Final Results of a Phase 1/2a, Dose Escalation Study of Pvx-410 Multi-Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM)

Introduction: PVX-410 Multi-Peptide Vaccine (OncoPep, Inc.) is being developed for the treatment of SMM. PVX-410 consists of 4 human leukocyte antigen-A2 (HLA-A2), synthetic 9-mer peptides from unique regions of 3 multiple myeloma (MM)-associated antigens (XBP1 US_184-192; XBP1 SP_367-375; CD138_260-268; and CS1_239-247) emulsified in Montanide^® ISA-720 VG (Seppic). Adults with SMM at high risk of progression to active MM who were HLA-A2-positive were eligible. The primary objective was to determine the tolerability of PVX-410, initially as monotherapy and then in combination with lenalidomide (len). Immune and disease response also were assessed.

Methods: All patients received 6 bi-weekly subcutaneous injections of PVX-410, initially at the low-dose of 0.4 mg (0.1 mg/peptide or 0.4 mg total) and then at the target dose of 0.8 mg (0.2 mg/peptide or 0.8 mg total). In the PVX-410+len cohort, patients received 3 standard cycles of len (25 mg orally on Days 1-21 every 28 days, without dexamethasone). All patients also received 0.5 mL (1 mg) Hiltonol^® (poly-ICLC) (2 mg/mL) via intramuscular injection at the time of PVX-410 administration. Patients were followed for 12 months post-treatment. Blood samples for immune response evaluation were collected at Week 0 (Baseline; pre-dose), 2, 4, and 8 weeks during treatment and at Months 1, 3, 6, 9, and 12 post-treatment. Disease response was assessed at the same time points, except Weeks 0 and 2, using International Myeloma Working Group and modified European Group for Blood and Bone Marrow Transplant criteria.

Results: Overall, 22 patients with high-risk SMM were enrolled (age range 39 to 82 years), of whom 12 received PVX-410 monotherapy (3 low-dose; 9 target dose) and 10 received PVX-410 (target dose) + len. All 22 patients have either completed the study through post-treatment Month 12 (N=15) or discontinued before that time (N=7).

PVX-410 was well-tolerated, with a treatment-emergent adverse event (TEAE) profile consistent with that expected, based on previous clinical studies with peptide vaccines. All (100%) 22 patients experienced at least 1 TEAE. Among monotherapy patients, the most common TEAEs were injection site pain (50%); fatigue (33%); and injection site erythema, pyrexia, and rash (each 25%). The TEAE profile of PVX-410+len was generally similar to that see with PVX-410 alone, although the incidence of commonly reported TEAEs was higher with the combination than with PVX-410 alone. The majority of TEAEs were Grade 1 in intensity and occurred within 2 days after study vaccine injection. No deaths or study drug-related serious adverse events were reported.

PVX-410 was immunogenic as monotherapy (10/11 patients) and in combination with len (9/9), as demonstrated by an increase in the percentage of tetramer+ cells (≥1.5-fold increase over baseline) and interferon-gamma+ (IFN-γ) cells (≥2.0-fold increase over baseline) in the CD3⁺CD8⁺ cell population. This increase was statistically higher for IFN-γ⁺ cells after 2 vaccinations in the combination group. The CD8⁺ T-lymphocyte response was also characterized by increases from baseline in interleukin-2-, tumor necrosis factor-alpha-, and CD137-positive cells in both treatment groups. Furthermore, decreases in the naïve memory cell population and increases in the effector memory cell population were seen post-vaccination; this response was enhanced by the addition of len.

Among the 12 monotherapy patients, 5 (2 low-dose; 3 target-dose) experienced progression to active disease within 9 months post-treatment, and 7 had stable disease (SD) at follow-up Month 12. Among the 9 evaluable PVX-410+len patients, 5 achieved at least a minimal response, with 1 patient achieving a partial response; 1 of these 5 patients then progressed to MM by Month 5 post-treatment. Four patients had SD at follow-up Month 12.

Conclusions: Six doses of PVX-410 were well tolerated in 22 patients with high-risk SMM, with an expected AE profile both as monotherapy and in combination with len. An immune response to PVX-410 was seen with PVX-410 alone, which was enhanced by the addition of len. Based on these promising findings to date, investigation of PVX-410 in combination with immunogenic agents is continuing.