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

ABSTRACT: 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.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.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.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.

SUBMITTER: Khawaja MR

PROVIDER: S-EPMC5978416 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Khawaja Muhammad R MR Nick Alpa M AM Madhusudanannair Vinu V Fu Siqing S Hong David D McQuinn Lacey M LM Ng Chaan S CS Piha-Paul Sarina A SA Janku Filip F Subbiah Vivek V Tsimberidou Apostolia A Karp Daniel D Meric-Bernstam Funda F Lu Karen H KH Naing Aung A

Cancer chemotherapy and pharmacology 20160324 5

<h4>Purpose</h4>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.<h4>Methods</h4>Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500 ...[more]

PMID: 27014780

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

Publications

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

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