Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2018 Feb;36(1):53-61.
doi: 10.1007/s10637-017-0478-4. Epub 2017 Jun 15.

A phase Ib study of everolimus combined with metformin for patients with advanced cancer

Remco J Molenaar  1   2   3 , Tim van de Venne  1   2   3 , Mariëtte J Weterman  1   3 , Ron A Mathot  4 , Heinz-Josef Klümpen  1   3 , Dick J Richel  1   3 , Johanna W Wilmink  5   6
Affiliations
Clinical Trial

A phase Ib study of everolimus combined with metformin for patients with advanced cancer

Remco J Molenaar et al. Invest New Drugs. 2018 Feb.

Abstract

Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

Keywords: Cancer; Everolimus; Metformin; Pharmacokinetics; Safety; Toxicity.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

R.J.M. declares that he has no conflict of interest. T.v.d.V. declares that he has no conflict of interest. M.J.W. declares that she has no conflict of interest. R.A.M. declares that he has no conflict of interest. H-J.K. declares that he has no conflict of interest. D.J.R. declares that he has no conflict of interest. J.W.W. declares that she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. The study protocol was approved by the Medical Ethics Committee of the Academic Medical Center (reference number NL_37906.018.12).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Concentration curves of everolimus and metformin when administered as single-agent and in combination. a Mean ± SEM of the blood everolimus concentration-time curves in μg/l of 5 evaluable patients who received 10 mg everolimus qd. b Mean ± SEM of the serum metformin concentration-time curves in mg/l of 7 evaluable patients who received 500 mg metformin bid. Everolimus and metformin levels were determined in whole blood and in serum, respectively, by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The maximum concentration levels in the figure do not necessary correspond with the Cmax as described in Table 5, because not all patients had their Cmax at the same time point
See this image and copyright information in PMC

References

    1. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35. doi:10.1038/nrm3025 - PMC - PubMed
    1. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Delle Fave G, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME, Rad001 in Advanced Neuroendocrine Tumours FTSG Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968–977. doi: 10.1016/S0140-6736(15)00817-X. - DOI - PMC - PubMed
    1. Demetri GD, Chawla SP, Ray-Coquard I, Le Cesne A, Staddon AP, Milhem MM, Penel N, Riedel RF, Bui-Nguyen B, Cranmer LD, Reichardt P, Bompas E, Alcindor T, Rushing D, Song Y, Lee RM, Ebbinghaus S, Eid JE, Loewy JW, Haluska FG, Dodion PF, Blay JY. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol. 2013;31(19):2485–2492. doi: 10.1200/JCO.2012.45.5766. - DOI - PubMed
    1. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381(9861):125–132. doi: 10.1016/S0140-6736(12)61134-9. - DOI - PubMed
    1. 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. 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. 2009;27(23):3822–3829. doi: 10.1200/JCO.2008.20.7977. - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources