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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: To evaluate the safety of S-588210 in HLA-A*02:01-positive patients with MPM treated with S-588210 To determine the disease control rate (DCR) in HLA-A*02:01-positive patients with MPM treated with S-588210 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 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

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

Conditions
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Malignant Pleural Mesothelioma (MPM)

Intervention / Treatment
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* Biological: Multipeptide vaccine S-588210


Participation Criteria
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Eligibility Criteria
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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: 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) radiotherapy for the target disease 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Weekly Vaccination<br>Maintenance multipeptide vaccine (S-588210) administered every week | Biological: Multipeptide vaccine S-588210<br> <br> |
| Other: Every other Week Vaccination<br>Maintenance multipeptide vaccine (S-588210) administered every other week | Biological: Multipeptide vaccine S-588210<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Within 8 months from initiation of vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v4.03 |  | 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) |  | 6 months | 
| 6-month progression-free survival (PFS) rate |  | 6 months | 
| Peptide-specific cytotoxic T lymphocyte response determined by Enzyme-Linked ImmunoSpot (ELISPOT) assay |  | At 2, 3, 4, 6 and 8 months of vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mesothelioma, multipeptide vaccine, S-588210