Study of MTG201 in Combination with Nivolumab in Patients with Relapsed Malignant Pleural Mesothelioma (H-44850)

Primary objective: To assess the efficacy of MTG201 in combination with nivolumab in patients with relapsed malignant pleural mesothelioma

Secondary objectives:
• To characterize the safety and tolerability of MTG201 when given in combination with nivolumab;
• To assess the disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) in patients treated with MTG201 plus nivolumab
• To determine duration of response (DUR), progression-free survival (PFS) and overall survival (OS) in patients treated with MTG201 plus nivolumab
• To evaluate the presence of MTG201 DNA in the serum of patients with relapsed malignant mesothelioma following intratumoral injection

Exploratory:
• To evaluate the immunogenicity of MTG201
• To evaluate biomarkers of activity

This is a Phase 2 open-label, single-arm study of MTG201 plus nivolumab in patients with malignant mesothelioma who have failed front-line cisplatin-based chemotherapy. Eligible patients will receive intratumoral MTG201 at a total dose of three x 1012 virus particles (vp). Twenty-four hours after receiving the first injection(s) of MTG201, patients will begin treatment with nivolumab, 480 mg intravenously (IV) every 4 weeks. Patients will receive additional intratumoral injections of MTG201, three x 1012 vp, on days eight, 22, and 50 (total of four doses of MTG201). Each of the initial three subjects enrolled onto the study will be observed for safety for a minimum of four weeks prior to the treatment of the next subject.

Patients will return to the study site weekly for the first month of treatment, then every two weeks for eight weeks, and every month thereafter. Patient safety will be assessed by physical examinations, vital signs, and reported adverse events (AEs). Clinical laboratory studies, including hematology, chemistry, and urinalysis will be performed weekly for the first month, every two weeks for eight weeks, then monthly thereafter. Patients will receive treatment on study for up to two years or until disease progression or intolerable toxicity.

Efforts will be made to obtain a tumor biopsy at baseline, prior to injection on day eight and prior to injection on cay 50 to assess the presence of MTG201. A CT scan with contrast will be obtained on cays 29 (end of month one), 85 (end of month three), at six months, and every three months thereafter.

Blood samples for levels of MTG201 will be obtained at one hour, four hours, and 24 hours after the first and fourth doses of MTG201 and prior to the second and third doses. Blood samples for the determination of anti-MTG201 antibodies will be obtained at baseline, one month, two months, three months, and six months.

Subject Inclusion Criteria
1. Willing and able to provide written informed consent prior to undergoing any study specific procedures.
2. Has histologically confirmed locally advanced or metastatic malignant pleural mesothelioma: a. Has failed at least 1 prior treatment regimen including a cisplatin-based chemotherapy regimen,
b. Has measurable disease per RECIST v. 1.1 (Appendix 4).
3. Aged ≥ 18 years.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 3).
5. Adequate organ function defined as: hemoglobin (Hgb) ≥ 10 g/dL, absolute neutrophil count (ANC) ≥ 1.5, platelet count ≥ 75,000, ALT/AST < 1.5 x the upper limit or normal (ULN), bilirubin < 2.0 mg/dL, and serum creatinine < 1.5 mg/dL.
6. Tumor lesion(s) judged by interventional radiologist to be amenable to intratumoral injection.
7. Female subjects must be either post-menopausal for at least 1 year or surgically sterile or, if of child-bearing potential, must agree to use an acceptable method of birth control throughout the duration of the trial and for 30 days following the last dose of study drug including nivolumab.
8. Male subjects must be either surgically sterile or must agree to have their partner use an acceptable method of birth control throughout the duration of the trial and for 30 days following the last dose of study drug including nivolumab.
4.2. Subject Exclusion Criteria
1. Is a candidate for and agrees to surgical resection of mesothelioma.
2. Has a history of or has currently active autoimmune disease or primary or acquired immunodeficiency.
3. Has a history of significant cardiovascular disease including but not limited to New York Hearth Association (NYHA) Class III/IV congestive heart failure, uncontrolled or poorly controlled arrhythmia, unstable angina, myocardial infarction or myocarditis within 6 months prior to enrollment.
4. Has a history of or active interstitial lung disease (ILD)/pneumonitis requiring treatment with systemic steroids.
5. Has an oxygen saturation by pulse oximetry of < 90%.
6. Has any active infection requiring systemic treatment.
7. Has currently active HIV, hepatitis B, or hepatitis C infection.
8. INR > 1.6, aPTT > ULN.
9. Has a history of malignancy other than mesothelioma within 1 year prior to enrollment, with the exception of carcinoma in situ postdefinitive treatment and without evidence of recurrence, and completely excised non-melanomatous carcinoma of the skin.
10. Has previously received anti-PD-1, PD-L1, or CTLA-4 inhibitor immunotherapy.
Protocol MTG201-MPM-001 V2.0
Momotaro-Gene Inc. Confidential Page 23 of 56
11. Has received chemotherapy, radiotherapy, or other therapy for mesothelioma within 4 weeks prior to baseline.
12. Has a history of, or active, clinically significant respiratory, gastrointestinal, renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator’s opinion, could affect the conduct of the study.
13. Requires treatment with an immunosuppressive agent including corticosteroids at a dose > the equivalent of 20 mg prednisone.
14. Is currently enrolled in an investigational drug or device study or has used an investigational drug or device within 30 days prior to enrollment.
15. Has a known allergy and/or sensitivity to MTG201, nivolumab or their components.