Skip to main content

Advertisement

SpringerLink
Log in

A phase I study of temsirolimus and metformin in advanced solid tumours

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

The purpose of this phase I trial was to establish the maximum tolerated dose and define the dose-limiting toxicities of a combination of temsirolimus and metformin. Patients with advanced solid tumours who had exhausted standard treatment options were eligible. Treatment included weekly intravenous temsirolimus and daily oral metformin. Eleven patients were enrolled. Dose-limiting toxicities were observed in all patients at the initial dose level of 25 mg weekly of temsirolimus and metformin 500 mg po BID. At dose level -1, 2 of 8 patients experienced dose-limiting toxicities. Toxicities included grade 4 pneumonitis, persistent grade 3 fatigue, and thrombocytopenia requiring dose delays. The maximum tolerated dose (level -1) was 20 mg temsirolimus weekly and 500 mg po daily of metformin. One patient with head and neck cancer experienced a partial response. Five patients had stable disease including a patient with melanoma who had stable disease for 22 months.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sabatini DM (2006) mTor and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734

    Article  PubMed  CAS  Google Scholar 

  2. Shor B, Zhang WG, Toral-Barza L, Lucas J, Abraham RT, Gibbons JJ, Yu K (2008) A new pharmacologic action of CCI-779 involves FKBP 12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 68:2934–2943

    Article  PubMed  CAS  Google Scholar 

  3. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ, Global ARCC Trial (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281

    Article  PubMed  CAS  Google Scholar 

  4. Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822–3829

    Article  PubMed  CAS  Google Scholar 

  5. Oza AM, Elit L, Biagi J, Chapman W, Tsao M, Hedley D, Hansen C, Dancey J, Eisenhauer E (2006) Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer—NCIC IND 160. Proc Am Sci Clin Oncol Part I 24(18S), abstract 3003

    Google Scholar 

  6. Okuno SH, Mahoney MR, Bailey HH, Adkins DR, Maples WJ, Ettinger D, Fitch TR, Bot BM, Erlichman CE (2006) A multicenter phase 2 consortium (P2C) study of the mTOR inhibitor CCI-779 in advanced soft tissue sarcomas (STS). Proc Am Sci Clin Oncol Part I 24(18S), abstract 9504

    Google Scholar 

  7. Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, Le L, Oza A, Nicklee T, Ho J, Birle D, Pond GR, Arboine D, Dancey J, Aviel-Ronen S, Tsao MS, Hedley D, Siu LL (2006) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95:1148–1154

    Article  PubMed  CAS  Google Scholar 

  8. Ml R, Schadt EE (2007) Pharmacogenetics of metformin response: a step in the path toward personalized medicine. J Clin Invest 117:1126–1129

    Google Scholar 

  9. Bowker SL, Veuglers P, Majumdar SR, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diab Care 29:254–258

    Article  Google Scholar 

  10. Evans SM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305

    Article  PubMed  Google Scholar 

  11. Zakihani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP-kinase dependent growth inhibitor for breast cancer cells. Cancer Res 66:10269–10273

    Article  Google Scholar 

  12. Alimova IN, Liu B, Edgerton S, Dillon T, Thor A (2007) Metformin, an anti-diabetic agent inhibits breast cancer cell growth in vitro. AACR Annual Meeting 2007 Abstract 3277

  13. Buzzai M, Jones RJ, Lum ARK, JJ DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53 deficient tumor cell growth. Cancer Res 67:6745–6752

    Article  PubMed  CAS  Google Scholar 

  14. Zakikhani M, Pollack M (2007) Adiponectin and metformin inhibit prostate and colon cancer cell proliferation via AMP kinase dependent mechanism. AACR Annual meeting 2007 Abstract 4467

  15. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM (2007) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297–3302

    Article  Google Scholar 

  16. Sengupta TK, Leclerc GM, Hsieh-Kinser TT, Leclerc GJ, Singh I, Barredo JC (2007) Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia cells: implication for targeted therapy. Mol Cancer 6:46

    Article  PubMed  Google Scholar 

  17. Elizalde VS, Russillo M, Scaltriti M, Rodriguez O, Guzman M, Di Cosimo S, Baselga J (2010) Dual-targeting of AMPK and PI3K/mTOR in a panel of breast cancer cell lines. Proc Am Assoc Cancer Res Annual Gen Meeting abstract 4477

  18. Zakikhani M, Blouin MJ, Piura E, Pollack MN (2010) Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 123:271–279

    Article  PubMed  CAS  Google Scholar 

  19. Armstrong AJ, George DJ, Halabi S (2010) Evaluation of serum lactate dehydrogenase (LDH) as a predictive biomarker for mTOR inhibition in patients with metastatic renal cell carcinoma (RCC). Proc Am Sco Clin Oncol Genitourinary Symposium 2010, abstract 324

  20. Woodard J, Platanias LC (2010) AMP-activated kinase (AMPK)-generated signals in malignant melanoma cell growth and survival. Biochem Biophys Res Commun 398(1):135–139

    Article  PubMed  CAS  Google Scholar 

  21. Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AKL, Gans ROB, de Vries EGE (2010) Metformin: taking the candy away for cancer? Eur J Cancer 46:2369–2380

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. London Health Sciences Centre, 790 Commissioners Rd. East, London, ON, Canada, N6A 4L6

    Mary J. MacKenzie, Scott Ernst, Craig Johnson & Eric Winquist

Authors
  1. Mary J. MacKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott Ernst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Craig Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Winquist
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary J. MacKenzie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

MacKenzie, M.J., Ernst, S., Johnson, C. et al. A phase I study of temsirolimus and metformin in advanced solid tumours. Invest New Drugs 30, 647–652 (2012). https://doi.org/10.1007/s10637-010-9570-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-010-9570-8

Keywords

Search

Navigation