A Phase 1b Study of the Selective HDAC Inhibitor Mocetinostat in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma

Inclusion Criteria

• •Patients must have signed and dated an Institutional Review Board/Independent Ethics Committee -approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care
• •Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study.
• •All patients must be either Stage IIIb/c or Stage IV according to the American Joint Committee on Cancer (AJCC) (7th edition) and have histologically-confirmed melanoma that is felt to be surgically unresectable in order to be eligible. Please refer to the AJCC Cancer Staging Manual, 7th edition for a description of tumor, lymph node, metastasis and staging.
• •All melanomas, except ocular/uveal melanoma, regardless of primary site of disease will be allowed; mucosal melanomas are eligible.
• •Patients must not have received prior anticancer treatment for metastatic disease (for example, but not limited to, systemic, local, radiation, radiopharmaceutical).
• •Exceptions: Surgery for melanoma and/or postresection brain radiotherapy (RT) if central nervous system (CNS) metastases and/or prior treatment with adjuvant interferon (IFN) (as described in Exclusion Criterion 2).
• •--All patients must have their disease status documented by a complete physical examination and imaging studies within 4 weeks prior to the first dose of study drug. Imaging studies must include computerized tomography (CT) scan of neck, chest, abdomen, pelvis, and all known sites of resected disease in the setting of Stage IIIb/c or Stage IV disease, and brain magnetic resonance imaging (\[MRI\], brain CT allowable if MRI is contraindicated).
• •The complete set of baseline radiographic images must be available before treatment initiation.
• •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• •Tumor tissue from the resected site of disease must be provided for biomarker analyses
• •Prior treated CNS metastases must be without MRI evidence of recurrence for at least 4 weeks after treatment. Patients must be off immunosuppressive doses of systemic steroids (≥ 10 mg/day prednisone or equivalent) for at least 14 days prior to study drug administration, and must have returned to neurologic baseline status postoperatively
• •* The 4-week period of stability is measured after the completion of the neurologic interventions (ie, surgery and/or radiation).
• •In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids (doses ≥ 10 mg/day prednisone or equivalent) must be discontinued at least 14 days before study drug administration.
• •Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration.
• •All baseline laboratory requirements will be assessed and should be obtained within 14 days of first dose of study drug. Screening laboratory values must meet the following criteria:
• •White blood cells ≥ 2000/µL
• •Neutrophils ≥ 1500/µL
• •Platelets ≥ 100 × 10³/µL
• •Hemoglobin ≥ 9.0 g/dL
• •Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance \> 40 mL/minute (using Cockcroft/Gault formula)
• •Patient Re-enrollment: This study permits the re-enrollment of a patient that has discontinued the study as a screen failure (ie, patient has not been dosed/has not been treated). If re-enrolled, the patient must be re-consented.
• •Males and females ≥ 18 years of age.
• •Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin hormone) within 24 hours prior to the start of study drug.; Women must not be breastfeeding.
• •Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug plus 30 days (duration of ovulatory cycle). The half-lives of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. Given the blinded nature of this study, WOCBP should therefore use an adequate method to avoid pregnancy for a total of 23 weeks posttreatment completion.
• •Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half lives of the study drug(s) plus 90 days (duration of sperm turnover). The half-lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Given the blinded nature of this study, men should therefore use an adequate method of contraception for a total of 31 weeks posttreatment completion.
• •Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section.