Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

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

Fig. 1

Similar content being viewed by others

References

  1. Bjornsti M-A, Houghton PJ (2004) The tor pathway: a target for cancer therapy. Nat Rev Cancer 4(5):335–348

    Article  CAS  PubMed  Google Scholar 

  2. Carew J, Kelly K, Nawrocki S (2011) Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol 6(1):17–27. doi:10.1007/s11523-011-0167-8

    Article  PubMed  Google Scholar 

  3. Zakikhani M, Blouin M-J, Piura E, Pollak M (2010) Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 123(1):271–279. doi:10.1007/s10549-010-0763-9

    Article  CAS  PubMed  Google Scholar 

  4. Zakikhani 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(21):10269–10273. doi:10.1158/0008-5472.can-06-1500

    Article  CAS  PubMed  Google Scholar 

  5. Dowling RJO, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67(22):10804–10812. doi:10.1158/0008-5472.can-07-2310

    Article  CAS  PubMed  Google Scholar 

  6. Rozengurt E, Sinnett-Smith J, Kisfalvi K (2010) Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin Cancer Res 16(9):2505–2511. doi:10.1158/1078-0432.ccr-09-2229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E (2009) Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res 69(16):6539–6545. doi:10.1158/0008-5472.can-09-0418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330(7503):1304–1305. doi:10.1136/bmj.38415.708634.F7

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29(2):254–258. doi:10.2337/diacare.29.02.06.dc05-1558

    Article  PubMed  Google Scholar 

  10. Cifarelli V, Lashinger LM, Devlin KL, Dunlap SM, Huang J, Kaaks R, Pollak MN, Hursting SD (2015) Metformin and rapamycin reduce pancreatic cancer growth in obese prediabetic mice by distinct microRNA-regulated mechanisms. Diabetes 64(5):1632–1642. doi:10.2337/db14-1132

    Article  CAS  PubMed  Google Scholar 

  11. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, Thor AD, Salvesen HB (2009) Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 8(6):909–915

    Article  CAS  PubMed  Google Scholar 

  12. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung M-C, Hortobagyi GN, Gonzalez-Angulo AM (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27(20):3297–3302. doi:10.1200/jco.2009.19.6410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 IGH, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281. doi:10.1056/NEJMoa066838

    Article  CAS  PubMed  Google Scholar 

  14. MacKenzie M, Ernst S, Johnson C, Winquist E (2012) A phase I study of temsirolimus and metformin in advanced solid tumours. Invest New Drugs 30(2):647–652. doi:10.1007/s10637-010-9570-8

    Article  CAS  PubMed  Google Scholar 

  15. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B (2006) Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetologia 49(8):1711–1721. doi:10.1007/s00125-006-0316-2

    Article  CAS  PubMed  Google Scholar 

  16. Liu H, Scholz C, Zang C, Schefe JH, Habbel P, A-c Regierer, Schulz C-O, Possinger K, Eucker J (2012) Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res 32(5):1627–1637

    CAS  PubMed  Google Scholar 

  17. Mackay HJ, Eisenhauer EA, Kamel-Reid S, Tsao M, Clarke B, Karakasis K, Werner HMJ, Trovik J, Akslen LA, Salvesen HB, Tu D, Oza AM (2014) Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Cancer 120(4):603–610. doi:10.1002/cncr.28414

    Article  CAS  PubMed  Google Scholar 

  18. Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M, Levenback C, Zhang Q, Ring K, Munsell MF, Gershenson DM, Lu KH, Coleman RL (2015) Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33(8):930–936. doi:10.1200/jco.2014.58.3401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Soliman P (2015) A phase II, single-arm study of RAD001 (everolimus), letrozole, and metformin in patients with advanced or recurrent endometrial carcinoma. https://clinicaltrials.gov/ct2/show/study/NCT01797523?term=everolimus%2C+letrozole%2C+metformin&rank=1&show_desc=Y#desc. Accessed 11 April 2015

Download references

Acknowledgments

Authors acknowledge the support of Clinical Trials Support Resource and Department of Scientific Publications at M.D. Anderson Cancer Center.

Author information

Authors and Affiliations

  1. Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030, USA

    Muhammad R. Khawaja, Siqing Fu, David Hong, Lacey M. McQuinn, Sarina A. Piha-Paul, Filip Janku, Vivek Subbiah, Apostolia Tsimberidou, Daniel Karp, Funda Meric-Bernstam & Aung Naing

  2. Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX, USA

    Alpa M. Nick & Karen H. Lu

  3. Thomas Cancer Center and Affiliated Hospitals, Charleston, WV, USA

    Vinu Madhusudanannair

  4. Department of Diagnostic Radiology, MD Anderson Cancer Center, Houston, TX, USA

    Chaan S. Ng

  5. Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA

    Funda Meric-Bernstam

  6. Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Funda Meric-Bernstam

Authors
  1. Muhammad R. Khawaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alpa M. Nick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vinu Madhusudanannair
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Siqing Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lacey M. McQuinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chaan S. Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sarina A. Piha-Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Filip Janku
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vivek Subbiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Apostolia Tsimberidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Daniel Karp
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Funda Meric-Bernstam
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Karen H. Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Aung Naing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aung Naing.

Ethics declarations

Conflict of interest

This work was funded by the National Cancer Institute at the National Institute of Health (Award Number P30CA016672). The authors declare that they have no relevant conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khawaja, M.R., Nick, A.M., Madhusudanannair, V. et al. Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. Cancer Chemother Pharmacol 77, 973–977 (2016). https://doi.org/10.1007/s00280-016-3009-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-016-3009-7

Keywords

Search

Navigation