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

Michael (Luhua) Wang, Ajay K. Nooka, Andrew J. Yee, Sheeba K. Thomas, Elizabeth O'Donnell, Jatin Shah, Donna M. Weber, Jonathan L. Kaufman, Sagar Lonial, David Avigan and Noopur Raje

Abstract

Introduction: The standard of treatment for SMM is watchful waiting. PVX-410 (OncoPep, Inc.) is being developed for the treatment of SMM to stop progression to active MM.

Methods: PVX-410 consists of 4 HLA-A2 restricted, synthetic 9-mer peptides from unique regions of 3 multiple myeloma (MM)-associated antigens (XBP1 US184-192; XBP1 SP367-375; CD138260-268; and CS1239-247) emulsified in Montanide® ISA-720 VG (Seppic, Inc.). Adults with SMM at high risk of progression to active MM (ie, ≥2 of the following risk factors: serum monoclonal [M]-protein ≥3 g/dL; bone marrow clonal plasma cells >10%; and/or abnormal serum free light chain ratio [0.26-1.65]) and HLA-A2+were eligible. The primary objective of this study phase was to determine the tolerability of PVX-410 as a single agent. Immune response to PVX-410 and change in M protein were also assessed. This ongoing study is similarly evaluating PVX-410 co-administered with lenalidomide (Celgene Corp.).

Patients received 6 doses of PVX-410 subcutaneously plus 0.5 mL (1 mg) Hiltonol®(poly-ICLC, Oncovir, Inc.) intramuscularly over 10 weeks. Patients initially received PVX-410 0.4 mg (3 patients, 0.1 mg/peptide / 0.4 mg total dose; low-dose) with escalation to 0.8 mg (9 patients, 0.2 mg/peptide / 0.8 mg total dose; target-dose). Patients were followed for 12 months post-treatment. Blood for immune response evaluation is collected at Week 0 (Baseline; pre-dose), 2, 4, and 8 during treatment and at Months 1, 3, 6, 9, and 12 post-treatment; disease response is assessed at the same timepoints, except Weeks 0 and 2.

Immune response to PVX-410 was determined by interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) and multimer assays. Samples were tested for IFN-γ production in response to peptide stimulation using ELISPOT and analyzed according to the distribution free sampling (DFR) method (Moodie et al, 2010). A positive (+) response was defined as 1) DFR+ at the timepoint (p-value ≤0.05); and 2) >2-fold increase from Baseline. A result also was considered + if the Baseline value was negative and the post-dose value was DFR+. For determination of peptide-specific memory CD8+ T cell responses, a flow cytometry-based major histocompatibility complex (MHC) multimer assay was performed using tetramers specific for HLA-A2 and each of the 4 peptides. A + response was defined as a value ≥2 X the negative control; ≥Baseline; or, if the negative control or Baseline value was 0.0 or 0.1, the patient result was ≥0.03.

Results: Twelve patients were enrolled (3 low-dose; 9 target-dose). Ten subjects were male and all were white. Median age was 56 years. Median time since diagnosis was 0.8 years (range 0.3 to 7.3 years); time since diagnosis was <1 year for 8 patients. All patients had at least 2, and 6 had all 3 high-risk factors. Results are available for all 12 patients through at least 1 month post-treatment.

All 12 patients had a positive immune response to at least 1 peptide, as measured by IFN-γ ELISPOT: XBP1 US184-192 (9/12); XBP1 SP367-375 (8/12); CD138260-268 (5/12); and CS1239-247(2/9). DFR-positivity to 1, 2, 3, and all 4 peptides was seen in 5, 3, 3, and 1 patient, respectively.

The multimer assay was performed for 9 patients, of whom 7 had vaccine-induced, peptide-specific memory CD8+ T cells: XBP1 US184-192 (7/9); XBP1 SP367-375 (4/9); CD138260-268 (2/9); and CS1239-247(1/9).

Five subjects, 2 of 3 in the low-dose and 3 of 9 in the target-dose cohorts, experienced progression to active disease within 9 months post-treatment. Seven patients had stable disease at last follow-up (median follow up of 9 months).

PVX-410 was well-tolerated. All adverse events (AEs) were ≤Grade 2 and non-serious. Study vaccine-related AEs generally occurred within the first 2 days post-dose and consisted of systemic symptoms and local reactions commonly seen with vaccines (eg, fever, chills, fatigue, nausea, and other flu-like symptoms / localized erythema, induration, pain, rash, and pruritus).

Conclusions: Six doses of PVX-410 were well tolerated in 12 patients with SMM. All 12 patients showed an immune response to the vaccine, with 4 having an immune response to ≥3 of 4 peptides. Based on these promising findings, PVX-410 is being investigated in combination with 3 cycles of fixed-dose lenalidomide. Given its immunomodulatory properties, it is hypothesized that co-administration of lenalidomide will enhance the T cell-mediated immune response induced by PVX-410.

Disclosures Thomas: Novartis, Celgene, Millenium, Idera Pharmaceuticals: Consultancy, Research Funding. Weber: OncPep: Research Funding. Kaufman: Millennium; Celgene; Novartis; Onyx; Janssen; Spectrum: Consultancy; Novartis; Onyx; Merck; Celgene: Research Funding; Millennium; Celgene; Novartis; Onyx; Janssen; Spectrum: Honoraria. Lonial: Millennium, Celgene, Novartis, BMS, Onyx: Consultancy, Research Funding. Raje: Eli Lilly, Acetylon: Research Funding; novartis, Amgen, Celgene, Millenium, Onyx: Consultancy.

  • * Asterisk with author names denotes non-ASH members.