Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers

Muhammad R. Khawaja, Alpa M. Nick, Vinu Madhusudanannair, Siqing Fu, David Hong, Lacey M. McQuinn, Chaan S. Ng, Sarina A. Piha-Paul, Filip Janku, Vivek Subbiah, Apostolia Tsimberidou, Daniel Karp, Funda Meric-Bernstam, Karen H. Lu, Aung Naing

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Purpose Mammalian target of rapamycin (mTOR) inhibitors like temsirolimus may result in undesirable AKT upregulation. Metformin inhibits mTOR through different mechanisms and may enhance temsirolimus’s antitumor activity. We conducted an open-label phase I dose escalation trial of this drug combination in patients with advanced/refractory cancers. Methods Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500; level 4: 2000 mg) by utilizing a standard 3 + 3 trial design. Treatment was administered in 28-day cycles following initial 2-week metformin titration during the first cycle. Results Twenty-one patients (median age, 56 years) with sarcoma (n = 8), colorectal (n = 3), endometrial (n = 4), uterine carcinosarcoma (n = 2), ovarian (n = 2), and other (n = 2) cancers were enrolled. Patients had received median of four prior systemic treatments. Two dose-limiting toxicities were observed (grade 3 mucositis, grade 3 renal failure); both patients continued treatment after dose modification. Fifty-six percent patients had stable disease as best response; clinical benefit rate was 22 %. Patients continued treatment for median of 11 weeks. Conclusions Combination temsirolimus/metformin was well tolerated with modestly promising effectiveness among this heavily pretreated patient cohort. We recommend a dose of temsirolimus 25 mg weekly and metformin 2000 mg daily for phase II study.

Original languageEnglish (US)
Pages (from-to)973-977
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume77
Issue number5
DOIs
StatePublished - Mar 24 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Khawaja, M. R., Nick, A. M., Madhusudanannair, V., Fu, S., Hong, D., McQuinn, L. M., Ng, C. S., Piha-Paul, S. A., Janku, F., Subbiah, V., Tsimberidou, A., Karp, D., Meric-Bernstam, F., Lu, K. H., & Naing, A. (2016). Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. Cancer Chemotherapy and Pharmacology, 77(5), 973-977. https://doi.org/10.1007/s00280-016-3009-7