SCT with Melphalan/Ascorbic Acid Safe for BRCA-Mutated PDAC

For patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who have BRCA1/2 mutations, the use of melphalan, BCNU, hydroxocobalamin (B12), and ascorbic acid followed by a stem cell transplant proved safe and feasible, according to results from the phase 1 SHARON trial (NCT04150042) presented at the European Society for Medical Oncology Congress 2025.

While the regimen was well-tolerated, the most common any grade treatment-related adverse effects (TRAEs) included neutropenia and thrombocytopenia (100%), infusion-related reaction (100%), anemia (50%), fatigue (42%), mucositis (42%), and diarrhea (25%).

Cytokine release syndrome (CRS) developed in 1 patient who was given 3.5 g/m² of ascorbic acid about 13 hours after the beginning of cycle 2. The patient was given supportive care, and the CRS resolved within 48 hours.

On day 22 of cycle 2, a patient with a history of gastric ulcer presented with a complex fluid/gas abdominal collection extending from the margin of the pancreatojejunostomy, suspicious for an anastomotic leak. The issue was resolved when a drain was placed, and antibiotics and anti-fungal therapy were given.

During or shortly after ascorbic acid infusions, infusion-related reactions (IRRs) occurred. They were resolved within about 1 hour and did not have any lasting effects. IRRs were managed with intravenous hydralazine, famotidine, narcotics, and lorazepam.

The maximum-tolerated dose of ascorbic acid was 1.5g/m² or greater. The time to neutrophil engraftment was when the absolute neutrophil count was 500/μL or greater for 3 days, with the date of engraftment on day 1 of 3. The mean time to neutrophil engraftment was 10 days, the minimum was 9, and the maximum was 13. Additionally, the time to platelet engraftment was when the platelet count was 20,000/μL or greater for 3 days, with the date of engraftment on day 1 of 3. The mean time was 14 days, the minimum was 10, and the maximum was 21.

No treatment-related deaths occurred.

The median progression-free survival (PFS) for patients with mPDAC was 14.2 months, with 18% of patients being disease-free at 23 and 48 months.

“Part of the continued study of this approach is to try to increase the dose of some of these [treatments] a little bit further. It was generally very well tolerated. Patients all got through the transplants very well. For the short term, we’re planning on enrolling anywhere from 15 to 20 more patients on the phase 1 trial and then expanding into a phase 2 trial thereafter. We hope this will be an option for patients with BRCA mutations, perhaps after platinum-based chemotherapy,” Kenneth H. Yu, MD, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center, and lead author of the SHARON trial, said in an interview with CancerNetwork®.

The trial aimed to assess patients with stage IV PDAC or breast adenocarcinoma with BRCA1/2 or PALB2 mutations.

The treatment regimen consisted of stem cell mobilization and apheresis followed by melphalan at 100 mg/m² plus BCNU at 150 mg/m², B12 at 1450 mg/m², and ascorbic acid at 1.5 to 8.0 g/m², concluded by stem cell infusion.

The primary end point was safety; the secondary end points included objective response rate, overall survival, and PFS.

Of the 12 patients enrolled in the study, gender was equally represented, the minimum age was 40 years, the maximum age was 75, the median number of lines of therapy was 3, and 91.7% of patients had PDAC. Germline mutations included 33.3% having BRCA1, 58.3% having BRCA2, and 8.3% having PALB2. The most common sites of lesions included 41.7% in the pancreas, 41.7% in the liver, 25.0% in the lung, and 16.7% in the lymph node.

Reference

Yu KH, Dahi PB, Weekes CD, et al. The SHARON trial: melphalan, BCNU, B12b, asc, and stem cells for pancreatic and breast cancer and inherited BRCA/PALB2 mutation. Presented at the European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 228P.