Metronomic Cyclophosphamide With Pembrolizumab in Checkpoint Inhibitor Refractory 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 perAmerican Joint Committee on Cancer 8th Edition Staging Criteria not amenable tolocal therapy

• Participants must have measurable disease by RECIST v1.1 criteria as assessed byinvestigator/ radiology. Lesions situated in a previously irradiated area areconsidered 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 theUpper 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 weekdosing) prior to the first dose of the investigational therapy

• Women of childbearing potential must have had a negative pregnancy test performedwithin 7 days prior to the start of treatment

• Females of childbearing potential and males must be willing and able to use anadequate method of contraception to avoid pregnancy for the duration of the study.

• Male and female participants of childbearing potential who are sexually active witha non-sterilized partner must agree to use highly effective methods of birth controlfrom the trial screening date until 3 months after the final dose of studyintervention; cessation of birth control after this point shall be discussed with aresponsible 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 inthis 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 PrincipalInvestigator.

• Completely resected basal cell and squamous cell skin cancers.

• Any malignancy considered to be indolent and that has never required therapy, suchas chronic lymphocytic leukemia.

• Completely resected carcinoma in situ of any type

• Participants ineligible to be retreated with pembrolizumab due to atreatment-related AE while on a prior anti-PD(L)-1 regimen that led todiscontinuation of that prior therapy and would thus prevent retreatment or with animmune-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 previouslytreated 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 steroidsfor 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 firstdose 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 totolerate BRAF and/or MEK inhibitors.

• Participants with a known history of chronic viral infections as indicated below. Ifpatients do not have a known history, testing is not required during the screeningperiod 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 tothe planned first study intervention and viral load confirmed as undetectable duringScreening 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 curativetreatment and viral load is confirmed as undetectable during Screening.

• Active HIV infection. Those with HIV infections on combination antiretroviralmedications with stable CD4 count >200/microliters as measured within screening timeperiod. If the patient does not have a known history of HIV, then testing is notrequired 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. Orblood product transfusion or from any dose of hematologic growth factor.

• Glomerular filtration rate (calculated using the Chronic Kidney Disease EpidemiologyCollaboration formula) < 30 mL/min

• Total bilirubin > 1.5 × ULN; participants with Gilbert's syndrome are excluded iftotal 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