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

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.

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

doi

10.1007/s00280-016-3009-7

subject

Has Abstract

pub_date

2016-05-01 00:00:00

pages

973-7

issue

5

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-016-3009-7

journal_volume

77

pub_type

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