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A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid
Mohammad Wasif Saif1,2, Shrikar Rajagopal3, Jennifer Caplain3
1Northwell Health Cancer Institute, 1111 Marcus Avenue, 2nd Floor, Lake Success, NY, 11042, USA. wsaif@northwell.edu.
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.
Insights
Metformin can be safely combined with chemotherapy in solid tumor patients. This combination therapy activates AMPK, potentially explaining why nearly half of patients experienced no disease progression.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Metformin activates AMP-related pathways, inhibiting mTOR, a key driver of cancer growth.
- Epidemiological studies suggest metformin use is associated with reduced cancer incidence and improved survival.
Purpose of the Study:
- To assess the safety and tolerability of metformin in combination with chemotherapy in patients with solid tumors.
- To evaluate dose-limiting toxicities (DLTs) and adverse events (AEs) of the combination therapy.
Main Methods:
- A prospective, two-stage, randomized phase I trial involving 100 non-diabetic patients with solid tumors.
- Patients received either concurrent metformin and chemotherapy or chemotherapy alone, with crossover in the delayed arm.
- Assessed DLTs, AEs, response rates, and translational correlates including AMPK phosphorylation in peripheral blood mononuclear cells (PBMCs).
Main Results:
- The combination of metformin and chemotherapy demonstrated a DLT rate of 6.1%, comparable to chemotherapy alone (7.8%).
- No cases of lactic acidosis or hypoglycemia were observed.
- Stable disease was observed in 46% of patients at metformin cessation, and 28% with measurable tumor markers showed improvement.
- A significant four- to sixfold increase in AMPK phosphorylation was noted after metformin administration.
Conclusions:
- Metformin can be safely administered in combination with chemotherapy for solid tumors.
- The observed increase in AMPK phosphorylation post-metformin may contribute to the lack of disease progression in a substantial portion of patients.
