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|Ref Type||Journal Article|
|Authors||Khawaja MR, Nick AM, Madhusudanannair V, Fu S, Hong D, McQuinn LM, Ng CS, Piha-Paul SA, Janku F, Subbiah V, Tsimberidou A, Karp D, Meric-Bernstam F, Lu KH, Naing A|
|Title||Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers.|
|Journal||Cancer chemotherapy and pharmacology|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||Metformin + Temsirolimus||Phase I||Actionable||In a Phase I clinical trial, the combination of Torisel (temsirolimus) and Glucophage (metformin) demonstrated safety and resulted in a clinical benefit rate of 22% in patients with advanced or refractory tumors, with 4/18 patients achieving stable disease for greater than 6 cycles (PMID: 27014780).||27014780|