A Phase I Study of Safety, Tolerability and Immunological Effects of SVN53-67/M57-KLH in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance Therapy

Background: Survivin is an inhibitor of apoptosis protein (IAP) and is highly expressed in multiple human cancers, including multiple myeloma (MM). Inhibition of survivin function results in apoptosis of tumor cells, and survivin knockdown leads to growth inhibition in MM cell lines. In patients with MM, a higher level of survivin expression is associated with inferior survival and a more aggressive clinical course. Survivin-reactive T cells have been identified in patients with MM confirming its immunogenicity and providing the basis for cytotoxic immunity against survivin as an attractive antitumor strategy. In this study, we present interim results of a Phase I trial testing the safety and tolerability of a cancer vaccine regimen consisting of the survivin peptide conjugate SVN53-67/M57-Keyhole Limpet Hemocyanin (KLH) before or after lenalidomide (Len) maintenance in patients with MM.

Methods: Patients age ≥18 years with newly diagnosed MM not eligible or planned for high dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) were enrolled if they at least had achieved a partial response (PR) after induction therapy. An accrual of 18 patients was planned in 2 groups (Group A and Group B) with 9 in each group, following an alternating inclusion schedule with cohorts of 3 starting with Group A. Patients were treated with 500 mcg SVN53- 67/M57-KLH in Montanide ISA 51 with GM-CSF every two weeks for a total of 4 doses per patient. A booster of 500 mcg SVN53-67/M57-KLH in Montanide ISA 51 with GM-CSF was given 3 months from the first vaccine dose. In group A, oral Len 10 mg daily was initiated 4 weeks following the first vaccine dose. In group B, the first vaccine dose was administered 4 weeks following Len initiation. All patients in each cohort (n=3) were followed for at least 2 weeks after the 4th dose of vaccine before the next cohort of 3 patients could begin treatment. The dose of vaccine was not escalated in an individual patient, or between cohorts of patients. Immunologic assays and disease evaluation were done every 4 weeks for the first 24 weeks after which patients were followed every 3 months for 5 years or until disease progression/death due to any cause. The NCI common terminology criteria for adverse events (CTCAEv4.0) was used to evaluate toxicity.

Results: At the time of this analysis, 18 patients had received treatment, 9 in group A, and 9 in Group B. The median follow up was 41.5 months. The median age was 75 years, and 10 (55.5%) patients were male. A total of 18 patients received all four doses of vaccine. One patient had to discontinue treatment after 4 doses due to DLT, one patient for logistical reasons, and one patient for non-compliance. In the whole study cohort, 12/18 (67%) patients had adverse events (AE) of any grade, and 4/18 (22%) patients had grade 3 or higher AE. No grade 5 AEs were observed. The most common AEs were fatigue (n=7, all grade 1-2) and injection site reactions (n=7, all grade 1-2). A serious AE (colitis) was observed in 1 (6%) patient. Anti-IgG antibodies to epitopes within the survivin peptide and to the corresponding wild-type survivin peptide were detected in 16/17 (94%) patients that were tested, with no difference in titers between Group A and B patients. Of these, 10/17 (59%) patients had high-titers (defined as >1:30,000) to the survivin vaccine peptide. CD8+ T cell reactivity (>1% increased expression) for T cell markers or cytokines in response to survivin epitopes ex vivo was present for HLA-DR, 3/17 (18%); CD69, 4/17 (24%); TNFa, 4/17 (24%); and IFNg, 3/17 (18%). At data-cut off, 7 out of 18 (39%) patients had evidence of disease progression, and 1 patient had died. The median progression free survival for all patients (A&B) was 24.8 months (95% CI, 16.7 - 30.2 months), and median overall survival was not yet reached. Overall survival at 36 months (OS36) remained at 90.1% (95% CI, 50.8-98.7%).

Conclusion: A cancer vaccine regimen consisting of a survivin peptide conjugate is safe, well tolerated and highly immunogenic following induction therapy in patients with MM not proceeding to receive HDC-ASCT. There was no difference in anti-survivin immunoglobulin levels in patients who received the vaccine prior to, or after initiation of Len maintenance. Further randomized studies are needed to determine the benefit of adding a survivin vaccine regimen to maintenance therapy in these patients.

Hillengass:Beijing Life Oasis Public Service Center: Honoraria; Beijing Medical Award Foundation: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Curio Science: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Adaptive: Honoraria. Lipe:Amgen: Research Funding; Seagen Inc.: Research Funding; GSK: Consultancy; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Harpoon: Research Funding. Fenstermaker:MimiVax, LLC: Current equity holder in private company. Ciesielski:MimiVax, LLC: Current equity holder in private company.