A Study of Nivolumab and Hydroxychloroquine or Nivolumab/Ipilimumab and Hydroxychloroquine in Advanced Melanoma

Inclusion Criteria:

• Histological or cytological evidence of melanoma, unresectable Stage III or StageIV, any genotype, and any programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) status

• Phase 1a: nivolumab + HCQ: any prior treatment, or treatment naïve

• Phase 2: nivolumab + HCQ:

• Cohort 2a: prior immunotherapy in the adjuvant or metastatic setting isrequired

• Cohort 2b: anti-PD-1 Ab-naïve, but may have received any prior othertherapy

• Phase 1b nivolumab + ipilimumab + HCQ: anti-PD-1 refractory

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• At least one measurable site of disease by RECIST 1.1 criteria that has not beenpreviously irradiated.

• Fresh or archived primary or metastatic tissue available for submission forcorrelative analyses

• Negative serum pregnancy test within 28 days prior to commencement of dosing inpremenopausal women. Negative urine pregnancy test within 24 hours of startingtreatment.

• Able to swallow and retain oral medication and no clinically significantgastrointestinal abnormalities that may alter absorption such as malabsorptionsyndrome or major resection of the stomach or bowels

• Adequate baseline organ function

Exclusion Criteria:

• Known serious concurrent infection or medical illness, including psychiatricdisorders, which would jeopardize the ability to receive the protocol treatment withreasonable safety.

• Pregnant or breast-feeding.

• Patients with brain metastases treated with whole brain radiation that have beenstable for 2 months are eligible; patients with brain metastases treated with gammaknife or surgery are allowed to participate after 2 weeks have elapsed since theirprocedure. Subjects are excluded if they have leptomeningeal disease or metastasescausing spinal cord compression that are symptomatic or untreated or not stable forgreater than or equal to 3 months (documented by imaging) or requiringcorticosteroids greater than 20 mg prednisone equivalent daily.

• Must have discontinued active immunotherapy, chemotherapy, or investigationalanticancer therapy at least 4 weeks prior to entering the study and oral targetedtherapy at least 2 weeks prior to entering the study.

• All prior anti-cancer treatment-related toxicities (except alopecia and laboratoryvalues listed in protocol eligibility) must be less than or equal to Grade 1 orirreversible (hypophysitis) according to the Common Terminology Criteria for AdverseEvents version 5 at the time of starting treatment. Patients that are asymptomaticon low dose maintenance hormone replacement delivered at a stable dose for priortoxicities are eligible.

• Prior or concurrent cancer therapy. Active immunotherapy, chemotherapy, orinvestigational anticancer therapy within 4 weeks prior to entering the study ororal targeted therapy within 2 weeks prior to entering the study

• Phase 2 nivolumab + HCQ Cohort B: No prior immunotherapy is permitted

• Patients known to be experiencing an objective partial response to immunotherapy atthe time of study enrollment.

• History of malignancy other than disease under study within 3 years of studyenrollment EXCEPT: history of completely resected non-melanoma skin cancer, orhistory of 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 priorimmunotherapy. Prior interstitial pneumonitis related to immunotherapy that wascompletely treated with no need for ongoing clinical management is allowed.

• Due to risk of disease exacerbation patients with porphyria or psoriasis areineligible unless the disease is well controlled and they are under the care of aspecialist for the disorder who agrees to monitor the patient for exacerbations.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugschemically 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 weeksof the start of the study treatment

• Current use of a prohibited medication as described in section on Potential forDrug-Drug Interaction.

• History or evidence of increased cardiovascular risk