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

Muhammad 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)973-977
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume77
Issue number5
DOIs
StatePublished - Mar 24 2016

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Metformin
Refractory materials
Patient treatment
Sirolimus
Neoplasms
Drug Combinations
Titration
Carcinosarcoma
Toxicity
Mucositis
Labels
Therapeutics
temsirolimus
Sarcoma
Renal Insufficiency
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Khawaja, Muhammad ; Nick, Alpa M. ; Madhusudanannair, Vinu ; Fu, Siqing ; Hong, David ; McQuinn, Lacey M. ; Ng, Chaan S. ; Piha-Paul, Sarina A. ; Janku, Filip ; Subbiah, Vivek ; Tsimberidou, Apostolia ; Karp, Daniel ; Meric-Bernstam, Funda ; Lu, Karen H. ; Naing, Aung. / Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. In: Cancer Chemotherapy and Pharmacology. 2016 ; Vol. 77, No. 5. pp. 973-977.
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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.",
author = "Muhammad Khawaja and Nick, {Alpa M.} and Vinu Madhusudanannair and Siqing Fu and David Hong and McQuinn, {Lacey M.} and Ng, {Chaan S.} and Piha-Paul, {Sarina A.} and Filip Janku and Vivek Subbiah and Apostolia Tsimberidou and Daniel Karp and Funda Meric-Bernstam and Lu, {Karen H.} and Aung Naing",
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Khawaja, M, 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 2016, 'Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers', Cancer Chemotherapy and Pharmacology, vol. 77, no. 5, pp. 973-977. https://doi.org/10.1007/s00280-016-3009-7

Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. / Khawaja, Muhammad; Nick, Alpa M.; Madhusudanannair, Vinu; Fu, Siqing; Hong, David; McQuinn, Lacey M.; Ng, Chaan S.; Piha-Paul, Sarina A.; Janku, Filip; Subbiah, Vivek; Tsimberidou, Apostolia; Karp, Daniel; Meric-Bernstam, Funda; Lu, Karen H.; Naing, Aung.

In: Cancer Chemotherapy and Pharmacology, Vol. 77, No. 5, 24.03.2016, p. 973-977.

Research output: Contribution to journalArticle

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T1 - Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers

AU - Khawaja, Muhammad

AU - Nick, Alpa M.

AU - Madhusudanannair, Vinu

AU - Fu, Siqing

AU - Hong, David

AU - McQuinn, Lacey M.

AU - Ng, Chaan S.

AU - Piha-Paul, Sarina A.

AU - Janku, Filip

AU - Subbiah, Vivek

AU - Tsimberidou, Apostolia

AU - Karp, Daniel

AU - Meric-Bernstam, Funda

AU - Lu, Karen H.

AU - Naing, Aung

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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.

AB - 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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