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24.03.2016 | Original Article

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

verfasst von: Muhammad R. Khawaja, Alpa M. Nick, Vinu Madhusudanannair, Siqing Fu, David Hong, Lacey M. McQuinn, Chaan S. Ng, Sarina A. Piha-Paul, Filip Janku, Vivek Subbiah, Apostolia Tsimberidou, Daniel Karp, Funda Meric-Bernstam, Karen H. Lu, Aung Naing

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2016

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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.

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Titel: Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers
verfasst von: Muhammad R. Khawaja
Alpa M. Nick
Vinu Madhusudanannair
Siqing Fu
David Hong
Lacey M. McQuinn
Chaan S. Ng
Sarina A. Piha-Paul
Filip Janku
Vivek Subbiah
Apostolia Tsimberidou
Daniel Karp
Funda Meric-Bernstam
Karen H. Lu
Aung Naing
Publikationsdatum: 24.03.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2016
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3009-7

Springer Medizin

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