Phase Ib/II Study of Momelotinib Combined with Anti‑PD‑1 Therapy (Nivolumab or Pembrolizumab) in Unresectable Stage III/IV Cutaneous Melanoma

Primary objective: Phase Ib – assess safety and tolerability of momelotinib combined with anti‑PD‑1 therapy and define the maximum tolerated dose and the recommended Phase II dose; Phase II – determine the preliminary anti‑tumor activity of the combination at 6 months in patients with unresectable stage III or stage IV cutaneous melanoma. Secondary objectives include: • Phase Ib – incidence of dose‑limiting toxicities and treatment‑emergent adverse events, evaluation of overall response rate, complete and partial responses, stable disease, and time to response at 3, 6 and 12 months; • Phase II – overall survival, progression‑free survival, melanoma‑specific survival, overall response rate at 3 and 12 months, duration of response, time to response, incidence and severity of adverse events, and quality‑of‑life assessment using the EORTC QLQ‑C30; • Exploratory – pharmacodynamic profiling of momelotinib, biomarker analyses of response and toxicity, and immunohistochemical assessment of SAMHD1 expression.

The sponsor did not provide the total number of participants. Eligible participants were adult men and women aged 18 years or older with histologically or cytologically confirmed unresectable stage III or stage IV cutaneous melanoma, including cutaneous, acral, or unknown primary subtypes. All subjects were required to have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 and a life expectancy greater than three months. Inclusion criteria mandated a documented BRAF mutation status, availability of a tissue sample for SAMHD1 analysis, and no prior drug insensitivity to immune‑checkpoint inhibitors or momelotinib. Female participants of childbearing potential needed a negative pregnancy test within 72 hours before the first dose and agreement to use a highly effective contraceptive method throughout the study and for 150 days after the last dose; analogous contraception requirements applied to male participants of childbearing potential. General health status allowed enrollment of patients with stable disease per RECIST v1.1 after six months of first‑line anti‑PD‑1 therapy, and participants could be classified as vulnerable according to study definitions.

The study is a Phase Ib/II clinical trial evaluating the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of the oral momelotinib tablet in combination with an anti‑PD‑1 antibody (pembrolizumab or nivolumab) in patients with unresectable stage III or stage IV cutaneous melanoma. After a screening visit to confirm eligibility criteria, baseline assessments—including physical examination, laboratory tests, imaging per RECIST v1.1, and collection of tumor and blood specimens for biomarker analyses—are performed. Eligible participants then receive the assigned study medication regimen, with oral momelotinib administered daily and intravenous pembrolizumab or nivolumab given according to the standard dosing schedule. Follow‑up visits occur at each infusion cycle (approximately every 2–3 weeks) to monitor adverse events graded by CTCAE v5.0, conduct safety laboratory evaluations, and assess compliance. Radiologic response evaluations are scheduled at 3, 6 and 12 months from the first dose, with the primary efficacy assessment at 6 months (overall response rate by RECIST v1.1). The end‑of‑study visit is conducted after completion of the 6‑month treatment period or earlier if the participant experiences disease progression, unacceptable toxicity, withdrawal of consent, or death. Overall participant involvement therefore spans approximately 6 months of active treatment plus scheduled follow‑up assessments, with additional yearly follow‑up for long‑term safety and survival outcomes as defined in the protocol.

Omjjara film‑coated tablets contain the oral kinase inhibitor momelotinib. The product is supplied in three strength variants—100 mg, 150 mg, and 200 mg per tablet. Each tablet is administered by the oral route, typically once daily according to the study dosing schedule. Compliance with the oral regimen is assessed through pill counts and patient‑reported dosing diaries.

KEYTRUDA 25 mg/mL concentrate for solution for infusion provides the anti‑PD‑1 monoclonal antibody pembrolizumab. The medication is prepared for intravenous infusion and delivered according to the protocol‑specified infusion schedule. Administration details, including dose volume and infusion frequency, are recorded in the infusion log to ensure adherence.

OPDIVO 10 mg/mL concentrate for solution for infusion delivers the anti‑PD‑1 monoclonal antibody nivolumab. This agent is administered intravenously following the protocol‑defined infusion schedule. Dosing information and infusion timing are documented in the study’s infusion records to monitor participant compliance.

Efficacy will be evaluated primarily by the overall response rate (ORR) at month 6, defined as the proportion of patients achieving a complete response (CR) or partial response (PR) according to RECIST v1.1 criteria and analyzed on an intention‑to‑treat basis. Radiological assessments will be performed at the end of 4, 6, 8 and 12 cycles of anti‑PD‑1 therapy, corresponding to the 3‑month, 6‑month and 12‑month time points, with the primary analysis conducted when all participants have completed six months of treatment or have discontinued earlier due to progression, toxicity, or withdrawal.

Secondary efficacy measures include counts of CR, PR, stable disease (SD) and progressive disease (PD) at the 3‑, 6‑ and 12‑month evaluations, clinical benefit rate (CR + PR + SD), time to response (TTR), duration of response (DoR), overall survival (OS), progression‑free survival (PFS), and melanoma‑specific survival (MSS). Quality of life will be assessed using the QLQ‑C30 questionnaire at screening and annually during follow‑up. Additional pharmacodynamic and biomarker analyses will be performed on sequential blood and tumor samples, including RNA‑sequencing, interferon‑stimulated gene expression, cytokine profiling, and circulating tumor DNA, to explore correlations with efficacy outcomes.