TPS9599 Background: Immune checkpoint inhibitors (ICI) are standard of care treatment in advanced, metastatic melanoma as well as adjuvant treatment of resected high-risk disease. However, approximately 50% of patients do not respond to primary anti-programmed death ligand-1 (anti-PD1) treatment (primary resistance) or progress after initial response (secondary resistance). Second line treatments in this setting include addition of the anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) drug ipilimumab or targeted treatment in BRAF mutant melanomas. However, CTLA-4 blockade can confer significant immune-mediated toxicity in a low performance status (PS) population, and not all patients are eligible for BRAF/MEK inhibition. There remains an unmet clinical need to optimize ICI efficacy and overcome resistance. It is hypothesized that suppressive regulatory T-cells (T reg )may inhibit the anti-tumor effect of ICI. Cyclophosphamide (CTX) is an alkylating anticancer agent. Prior studies in patients with recurrent ovarian cancer and soft tissue sarcoma have demonstrated that the combination of anti-PD1 agents with metronomic, or low dose, frequent, CTX was effective with no new safety signals. Methods: This phase 2, single-center, single-arm study explores the efficacy of adding oral metronomic CTX to intravenous pembrolizumab in patients with ICI-refractory locally advanced or metastatic melanoma. Key inclusion criteria are measurable disease by RECIST v.1.1 and receipt of investigational treatment within 9 weeks of last ICI treatment. Patients may have previously received single agent pembrolizumab or dual ICI with anti-LAG3 and anti-PD1 (relatlimab/nivolumab). Key exclusion criteria are symptomatic, untreated brain metastases, BRAF V600 mutation without prior receipt of BRAF/MEK inhibition, or prior grade 3 or greater immune-related adverse event (irAE). The primary endpoint is objective response rate (RR) as defined by complete response (CR) + partial response (PR) by RECIST v 1.1. A Simon's minimax two-stage design will be used, with the null hypothesis that the true response rate is .05 and the alternative hypothesis that true response rate is 0.3. In Stage I, a total number of 7 patients will be accrued. If there are 0 responses among 7 patients, the study will be stopped; otherwise, an additional 7 patients will be accrued to Stage II. 3 of 14 planned patients have been enrolled. This trial was approved by the UC Irvine Institutional Review Board; approval number is 6168. Trial registration NCT06771544. Clinical trial information: NCT06771544 .
Vaidya et al. (Thu,) studied this question.