KEY TAKEAWAYS
- The phase I trial aimed to combine phen with dab/tram in metastatic BRAF V600-mutated melanoma pts.
- Phen was manufactured at MSKCC’s Pharmaceutical Product Facility using cGMP procedures and was administered under an IND held by MSKCC.
- The study found Phenformin 100 mg bid safe with dab/tram, which warrants further investigation.
Phenformin (phen), a biguanide that activates AMP-activated protein kinase(AMPK), can enhance BRAF inhibitors (BRAFi) effects in sensitive and BRAFi-resistant melanoma(mel) cell lines, unlike metformin. Phen can also reduce myeloid-derived suppressor cells (MDSCs), boosting the immune response against mel. Researchers aimed to combine phenformin with dabrafenib/trametinib (dab/tram) in patients(pts) with metastatic BRAF V600-mutated mel.
Bulk phen was provided by the Division of Cancer Treatment and Diagnosis of the National Cancer Institute under a materials transfer agreement. Phen was encapsulated at the Pharmaceutical Product Facility at MSKCC under cGMP procedures and used under an IND held by MSKCC. Eligible pts had metastatic BRAF V600-mutated mel. For the dose-escalation phase, prior BRAF inhibitor therapy was allowed.
The study used a 3+3 dose escalation design starting at a phen dose of 50 mg bid and standard dosing of dab/tram(150 mg bid/2 mg qd). Subsequent planned dose levels were 100 mg bid, 200 mg bid, and 300 mg bid with de-escalation to intermediate doses for toxicity. Plasma PK samples were collected and assayed by MRI Global Inc using a validated, GLP-compliant, HPLC-MS/MS assay. PBMC was collected to measure circulating MDSCs. At the recommended phase 2 dose (RP2D), we planned to treat 10 BRAF inhibitor-naïve pts.
The study enrolled 18 pts who were treated with a medication. They tried increasing the dose to 200 mg twice daily and then 150 mg twice daily, but it wasn’t tolerated. They settled on 100 mg twice daily as the recommended dose and could only add 2 more pts due to the COVID-19 pandemic. The most common side effects were gastrointestinal issues like nausea, vomiting, and liver enzyme elevations, accounting for 9 severe reactions. About 2 pts were hospitalized for lactic acidosis, and there were other side effects related to the medication. Most pts experienced weight loss, averaging 3.7% by week 8, likely due to the medication. There were 8 partial and 2 complete responses, with some positive outcomes for pts previously receiving BRAF inhibitor therapy. One complete response lasted over a year. Among pts who had not received BRAF inhibitors before, 73% showed a positive response. At the recommended dose of 100 mg twice a day, the median phen plasma level on day 8 was 73.4 ng/ml (range 32.8-253.2), and at the 50 mg twice a day dose, it was 40.8 ng/ml (range 29.7-110.2). MDSC levels were analyzed in 7 pts at the 150 mg and 200 mg twice-a-day dose levels, and in all but 1 patient, MDSCs decreased while on phen.
The study found phen 100 mg bid safe with dab/tram, which warrants further investigation.
Source: https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.9536
Clinical Trial: https://www.clinicaltrials.gov/study/NCT03026517
Paul B. Chapman, Mark Klang, Michael A. Postow, Alexander Noor Shoushtari, Ryan J. Sullivan, Jedd D. Wolchok, Phillip Wong, Margaret K. Callahan, and Jonathan Zippin. DOI: 10.1200/JCO.2023.41.16_suppl.9536 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 9536-9536.
