This is a single-center, open-label, single-arm Phase 1b/2 clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of pembrolizumab in combination with irinotecan in patients with metastatic melanoma who have relapsed at least 6 months after completion of adjuvant pembrolizumab therapy or who are immune checkpoint inhibitor-naïve.
The study consists of two sequential parts: a Phase 1b safety lead-in and a Phase 2 efficacy evaluation using Simon's optimal two-stage design. During the Phase 1b portion, six patients will be enrolled to assess the initial safety and tolerability of the combination regimen. Dose-limiting toxicities (DLTs) will be evaluated during the first two treatment cycles (42 days). Following completion of the safety observation period, a safety review will be conducted. If fewer than two of six patients experience a DLT, the regimen will be considered adequately tolerable and the study will proceed to the Phase 2 portion. Patients enrolled in the Phase 1b portion will be included in the efficacy analysis of Phase 2.
In the Phase 2 portion, efficacy will be evaluated using Simon's optimal two-stage design with objective response rate (ORR) as the primary endpoint. The null hypothesis ORR is 30%, and the alternative hypothesis ORR is 50%, with a one-sided type I error rate of 5% and 80% power. In Stage 1, a total of 15 evaluable patients, including the six patients enrolled during the Phase 1b portion, will be assessed. If five or fewer objective responses are observed, the study will be terminated early for futility. If six or more responses are observed, additional patients will be enrolled in Stage 2. A total of 46 patients will be enrolled, and the regimen will be considered worthy of further investigation if at least 19 objective responses are observed.
Participants will receive pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle. Irinotecan 125 mg/m² will be administered intravenously on Days 1 and 8 beginning in Cycle 2. Cycle 1 consists of pembrolizumab monotherapy to allow evaluation of early immunologic changes induced by PD-1 blockade without potential interference from irinotecan. Blood and tumor samples will be collected at baseline and prior to irinotecan administration on Cycle 2 Day 1 for translational immune analyses.
Tumor assessments will be performed according to RECIST version 1.1 every 6 weeks during the first year and every 12 weeks thereafter. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), dose-limiting toxicity (DLT), and safety and tolerability as assessed by the incidence of adverse events graded according to CTCAE version 5.0. Exploratory analyses will evaluate tumor microenvironment characteristics and peripheral blood immune biomarkers, including immune cell phenotypes, cytokine profiles, and potential biomarkers associated with treatment response and resistance.
Patients with histologically confirmed non-uveal melanoma, diagnosed as Stage IV or unresectable Stage III melanoma.
Age ≥19 years at the time of signing the informed consent form.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Patients with CNS metastases must have stable neurological function without evidence of CNS progression within 4 weeks prior to enrollment (i.e., treated/controlled or asymptomatic CNS metastases, or resected CNS metastases without radiographic evidence of disease).
Female subjects of childbearing potential (WOCBP) with a positive urine pregnancy test within 72 hours prior to study enrollment (see Appendix 3). If the urine test is positive or inconclusive, a serum pregnancy test must be performed.
Receipt of radiotherapy within 2 weeks prior to initiation of study intervention. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and have no evidence of radiation pneumonitis. For palliative radiotherapy to non-CNS disease (<2 weeks duration), a 1-week washout period is permitted.
Receipt of a live or live-attenuated vaccine within 30 days prior to the first dose of study drug. Inactivated vaccines are allowed.
Participation in another clinical study or receipt of systemic therapy (e.g., cytotoxic chemotherapy, immunotherapy, or investigational agents) within 4 weeks prior to the first dose of study intervention.
Single group
Pembrolizumab and Irinotecan
DrugParticipants will receive pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle. Cycle 1 consists of pembrolizumab monotherapy, and irinotecan 125 mg/m² will be added on Days 1 and 8 from Cycle 2 onward. The study includes a Phase 1b safety lead-in and a Phase 2 efficacy evaluation using Simon's optimal two-stage design. Treatment will continue for up to 35 cycles or until disease progression, unacceptable toxicity, or study discontinuation.
Overall Response Rate
Tumor response will be assessed according to RECIST version 1.1. ORR is defined as the proportion of patients achieving a complete response (CR) or partial response (PR) as their best overall response.
Disease Control Rate (DCR)
Disease control rate is defined as the proportion of participants who achieve complete response (CR), partial response (PR), or stable disease (SD) as their best overall response according to RECIST version 1.1.
Progression-Free Survival (PFS)
Progression-free survival is defined as the time from treatment initiation to the first documented disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first.
Overall Survival (OS)
Overall survival is defined as the time from treatment initiation until death from any cause.
Safety and Tolerability
Safety and tolerability will be assessed by the incidence, severity, and relationship to study treatment of adverse events (AEs), treatment-related adverse events (TRAAEs), and serious adverse events (SAEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
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