metronomic cyclophosphamide with pembrolizumab in checkpoint inhibitor refractory melanoma

Conditions: Melanoma; Melanoma Stage III; Melanoma (Skin); Melanoma Stage IV

Summary: this is a phase 2, single-arm, open label clinical trial determining efficacy of cyclophosphamide and pembrolizumab in subjects with melanoma.


Eligibility criteria:
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

Keywords: melanoma melanoma, stage iii skin melanoma, stage iv pembrolizumab cyclophosphamide