The SHARON trial: A study of melphalan, BCNU, hydroxocobalamin, ascorbic acid, and autologous stem cell rescue for metastatic pancreatic cancer with an inherited BRCA mutation.

Abstract

TPS774 Background: SHARON is a phase 1, single-arm trial to assess the safety and preliminary efficacy of 2 cycles of melphalan, BCNU, hydroxocobalamin (vitamin B12b), dose-escalated vitamin C, and autologous stem cells in patients with stage IV pancreatic cancer and an inherited, deleterious BRCA1/2 mutation. Cancers that evolve in patients with a germline BRCA1/ 2 mutation generally have loss or inactivation of the wild type allele, which results in hypersensitivity to melphalan. The melphalan dose-response is log-linear: doubling the melphalan area under the curve (AUC) doubles the log reduction in clonogenic survival. The melphalan AUC that can safely be achieved with melphalan followed by stem cell rescue has the potential to provide major log reductions in cancer cell survival in BRCA-deficient cancers. However, reversion mutations in BRCA can cause resistance to DNA-crosslinking agents such as melphalan. Studies have shown that oxidizing cellular glutathione (GSH) to glutathione disulfide (GSSG) can inhibit DNA repair and hypersensitize wild-type cancer cells to melphalan. In this trial, BCNU, vitamin B12b, and vitamin C are used to increase cancer cell GSSG levels. Methods: Eligibility criteria include stage IV pancreatic cancer, an inherited deleterious BRCA1/2 mutation, life expectancy of at least 6 months, measurable or non-measurable disease, and suitability for apheresis, chemotherapy, and stem cell infusion. Prior treatment with PARP inhibitors is allowed. Stem cells are collected by apheresis. Participants receive 2 cycles of melphalan 100 mg/m2, BCNU 150 mg/m2, vitamin B12b 1.45 g/m2, and vitamin C 3, 6, or 8 g/m2 on Day −2. Stem cell infusion administered on day 0. A 2 + 4 dose-escalation schedule is employed for vitamin C. Adverse reactions summarized by CTCAE 5.0. The primary endpoint is safety, and secondary endpoints are objective response rate (overall and for metastatic lesions) and overall and progression-free survival. Amendment pending to include stage IV, BRCA-related, HER2-negative breast cancer and PALB2 mutations. The trial is enrolling at Memorial Sloan Kettering Cancer Center and Massachusetts General Hospital. Clinical trial information: NCT04150042 .