Initial Results of a Phase 1/2a, Dose Escalation Study of PVX-410 Multi-Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM)
Authors: Wang Michael (Luhua) , Nooka Ajay K. , Yee Andrew J. , Thomas Sheeba K. , O'Donnell Elizabeth , Shah Jatin , Weber Donna M. , Kaufman Jonathan L. , Lonial Sagar , Avigan David , Raje Noopur 
Published: October 2019

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.