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Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission BV301 Phase III clinical trial results. Schuster SJ*, Neelapu SS*, Gause BL, Muggia FM, Gockerman JP, Sotomayor EM, Winter JN, Flowers CR, Stergiou AM, Kwak LW

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  1. 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

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  3. 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#1 2 American Cancer Society. Cancer Facts & Figures 2009. 3 Blood 89: 3909, 1997

  4. 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

  5. Id+KLH Protein (BiovaxID) • The idiotype of the SmIg of a B-cell lymphoma canbe 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 antigen binding site / idiotype KLH (with GM-CSF)

  6. Idiotype Vaccine Production tumor cell myeloma cell LN biopsy + fusion I heterohybridoma KLHconjugation Id scale-up affinity purification

  7. Id-KLH (BiovaxID) Pre-Clinical and Clinical Trials Start of Phase IIClinical Trial (1993) Biovest TransferIND from NCI (2004)

  8. NCI Phase II Follicular Lymphoma Idiotype Vaccine Study Results • 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) † *HLA class I restriction of cytokine release and cytotoxicity are suggestive of cytotoxic CD8+ T-cell response. †Molecular remission sustained for >18 mo. Bendandi et al. Nat Med 5:1171, 1999Santos et al. Blood (ASH Abstract #2441), 2005.

  9. 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

  10. BV301 Phase III Follicular Lymphoma Idiotype Vaccine Study Design Id-KLH + GM-CSF PACE Chemo Stratify for IPI1, cycles of PACE2 2:1 Randomization LN Bx KLH + GM-CSF Assign CR Timeline 6 - 12 months 6 months 6 - 8 months • Primary endpoint: disease-free survival • 14 sites enrolled patients from 2000-2007 1low, low-intermediate or high-intermediate, high groups 2 < 8 or > 8 cycles

  11. 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

  12. Induction Chemotherapy (PACE)

  13. 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

  14. 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

  15. 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)

  16. Results Enrollment Stratify / Randomize ITT (n=177) Post-InductionRecoveryPeriod(6-12 months) PD, no vax (n=60) modified ITT (n=117) Vaccination

  17. 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.

  18. Characteristics of Patients Relapsing After Randomization and Before Vaccination (n=60) No statistically significant (p < 0.05) differences between the two arms for any patient characteristics

  19. DFS for Patients Relapsing After Randomization and Before Vaccination (n = 60) Id-KLH (BiovaxID) arm control vaccine arm Probability Months from Randomization

  20. Characteristics of Patients Receiving Id-KLH (BiovaxID) vs. Control Vaccine (mITT, n=117) No statistically significant (p < 0.05) differences between the two arms for any patient characteristics

  21. Overall Survival from Randomization for Id-KLH (BiovaxID) vs. Control Arms (mITT) • Median OS • not yet reached at median follow-up 56.6 months • Overall Survival • Id-KLH (BiovaxID) = 95.4% • Control vaccine = 91.2% • N = 117 • Id-KLH (BiovaxID) N = 76 • Control vaccine N = 41 • Events • Id-KLH (BiovaxID) = 3 • Control vaccine = 2 • Cox PH Model • HR = 0.7 (p=0.7) Id-KLH (BiovaxID) arm control vaccine arm

  22. Disease Free Survival from Randomization for Id-KLH (BiovaxID) vs. Control Arms (mITT) • Median Follow-up • 56.6 mo (range 12.6 – 89.3) • Median DFS • Id-KLH (BiovaxID) = 44.2 mo • Control vaccine = 30.6 mo • N = 117 • Id-KLH (BiovaxID) N = 76 • Control vaccine N = 41 • Events • Id-KLH (BiovaxID) = 44 • Control vaccine = 29 • Cox PH Model • HR = 0.62; [95% CI: 0.39,0.99] (p=0.047) Id-KLH (BiovaxID) arm control vaccine arm log-rank p=0.045

  23. Safety Summary: AEs During Vaccination CTCAE Version 2

  24. Results: Local Injection Site Reactions

  25. 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

  26. 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

  27. 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

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