine = 30.6

mo

N = 117 Id-KLH (BiovaxID) N = 76Control vaccine N = 41

Events Id-KLH (BiovaxID) = 44Control vaccine = 29

Cox PH Model

HR = 0.62; [95% CI: 0.39,0.99] (p=0.047)

control vaccine arm

Id-KLH (BiovaxID) arm

System Control N (%) Id-KLH N (%)

Grade 3 Grade 4 Grade 3 Grade 4

Allergy 0 0 1 (1%) 0

Cardiovascular 1 (2%) 0 1 (1%) 1 (1%)

Constitutional 0 0 2 (3%) 0

Dermatology 1 (2%) 0 4 (5%) 0

Gastrointestinal 1 (2%) 0 3 (4%) 0

Infection 1 (2%) 0 0 0

Musculoskeletal 1 (2%) 0 1 (1%) 0

Neurological 1 (2%) 0 1 (1%) 0

Pain 6 (15%) 0 5 (7%) 0

Pulmonary 1 (2%) 0 0 0

Secondary Malignancy 1 (2%) 0 0 1 (1%)

Safety Summary: AEs During Vaccination

CTCAE Version 2

Maximum Local Reaction Severity Control (%) Id-KLH (%)

Erythema No reaction 12% 3%

< 1 cm 0% 0

1-10 cm 39% 51%

> 10 cm 49% 46%

Induration No reaction 24% 14%

< 1 cm 2% 4%

1-10 cm 46% 62%

> 10 cm 27% 20%

Ulceration No reaction 98% 93%

< 1 cm 2% 3%

1-10 cm 0% 3%

> 10 cm 0% 1%

Results: Local Injection Site Reactions

Conclusions

• Id-KLH (BiovaxID) + GM-CSF vaccination improves DFS following PACE in patients in CR/CRu at time of vaccination

• CR/CRu could be a prerequisite for achieving benefit from vaccination

• Long-term clinical experience with idiotype vaccination demonstrates low toxicity profile

• Tumor-specific idiotype vaccine can be successfully manufactured using heterohybridoma and bioreactor technologies

Future Plans

• Complete immune response testing on samples collected during the clinical trial

• Study Id-KLH (BiovaxID) following rituximab-combination chemotherapy regimens

• Study Id-KLH booster vaccination schedules

• Sponsor will continue regulatory approval discussions with US and EU regulatory agencies

BV301 Trial Sites

• National Cancer Institute• Duke University Medical

Center• Emory University Winship

Cancer Institute• H. Lee Moffitt Cancer

Center• New England Medical

Center • New York University

Medical Center• Virginia Oncology

Associates

• North Mississippi Hem & Oncology Associates

• Northwestern University• St. Mary's/Duluth Clinic

(SMDC) Health System• Abramson Cancer Center

University of Pennsylvania• The University Of Texas MD

Anderson Cancer Center• Westchester Oncology &

Hematology Group • Southern Oncology

Research