A Phase Ib Trial of a Maintenance Multipeptide Vaccine (S-588210) in Patients With Unresectable Malignant Pleural Mesothelioma Without Progression After First-Line Chemotherapy

University of Chicago

Overview

A phase Ib study investigating the safety, the immunogenicity and the optimal administration frequency of the S-588210 5-peptide vaccine in MPM patients without progression after pemetrexed-based chemotherapy will be conducted. Additionally, to identify more accurate predictive biomarkers of response to S-588210, T-cell-receptor-sequencing (TCR) pre- and post-vaccination will be performed in blood samples of patients treated with the vaccine. Immunohistochemical analysis of the vaccine oncoantigens will also be correlated with induction of antigen-specific T-cell responses. Finally, to explore the infiltration of tumors with T-cells and the potential presence of an immunosuppressive tumor microenvironment, immunohistochemistry for immune checkpoints (including PDL1/PD1, CTLA4) and immune suppressive cell subsets (T-regs, macrophages) will be performed.

Primary Objective: To evaluate the rate of peptide-specific CTL induction to S-588210 within the first 8 months in HLA-A\*02:01-positive patients with MPM who have not progressed on first-line pemetrexed-based chemotherapy treated on a weekly or every other week vaccination schedule. Secondary Objectives: 1. To evaluate the safety of S-588210 in HLA-A\*02:01-positive patients with MPM treated with S-588210 2. To determine the disease control rate (DCR) in HLA-A\*02:01-positive patients with MPM treated with S-588210 3. To determine the progression-free-survival (PFS) in HLA-A\*02:01-positive patients with MPM who have not progressed on first-line pemetrexed-based chemotherapy and who are treated with S-588210 4. To evaluate the peptide-specific CTL response to S-588210 over time up to 8 months in HLA-A\*02:01-positive patients with MPM who have not progressed on first-line pemetrexed-based chemotherapy

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Conditions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients with unresectable MPM that have completed 4-6 cycles of standard first-line pemetrexed-based chemotherapy for at least 1 month and have not progressed * Age\>18 * Able to provide informed consent for the study * HLA-A\*02:01 positive * ECOG PS=0-1 at enrollment * Measurable indicator lesion by modified RECIST criteria * Adequate bone marrow (ANC \> 1000cells/ml, PLT \> 50,000/ml, Hg \> 8gr/dL), renal (Cr \> 2.5xUNL) and liver function (AST, ALT\< 3x UNL, total bilirubin \< 2x UNL, ALP \< 3x UNL) * Archival tumor tissue available for IHC (1 paraffin-embedded block) * Epithelioid or biphasic histology Exclusion Criteria: * Chemotherapy or investigational antineoplastic drug within 1 month of planned initiation of vaccine therapy * Patients who received DEPDC1, MPHOSPH1, URLC10, CDCA1, or KOC1 peptide vaccines before * Active treatment with corticosteroids or other immunosuppressive agents * Patients who are expected to require any of the following therapies between enrollment and completion or discontinuation of the study treatment: 1. immunosuppressive drugs, including corticosteroids, methotrexate, mercaptopurine, azathioprine, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, ATG (anti-thymoglobulin), IL2-receptor antibodies (basiliximab, daclizumab), TNF-a antibodies (infliximab, etanercept, adalimumab) 2. radiotherapy for the target disease 3. surgical therapy for the target disease * History of bone marrow transplantation * Active infection * Human immunodeficiency virus infection * History of or active systemic autoimmune disorder or immunodeficiency syndromes * History of severe (CTCAE v.4.03 grade 3 or higher) allergic reaction to a drug, vaccination, or biological preparation. * Pregnancy * Patients who cannot or do not intend to practice effective contraception * Severe illness requiring hospitalization * Lymphocytes \<15% of total WBCs at baseline * Sarcomatoid histology * Severe (CTCAE v.4.03 grade 3 or higher) concurrent hepatic impairment, renal impairment, heart disease, hematological disease, respiratory disease, or metabolic disease

Outcomes

Primary Outcomes

Proportion of patients who show in vitro cytotoxic T lymphocyte induction to at least 2 of the 5 antigens determined by Enzyme-Linked ImmunoSpot (ELISPOT) assay

Time frame: Within 8 months from initiation of vaccination

Secondary Outcomes

Toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Time frame: Up to 4 weeks

Disease control rate defined as the proportion of patients who are assessed as having complete response (CR), partial response (PR), or stable disease (SD) (>3 months)

Time frame: 6 months

6-month progression-free survival (PFS) rate

Time frame: 6 months

Peptide-specific cytotoxic T lymphocyte response determined by Enzyme-Linked ImmunoSpot (ELISPOT) assay

Time frame: At 2, 3, 4, 6 and 8 months of vaccination