Abstract C44: Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced cancers
Authors: Khawaja Muhammad Rizwan , Madhusudanannair Vinu , Ng Chaan , Nick Alpa , Janku Filip , Piha-Paul Sarina , Coleman Robert , Soliman Pamela , Fu Siqing , Hong David , Karp Daniel , Subbiah Vivek , Tsimberidou Apostolia , Meric-Bernstam Funda , Lu Karen , Naing Aung 
Published: May 2016

Abstract
Background: The mTOR inhibitors may result in upregulation of Akt, leading to undesirable cell proliferation. Metformin inhibits mTOR through different mechanisms and may enhance antitumor activity of Temsirolimus.
Objectives: Primary objectives of this open-label phase 1 trial were to evaluate safety and tolerability, and to determine the maximum tolerated dose (MTD) of Temsirolimus plus Metformin combination in patients with advanced cancers refractory to standard therapies. Secondary objective was to assess clinical tumor response with this combination.
Methods: A fixed dose of intravenous (IV) Temsirolimus 25mg weekly was combined with an escalating dose of oral Metformin (level-1: 500mg daily, level-2: 1000mg daily, level-3: 1500mg daily, level-4: 2000g daily) by utilizing a standard 3 + 3 design. Treatment was administered in 28-day cycles following an initial 2 weeks of Metformin titration during the first cycle. MTD was defined as the highest dose studied in which the incidence of dose-limiting toxicity (DLT) was less than 33%.
Results: Twenty-one patients (male/female: 7/14) with sarcoma (n = 8), colorectal cancer (n = 3), endometrial cancer (n = 4), uterine carcinosarcoma (n = 2), ovarian cancer (n = 2) and other cancers (n = 2) were enrolled. Median age of patients was 56 (range 18-81) years. Patients had received median of 4 (range 2-11) lines of prior systemic treatments. Three DLTs were observed including one grade 3 mucositis in a patient with dose level-1, one grade 2 pneumonitis in level-2 and one grade 3 renal failure in level-4; all 3 patients who experienced DLT were able to continue treatment after dose modification. No grade 4 or 5 toxicities were observed. Patients continued treatment for a median of 11 (range 1-99; interquartile range 8-25) weeks.
Conclusion: Combination of Temsirolimus and Metformin is feasible and well tolerated. We recommend a dose of Temsirolimus 25mg IV weekly and Metformin 2000mg orally daily administered in 28-day cycles for phase 2 study. The combination showed modestly promising effectiveness among this cohort of heavily pretreated patients. Further expansion is being conducted among patients with metastatic endometrial cancer.
Citation Format: Muhammad Rizwan Khawaja, Vinu Madhusudanannair, Chaan Ng, Alpa Nick, Filip Janku, Sarina Piha-Paul, Robert Coleman, Pamela Soliman, Siqing Fu, David Hong, Daniel Karp, Vivek Subbiah, Apostolia Tsimberidou, Funda Meric-Bernstam, Karen Lu, Aung Naing. Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C44.