Clinical Trial Finder

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 ≥8.0 g/dL.

• - Platelets ≥75/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.

• - Recovered from toxicities of pembrolizumab, excluding endocrine toxicities.

• - Receipt of PD-1/PD-L1.

• - For melanoma patients: within 6 weeks (every 3 week dosing) or 9 weeks (every 6 week dosing) 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.

• - Investigational or standard immunotherapy (with exception of pembrolizumab, nivolumab, or relatlimab), 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.

• - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): > 2.5 × ULN (> 5 × ULN for participants with liver metastases) - Albumin < 3.0 g/dL.

• - Absolute neutrophil count < 1.5 × 10^9/L.

• - Absolute lymphocyte count < 0.5 × 10^9/L.

• - Platelet count < 100 × 10^9/L.

• - Hemoglobin < 9 g/dL.

- Participants with a history of allogeneic tissue/solid organ transplant

Arms

Experimental: Pembrolizumab + Cyclophosphamide

Pembrolizumab 200mg IV every 21 days or 400 mg IV every 42 days Cyclophosphamide 50mg PO daily on days 1-14 every 21 days for melanoma patients

Interventions

Drug: - Pembrolizumab

Given IV

Drug: - Cyclophosphamide

Given PO