phenformin / Memorial Sloan-Kettering Cancer Center - LARVOL DELTA

Targeting oxygen consumption with metformin and phenformin have differential effects on immune cells in the tumor microenvironment (AACR 2025) - "These studies show that while both drugs target tumor oxygen consumption (via inhibition of complex I), and can delay tumor growth in vivo, they have differential effects on the TME and will need further considerations when combining with ICBs and other immunotherapies. In addition, these studies will advance our understanding of how tumor metabolism impacts anti-tumor immune responses and could lead to better design of combination therapies for cancer patients treated with diabetes management drugs."

Biomarker • Immune cell • IO biomarker • Tumor microenvironment • Breast Cancer • Melanoma • Oncology • Solid Tumor • GZMB • IFNG • IL2RA • TNFA

Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov) - P1 | N=18 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed

Trial completion • Melanoma • Oncology • Solid Tumor

Targeting oxygen consumption with metformin and phenformin have differential effects on immune cells in the tumor microenvironment (AACR 2024) - "We found that while both drugs can significantly delay tumor growth as monotherapies, only metformin showed improved anti-tumor efficacy when combined with anti-PD-1 in vivo. These studies show that while both drugs target tumor oxygen consumption (via inhibition of complex I), and can delay B16 tumor growth in vivo, they have differential effects on the TME and will need further considerations when combining with immune based therapies such as ICBs."

Biomarker • Immune cell • IO biomarker • Tumor microenvironment • Melanoma • Oncology • Solid Tumor • GZMB • IFNG • IL2RA • TNFA

Optimizing breast cancer therapy by modulating oxygen consumption (AACR 2024) - "We propose that blocking tumor oxygen consumption using deferiprone (DFP), phenformin (Phen) and metformin (Met) will improve the efficacy of PD-1/PD-L1 and A2aR blockade. In addition, DFP, Phen and Met failed to improve the anti-tumor effect of anti-PD-1 treatment in both TNBC models. Future experiments will focus on charactering the adenosine pathway in vivo in 4T1 and E0771 tumors and examine how drugs targeting A2aR and oxygen consumption (DFP, Phen and Met) influence the activation of immune cells within the tumor microenvironment and potentially combinate these two strategies to improve their anti-tumor efficacy."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HIF1A

Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov) - P1 | N=18 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 ➔ Jan 2025 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Combination therapy • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor

Phase Ib trial of phenformin in patients with V600-mutated melanoma receiving dabrafenib and trametinib. (PubMed, Cancer Res Commun) - "We identified the recommended phase 2 dose of phenformin as 50 mg bid when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells."

Journal • P1 data • Infectious Disease • Melanoma • Metabolic Disorders • Novel Coronavirus Disease • Oncology • Solid Tumor • BRAF

Targeting AMP kinase in melanoma: A phase I trial of phenformin with dabrafenib/trametinib. (ASCO 2023) - P1 | "AMPK is activated by biguanides such as metformin and phenformin (phen). We observed 10/18 (55.5%) total responses with 2/7 among previously treated pts. Circulating MDSCs decreased on treatment. Phen at 100 mg bid can be combined safely with dab/tram and should be explored in future randomized phase II trials."

P1 data • Anorexia • Gastrointestinal Disorder • Infectious Disease • Melanoma • Metabolic Disorders • Novel Coronavirus Disease • Oncology • Solid Tumor • AMPK

Optimizing breast cancer therapy by inhibiting the adenosine receptor and oxygen consumption (AACR 2023) - "In addition, we propose that blocking tumor oxygen consumption using deferiprone (DFP), phenformin (Phen) and metformin (Met) will further enhance A2aR and PD-1/PD-L1 blockade efficacy. Both 4T1-HRE and E0771-HRE demonstrated increased luciferase activity that correlated with increasing doses of CoCl2 in vitro. Future experiments will focus on characterizing the adenosine pathway in vivo in 4T1-HRE and E0771-HRE tumors and examine how drugs that target the adenosine A2AaR receptor (AZD4635), and oxygen consumption (DFP, Phen and Met) influence tumor oxygen consumption in vivo as well as the activation states of immune cells in the tumor microenvironment."

IO biomarker • Breast Cancer • Melanoma • Oncology • Solid Tumor • CD4 • CD8 • GZMB • HIF1A • IL2RA

Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov) - P1 | N=18 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Recruiting ➔ Active, not recruiting | N=40 ➔ 18

Combination therapy • Enrollment change • Enrollment closed • Melanoma • Oncology • Solid Tumor

Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2023 ➔ Jan 2024 | Trial primary completion date: Jan 2023 ➔ Jan 2024

Combination therapy • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor