This is a phase 2, single-arm, open label clinical trial determining efficacy of Cyclophosphamide and Pembrolizumab in subjects with melanoma.

Inclusion Criteria:

• Age ≥18 years at the time of signing informed consent form (ICF)
• Patients must have unresectable Stage III or Stage IV non-ocular melanoma per American Joint Committee on Cancer 8th Edition Staging Criteria not amenable to local therapy
• Participants must have measurable disease by RECIST v1.1 criteria as assessed by investigator/ radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
• Participants must have Eastern Cooperative Group (ECOG) performance status score of 0, 1 or 2 at screening visit.
• Life expectancy of at least 12 weeks
• Adequate bone marrow, liver, and renal function
• Hemoglobin ≥9.0 g/dL
• Platelets ≥100/mm3
• ANC ≥1.5/mm3
• Creatinine Clearance ≥ 30mL/min Cockcroft-Gault CrCl, mL/min = (140 - age) × (weight, kg) × (0.85 if female) / (72 × Cr, mg/dL).
• AST and ALT less than 3 times the Upper Limit of Normal or less than 5 times the Upper Limit of normal with liver metastases. T Bilirubin < 3.1 mg/dL.
• Has progressed on a prior PD-1/PD-L1 treatment
• Recovered from toxicities of pembrolizumab to Grade ≤1, excluding endocrine toxicities
• Prior Receipt of PD-1/PD-L1 therapy within 9 weeks prior to the first dose of the investigational therapy.
• Women of childbearing potential must have had a negative pregnancy test performed within 7 days prior to the start of treatment
• Females of childbearing potential and males must be willing and able to use an adequate method of contraception to avoid pregnancy for the duration of the study.
• Male and female participants of childbearing potential who are sexually active with a non-sterilized partner must agree to use highly effective methods of birth control from the trial screening date until 3 months after the final dose of study intervention; cessation of birth control after this point shall be discussed with a responsible physician.
• Pregnant or lactating women are prohibited from enrolling in this study.
• Male participants are not allowed to donate sperm from the time of enrollment until 6 months after administration of study interventions.

Exclusion Criteria:

• Participants with a diagnosis of ocular or metastatic uveal melanoma
• Participants with a history of a malignant disease other than those being treated in this study. The following exceptions are permitted:
• Malignancies that were treated curatively and have not recurred within 2 years. Shorter intervals can be considered after discussion with the Principal Investigator.
• Completely resected basal cell and squamous cell skin cancers.
• Any malignancy considered to be indolent and that has never required therapy, such as chronic lymphocytic leukemia.
• Completely resected carcinoma in situ of any type
• Participants ineligible to be retreated with pembrolizumab due to a treatment-related AE while on a prior anti-PD(L)-1 regimen that led to discontinuation of that prior therapy and would thus prevent retreatment or with an immune-related adverse event (irAE) of grade 3 or greater
• Participants with known untreated or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. NOTE: Participants with previously treated brain metastases may participate provided ALL of the following apply:
• Treated CNS lesions are radiographically stable (without evidence of progression for ≥ 28 days prior to the first dose of study intervention) after intervention (eg, surgery and/or radiation).
• Neurologically stable and on stable dose of ≤ 10mg of prednisone equivalent steroids for at least 7 days prior to the first dose of study intervention.
• Any prior investigational or standard cancer therapy, with exception of PD-1/PD-L1 (includes nivolumab + Relatlimab) therapy, chemotherapy or radiation within 6-9 weeks of the first dose of the investigational therapy (see Inclusion Criteria)
• Presence of B-RAF driver mutation without prior receipt of BRAF +/- MEK inhibitors, unless patient declines BRAF +/-MEK inhibition for any reason or is unable to tolerate BRAF and/or MEK inhibitors.
• Participants with a known history of chronic viral infections as indicated below. If patients do not have a known history, testing is not required during the screening period to confirm the patient has an active infection.
• Known HBV infection defined as hepatitis B surface antigen reactive. NOTE: Participants with HBV infection on stable anti-viral therapy for > 4 weeks prior to the planned first study intervention and viral load confirmed as undetectable during Screening may be eligible.
• Known active HCV infection defined as detectable HCV RNA (qualitative) infection. NOTE: History of HCV is not exclusionary if participant has received curative treatment and viral load is confirmed as undetectable during Screening.
• Active HIV infection. Those with HIV infections on combination antiretroviral medications with stable CD4 count >200/microliters as measured within screening time period. If the patient does not have a known history of HIV, then testing is not required during screening to confirm presence or absence of HIV.
• Positive serum pregnancy test
• Participants with out-of-range screening laboratory values as defined below. NOTE: Hematology evaluations must be performed >7 days from any blood transfusion. Or blood product transfusion or from any dose of hematologic growth factor.
• Glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula) < 30 mL/min
• Total bilirubin > 1.5 × ULN; participants with Gilbert's syndrome are excluded if total bilirubin > 3.0 × ULN; or direct bilirubin > 1.5 × ULN
• Albumin < 3.0 g/dL
• Absolute lymphocyte count < 0.5 × 10^9/L
• Participants with a history of allogeneic tissue/solid organ transplant