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    DRUG:

    phenformin

    Company:
    Memorial Sloan-Kettering Cancer Center
    Drug class:
    mTOR inhibitor, AMPK activator
    Related drugs:
    9ms
    Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov)
    P1; Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025
    Combination therapy • Trial completion date • Trial primary completion date
    |
    BRAF V600E • BRAF V600 • BRAF V600K • BRAF V600E + BRAF V600K • BRAF exon 11 mutation • BRAF exon 15 mutation
    |
    MSK-IMPACT
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • phenformin
    1year
    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.
    P1 data • Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • phenformin
    over1year
    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.
    PD(L)-1 Biomarker • IO biomarker
    |
    CD8 (cluster of differentiation 8) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • IL2RA (Interleukin 2 receptor, alpha) • CD4 (CD4 Molecule) • GZMB (Granzyme B)
    |
    HIF1A expression
    |
    metformin • phenformin • imaradenant (AZD4635)
    over2years
    Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov)
    P1; Recruiting --> Active, not recruiting | N=40 --> 18
    Combination therapy • Enrollment change • Enrollment closed
    |
    BRAF V600E • BRAF V600 • BRAF V600K • BRAF exon 11 mutation • BRAF exon 15 mutation
    |
    MSK-IMPACT
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • phenformin
    over2years
    Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov)
    P1; Trial completion date: Jan 2023 --> Jan 2024 | Trial primary completion date: Jan 2023 --> Jan 2024
    Combination therapy • Trial completion date • Trial primary completion date
    |
    BRAF V600E • BRAF V600 • BRAF V600K • BRAF exon 11 mutation • BRAF exon 15 mutation
    |
    MSK-IMPACT
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • phenformin
    almost4years
    Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov)
    P1, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2021 --> Jan 2023 | Trial primary completion date: Jan 2021 --> Jan 2023
    Trial completion date • Trial primary completion date • Combination therapy
    |
    BRAF V600E • BRAF V600 • BRAF V600K • BRAF exon 11 mutation • BRAF exon 15 mutation
    |
    MSK-IMPACT
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • phenformin