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

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

Eligibility Criteria:
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