Phase 1/2 mercaptopurine (6‑MP) purine antagonist (DNA synthesis inhibitor) in HLRCC

This Phase 1/2, open-label, multi-cohort study evaluates oral mercaptopurine (6‑MP), a thiopurine antimetabolite/purine antagonist that disrupts DNA/RNA synthesis after intracellular activation, to define safety, tolerability, and a recommended dose while also looking for signals of activity across HLRCC manifestations. Patients take 6‑MP by mouth once daily on days 1–28 of each 28‑day cycle, continuing up to ~2 years for the kidney cancer cohort or ~1 year for uterine/skin cohorts, with serial blood sampling; imaging (CT/MRI) is used for kidney/uterine cohorts, and on-study biopsies are included for kidney tumors and skin lesions. Eligibility centers on fumarate hydratase (FH)–mutated HLRCC, with TPMT and NUDT15 wildtype requirements to reduce severe thiopurine toxicity risk. The sponsor is Jonsson Comprehensive Cancer Center (UCLA); commercially, 6‑MP is a long-approved generic (historically associated with brands such as Purinethol), so the angle is repurposing a well-known oral antimetabolite against a rare, metabolically defined hereditary cancer syndrome. For advanced HLRCC kidney cancer, today’s care often uses VEGF/EGFR-directed therapy (commonly bevacizumab + erlotinib) and/or clinical trials rather than classic clear-cell RCC standards alone, while symptomatic cutaneous/uterine leiomyomas are typically managed with procedures and symptom-directed medications—this trial tests whether systemic 6‑MP can modify multiple disease manifestations in a genotype-selected population.