Muhammad R Khawaja1, Alpa M Nick2, Vinu Madhusudanannair3, Siqing Fu1, David Hong1, Lacey M McQuinn1, Chaan S Ng4, Sarina A Piha-Paul1, Filip Janku1, Vivek Subbiah1, Apostolia Tsimberidou1, Daniel Karp1, Funda Meric-Bernstam1,5,6, Karen H Lu2, Aung Naing7. 1. Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA. 2. Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX, USA. 3. Thomas Cancer Center and Affiliated Hospitals, Charleston, WV, USA. 4. Department of Diagnostic Radiology, MD Anderson Cancer Center, Houston, TX, USA. 5. Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA. 6. Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. 7. Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA. anaing@mdanderson.org.
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.
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.
Authors: Brian M Slomovitz; Yunyun Jiang; Melinda S Yates; Pamela T Soliman; Taren Johnston; Maureen Nowakowski; Charles Levenback; Qian Zhang; Kari Ring; Mark F Munsell; David M Gershenson; Karen H Lu; Robert L Coleman Journal: J Clin Oncol Date: 2015-01-26 Impact factor: 44.544
Authors: Ryan J O Dowling; Mahvash Zakikhani; I George Fantus; Michael Pollak; Nahum Sonenberg Journal: Cancer Res Date: 2007-11-15 Impact factor: 12.701
Authors: Sao Jiralerspong; Shana L Palla; Sharon H Giordano; Funda Meric-Bernstam; Cornelia Liedtke; Chad M Barnett; Limin Hsu; Mien-Chie Hung; Gabriel N Hortobagyi; Ana M Gonzalez-Angulo Journal: J Clin Oncol Date: 2009-06-01 Impact factor: 44.544
Authors: Helen J Mackay; Elizabeth A Eisenhauer; Suzanne Kamel-Reid; Ming Tsao; Blaise Clarke; Katherine Karakasis; Henrica M J Werner; Jone Trovik; Lars A Akslen; Helga B Salvesen; Dongsheng Tu; Amit M Oza Journal: Cancer Date: 2013-10-25 Impact factor: 6.860
Authors: Remco J Molenaar; Tim van de Venne; Mariëtte J Weterman; Ron A Mathot; Heinz-Josef Klümpen; Dick J Richel; Johanna W Wilmink Journal: Invest New Drugs Date: 2017-06-15 Impact factor: 3.850
Authors: Christian Ramos-Peñafiel; Irma Olarte-Carrillo; Rafael Cerón-Maldonado; Etta Rozen-Fuller; Juan Julio Kassack-Ipiña; Guillermo Meléndez-Mier; Juan Collazo-Jaloma; Adolfo Martínez-Tovar Journal: J Transl Med Date: 2018-09-03 Impact factor: 5.531