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A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid tumors

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Abstract

Purpose

Metformin activates AMP-related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors, crucial for cancer growth. Epidemiologic studies showed a reduced incidence and improved survival in cancer patients. We conducted a prospective phase I study to assess the safety of metformin in combination with chemotherapy in patients with solid tumors.

Methods

We conducted a delayed-start randomized trial of non-diabetic patients in two stages. In Stage 1, we randomized patients to two arms: concurrent arm (metformin with chemo) vs. delayed arm (chemo alone). In Stage 2, patients in delayed arm were crossed over to receive metformin. Patients received metformin 500 mg twice daily with chemotherapy to define dose-limiting toxicities (DLTs) in both stages. Secondary endpoints assessed adverse events (AEs) and response rates. Translational correlates included effects of metformin on expression and phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK) by western blot in PBMCs.

Results

A total of 100 patients were enrolled (51 in delayed arm vs. 49 concurrent arm). Rate of DLTs in patients receiving metformin with chemotherapy was 6.1% vs. 7.8% in patients receiving chemotherapy alone. DLTs seen with addition of metformin included those associated with established chemo adverse events. No lactic acidosis or hypoglycemia occurred. Restaging showed stable disease in 46% at cessation of metformin. 28% of patients with measurable tumor markers showed improvement. AMPK phosphorylation showed a four- to sixfold increase in AMPK phosphorylation after metformin.

Conclusions

This is the largest phase I study of metformin combined with chemotherapy, which suggests that metformin can be given safely with chemotherapy, and offers a platform for future studies. Post-metformin increase in AMPK phosphorylation may potentially explain lack of disease progression in nearly half of our patients.

Funding

UL1 TR001064.

Clinical trial information

NCT01442870.

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Acknowledgements

I wish to acknowledge and thank Diane Barker for her assistance in the tedious work of typing the several rounds of revisions, modifications and format changes, all of which are an integral part of the publication process.

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Authors and Affiliations

  1. Northwell Health Cancer Institute, 1111 Marcus Avenue, 2nd Floor, Lake Success, NY, 11042, USA

    Mohammad Wasif Saif

  2. Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA

    Mohammad Wasif Saif, Shrikar Rajagopal, Jennifer Caplain, Elizabeth Grimm, Oksana Serebrennikova, Madhumita Das, Philip N. Tsichlis & Robert Martell

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  1. Mohammad Wasif Saif
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  2. Shrikar Rajagopal
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  3. Jennifer Caplain
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Correspondence to Mohammad Wasif Saif.

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The author(s) declare that they have no competing interests.

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All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at Tufts Medical Center, Boston, MA and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Saif, M.W., Rajagopal, S., Caplain, J. et al. A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid tumors. Cancer Chemother Pharmacol 84, 1323–1331 (2019). https://doi.org/10.1007/s00280-019-03967-3

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  • DOI: https://doi.org/10.1007/s00280-019-03967-3

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