Nivolumab and Hydroxychloroquine or Nivolumab, Ipilimumab, and Hydroxychloroquine for the Treatment of Stage III-IV Melanoma

Inclusion Criteria

• Histological or cytological evidence of melanoma, unresectable stage III or stage IV, any genotype, and any PD-L1 IHC status
• Phase 1a nivolumab + HCQ: any prior treatment, or treatment naive * Phase 2 nivolumab + HCQ: ** Cohort 2a: prior immunotherapy in the adjuvant or metastatic setting is required ** Cohort 2b: patients must be anti-PD-1 Ab-naive, but may have received any prior other therapy * Phase 1b nivolumab + ipilimumab + HCQ: patients must be anti-PD-1 refractory
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Age 18 years of age or older
• Patients must have at least one measurable site of disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria that has not been previously irradiated. If there is only one RECIST 1.1 measurable lesion, serial research biopsies will not be pursued, but the patient is eligible
• Patients must have fresh or archived primary or metastatic tissue available for submission for correlative analyses
• Patients must be able to provide written informed consent
• Negative serum pregnancy test within 28 days prior to commencement of dosing in premenopausal women. Negative urine pregnancy test within 24 hours of starting treatment Women of nonchildbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for >= 1 year. Women and men must use an effective method of contraception from 14 days prior to start of treatment, throughout the treatment period, and for at least 6 months after the last dose of study treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, or intra-uterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.) Hormonal-based methods (e.g., oral contraceptives) are permitted
• Patients must be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Hemoglobin >= 9 g/dL
• Platelet count >= 100 x 10^9/L
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x upper limit of normal (ULN) * Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to enrollment
• Total bilirubin =< 1.5 x ULN * Subjects with known Gilbert’s syndrome must have a total bilirubin < 3.0 x ULN
• Aspartate aminotransferase (AST) and alanine transaminase (AL) =< 2.5 x ULN
• Serum creatinine =< 1.5 mg/dL * If serum creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft-Gault formula. Creatinine clearance must be >= 50 mL/min to be eligible

Exclusion Criteria

• Patients with known serious concurrent infection or medical illness, including psychiatric disorders, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety
• Patients who are pregnant or breast-feeding
• Patients with brain metastases treated with whole brain radiation that have been stable for 2 months are eligible; patients with brain metastases treated with gamma knife or surgery are allowed to participate after 2 weeks have elapsed since their procedure. Subjects are excluded if they have leptomeningeal disease or metastases causing spinal cord compression that are symptomatic or untreated or not stable for >= 3 months (must be documented by imaging) or requiring corticosteroids > 20 mg prednisone equivalent daily. Subjects on a stable dose of corticosteroids > 1 month or who are tapering off steroids and have reached an equivalent of 20 mg prednisone can be enrolled with approval of the study principal investigator (PI)
• Patients must have discontinued active immunotherapy (IL-2, interferon, CTLA-4, etc.), chemotherapy, or investigational anticancer therapy at least 4 weeks prior to entering the study and oral targeted therapy at least 2 weeks prior to entering the study
• All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be =< grade 1 or irreversible (hypophysitis) according to the Common Terminology Criteria for Adverse Events version 5 at the time of starting treatment. Patients that are asymptomatic on low dose maintenance hormone replacement delivered at a stable dose for prior toxicities are eligible
• Prior or concurrent cancer therapy (e.g. chemotherapy or investigational agents). Active immunotherapy (IL-2, interferon, CTLA-4, etc.), chemotherapy, or investigational anticancer therapy within 4 weeks prior to entering the study or oral targeted therapy within 2 weeks prior to entering the study * Phase 2 nivolumab + HCQ Cohort B: No prior immunotherapy is permitted
• Patients who are known to be experiencing an objective partial response to immunotherapy at the time of study enrollment
• History of malignancy other than disease under study within 3 years of study enrollment with exceptions below: Subjects with a history of completely resected non-melanoma skin cancer, or subjects with indolent second malignancies are eligible
• Diagnosis of severe autoimmune disease requiring immunosuppressive medications. Patients with adrenal insufficiency on replacement dose steroids are eligible
• History of interstitial lung disease or chronic pneumonitis unrelated to prior immunotherapy. Prior interstitial pneumonitis related to immunotherapy that was completely treated with no need for ongoing clinical management is allowed
• Due to risk of disease exacerbation patients with porphyria or psoriasis are ineligible unless the disease is well controlled and they are under the care of a specialist for the disorder who agrees to monitor the patient for exacerbations
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide
• Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (i.e. phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of the start of the study treatment
• Current use of a prohibited medication
• History or evidence of increased cardiovascular risk including any of the following: * Left ventricular ejection fraction (LVEF) < institutional lower limit of normal. Baseline echocardiogram is not required * A QT interval corrected for heart rate using the Bazett‘s formula > 500 msec * Current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment * Current >= class II congestive heart failure as defined by New York Heart Association