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

Abstract

Purpose 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 two-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 4 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.

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

“…Although temsirolimus is well tolerated as a single agent, phase I combination studies including temsirolimus have frequently been found to have significant toxicities . Oral mucositis was the predominant toxicity in a pediatric phase I combination of temsirolimus with cixutumumab, resulting in two grade 3 mucositis DLTs and required two dose deescalations to achieve a RP2D (temsirolimus 8 mg/m 2 ) .…”

“…12 Although temsirolimus is well tolerated as a single agent, phase I combination studies including temsirolimus have frequently been found to have significant toxicities. [16][17][18][19][20][21][22] Oral mucositis was the predominant toxicity in a pediatric phase I combination of temsirolimus with cixutumumab, resulting in two grade 3 mucositis DLTs and required two dose deescalations to achieve a RP2D (temsirolimus 8 mg/m 2 ). 19 Significant oral mucositis and hypertriglyceridemia, accounting for four DLTS, occurred in a pediatric study of temsirolimus (15 mg/m 2 weekly) with vinorelbine and cyclophosphamide for rhabdomyosarcoma.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…Two different phase I clinical trials have combined temsirolimus with metformin. In one study, 56% of patients with advanced or refractory cancers were observed with stable disease after treatment of temsirolimus and metformin [310]. In another study, one of 11 patients experienced partial response while five of the remaining patients experienced stable disease.…”

The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy

“…The antidiabetic drug metformin is one of the best examples of drug repositioning; diabetics treated with metformin exhibit a lower incidence of several cancers, and metformin is now being used in clinical trials for cancer chemotherapy [51,52]. Several studies show that a wide range of pharmaceuticals exhibit AhR activity in one or more assays, and these compounds are now being investigated as anticancer agents [24,53].…”