Using Cyclophosphamide and Pembrolizumab for advanced melanoma treatment

Metronomic Cyclophosphamide With Pembrolizumab in Checkpoint Inhibitor Refractory Melanoma

This study is testing if a combination of Cyclophosphamide and Pembrolizumab can help people with advanced melanoma who haven't responded to other treatments feel better and improve their health.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 14 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of California, Irvine (Academic / other)
• Drugs / interventions: pembrolizumab, nivolumab, Relatlimab, chemotherapy, radiation, prednisone, Cyclophosphamide
• Locations: 1 site (Orange, California)
• Trial ID: NCT06771544 on ClinicalTrials.gov

What this trial studies

This phase 2 clinical trial evaluates the effectiveness of combining Cyclophosphamide with Pembrolizumab in patients with unresectable Stage III or IV melanoma who have not responded to previous checkpoint inhibitor therapies. The study is single-arm and open-label, meaning all participants will receive the same treatment without a control group. Patients will be assessed for measurable disease using RECIST criteria, and their overall health will be monitored to ensure they meet specific eligibility requirements. The goal is to determine if this combination can improve outcomes for these patients.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with unresectable Stage III or IV melanoma that is not amenable to local therapy.

Not a fit: Patients with ocular melanoma or those who have not met the specified health criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment approach could provide a new option for patients with advanced melanoma who have limited treatment alternatives.

How similar studies have performed: While the combination of Cyclophosphamide and Pembrolizumab is being explored, similar approaches in treating melanoma have shown promise, but this specific combination is relatively novel.

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 ≥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

Where this trial is running

Orange, California

• Chao Family Comprehensive Cancer Center University of California, Irvine — Orange, California, United States (Recruiting)

Study contacts

• Principal investigator: Warren Chow, MD — Chao Family Comprehensive Cancer Center
• Study coordinator: Chao Family Comprehensive Cancer Center University of California, Irvine

Conditions Melanoma; Melanoma Stage III; Melanoma Stage IV; Melanoma, Stage III; Skin; Melanoma, Stage IV; Pembrolizumab; Cyclophosphamide