A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors

Amikar Sehdev, Theodore Karrison, Yuanyuan Zha, Linda Janisch, Michelle Turcich, Ezra E.W. Cohen, Michael Maitland, Blase N. Polite, Thomas F. Gajewski, Ravi Salgia, Navin Pinto, Marc B. Bissonnette, Gini F. Fleming, Mark J. Ratain, Manish R. Sharma

Research output: Contribution to journalArticle

Abstract

Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis. Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin). Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (− 0.12 vs. − 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities. Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers. Impact: Combining metformin with sirolimus did not improve mTOR inhibition.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalCancer Chemotherapy and Pharmacology
DOIs
StateAccepted/In press - Jun 9 2018

Fingerprint

Pharmacodynamics
Metformin
Sirolimus
Tumors
Neoplasms
70-kDa Ribosomal Protein S6 Kinases
Biomarkers
Toxicity
Blood Cells
Blood
Serum
C-Peptide
Random Allocation
Leptin
Insulin-Like Growth Factor I
Fasting
Triglycerides

Keywords

  • Metformin
  • P70S6K and mTOR
  • Pharmacodynamics
  • Sirolimus
  • Solid tumors

ASJC Scopus subject areas

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

Cite this

A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors. / Sehdev, Amikar; Karrison, Theodore; Zha, Yuanyuan; Janisch, Linda; Turcich, Michelle; Cohen, Ezra E.W.; Maitland, Michael; Polite, Blase N.; Gajewski, Thomas F.; Salgia, Ravi; Pinto, Navin; Bissonnette, Marc B.; Fleming, Gini F.; Ratain, Mark J.; Sharma, Manish R.

In: Cancer Chemotherapy and Pharmacology, 09.06.2018, p. 1-9.

Research output: Contribution to journalArticle

Sehdev, A, Karrison, T, Zha, Y, Janisch, L, Turcich, M, Cohen, EEW, Maitland, M, Polite, BN, Gajewski, TF, Salgia, R, Pinto, N, Bissonnette, MB, Fleming, GF, Ratain, MJ & Sharma, MR 2018, 'A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors', Cancer Chemotherapy and Pharmacology, pp. 1-9. https://doi.org/10.1007/s00280-018-3619-3
Sehdev, Amikar ; Karrison, Theodore ; Zha, Yuanyuan ; Janisch, Linda ; Turcich, Michelle ; Cohen, Ezra E.W. ; Maitland, Michael ; Polite, Blase N. ; Gajewski, Thomas F. ; Salgia, Ravi ; Pinto, Navin ; Bissonnette, Marc B. ; Fleming, Gini F. ; Ratain, Mark J. ; Sharma, Manish R. / A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 2018 ; pp. 1-9.
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AU - Sehdev, Amikar

AU - Karrison, Theodore

AU - Zha, Yuanyuan

AU - Janisch, Linda

AU - Turcich, Michelle

AU - Cohen, Ezra E.W.

AU - Maitland, Michael

AU - Polite, Blase N.

AU - Gajewski, Thomas F.

AU - Salgia, Ravi

AU - Pinto, Navin

AU - Bissonnette, Marc B.

AU - Fleming, Gini F.

AU - Ratain, Mark J.

AU - Sharma, Manish R.

PY - 2018/6/9

Y1 - 2018/6/9

N2 - Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis. Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin). Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (− 0.12 vs. − 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities. Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers. Impact: Combining metformin with sirolimus did not improve mTOR inhibition.

AB - Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis. Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin). Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (− 0.12 vs. − 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities. Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers. Impact: Combining metformin with sirolimus did not improve mTOR inhibition.

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