title: 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.
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Muhammad R
authors.initials: MR
authors.lastname: Khawaja
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.affiliation: Thomas Cancer Center and Affiliated Hospitals, Charleston, WV, USA.
authors.forename: Vinu
authors.initials: V
authors.lastname: Madhusudanannair
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Lacey M
authors.initials: LM
authors.lastname: McQuinn
authors.affiliation: Department of Diagnostic Radiology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chaan S
authors.initials: CS
authors.lastname: Ng
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Apostolia
authors.initials: A
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Karp
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA.|Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.|Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA. anaing@mdanderson.org.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D066066:Response Evaluation Criteria in Solid Tumors; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: C401859:temsirolimus; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Advanced/refractory cancer; Metformin; Temsirolimus; mTOR