A phase I study of temsirolimus in combination with metformin in patients with advanced or recurrent endometrial cancer
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Published on: June 20, 2015
Jibran Ahmed1, Bettzy Stephen1, Muhammad R Khawaja1
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Introduction:
Molecular alterations in the PI3K/AKT and Ras/Raf/MEK/ERK pathways are frequently observed in patients with endometrial cancers. However, mTOR inhibitors, such as temsirolimus, have modest clinical benefits. In addition to inducing metabolic changes in cells, metformin activates AMPK, which in turn inhibits the mTOR pathway. In this phase 1 clinical trial we hypothesized that combining metformin with temsirolimus would potentiate the antitumor activity against advanced or recurrent endometrial cancer.
Methods:
The dose-expansion cohort used a Simon Minimax two-stage design. The objectives of the endometrial cancer expansion cohort were to evaluate the clinical tumor response, as indicated by the objective response and clinical benefit rates, as well as an ongoing safety assessment of the combination treatment.
Results:
Forty patients were enrolled in this study. The most common treatment-related adverse events (reported in 32 patients) were hypertriglyceridemia (n = 14), diarrhea (n = 13), mucositis (n = 13), anorexia (n = 12), and anemia (n = 10). The grade 3 adverse events were 2 instances each of anemia and thrombocytopenia and 1 instance each of mucositis, fatigue, weight loss, hypokalemia, hypophosphatemia, and increased aspartate aminotransferase and alanine transaminase levels. Among the 33 patients evaluable for response, objective response was seen in two (6 %; both partial responses), and 13 (39 %) patients had stable disease, including 11 for ≥4 months, representing a clinical benefit rate of 39 %.
Conclusions:
The results of this single-center clinical trial showed that, in patients with advanced or recurrent endometrial cancer, metformin can be safely added to temsirolimus providing limited response without added safety concerns.
Clinical Trial Registration Number:
NCT01529593.
Insights
Metformin can be safely combined with temsirolimus in advanced endometrial cancer patients. This combination showed limited antitumor activity but no added safety concerns in a phase 1 trial.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Endometrial cancers frequently exhibit molecular alterations in PI3K/AKT and Ras/Raf/MEK/ERK pathways.
- mTOR inhibitors like temsirolimus offer modest clinical benefits.
- Metformin activates AMPK, inhibiting the mTOR pathway, suggesting a potential synergistic effect with temsirolimus.
Purpose of the Study:
- To evaluate the safety and efficacy of combining metformin with temsirolimus in patients with advanced or recurrent endometrial cancer.
- To assess clinical tumor response, including objective response and clinical benefit rates.
- To conduct an ongoing safety assessment of the combination treatment.
Main Methods:
- A phase 1 clinical trial with a Simon Minimax two-stage design for the dose-expansion cohort.
- Enrollment of forty patients with advanced or recurrent endometrial cancer.
- Evaluation of objective response, clinical benefit rates, and treatment-related adverse events.
Main Results:
- Forty patients were enrolled; common adverse events included hypertriglyceridemia, diarrhea, mucositis, anorexia, and anemia.
- Grade 3 adverse events were infrequent.
- Among 33 evaluable patients, an objective response rate of 6% (two partial responses) and a clinical benefit rate of 39% (13 patients with stable disease for ≥4 months) were observed.
Conclusions:
- Metformin can be safely added to temsirolimus in patients with advanced or recurrent endometrial cancer.
- The combination demonstrated limited antitumor response.
- No additional safety concerns were identified with the combination therapy.
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