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Oncology
Protocol
Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours
  1. Remco J Molenaar1,2,
  2. Robert JS Coelen3,
  3. Mohammed Khurshed1,2,
  4. Eva Roos3,
  5. Matthan WA Caan4,
  6. Myra E van Linde5,
  7. Mathilde Kouwenhoven6,
  8. Jos AM Bramer7,8,
  9. Judith VMG Bovée1,9,
  10. Ron A Mathôt10,
  11. Heinz-Josef Klümpen1,
  12. Hanneke WM van Laarhoven1,
  13. Cornelis JF van Noorden2,
  14. W Peter Vandertop8,11,
  15. Hans Gelderblom12,
  16. Thomas M van Gulik3,
  17. Johanna W Wilmink1
  1. 1 Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
  2. 2 Department of Medical Biology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
  3. 3 Department of Experimental Surgery, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
  4. 4 Department of Radiology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
  5. 5 Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
  6. 6 Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands
  7. 7 Department of Orthopaedic Surgery, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
  8. 8 Department of Neurosurgery, Academic Medical Centre, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
  9. 9 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  10. 10 Department of Clinical Pharmacology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands
  11. 11 Department of Neurosurgery, VU University Medical Centre, Amsterdam, The Netherlands
  12. 12 Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands
  1. Correspondence to Dr Johanna W Wilmink; j.w.wilmink{at}amc.uva.nl

Abstract

Introduction High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.

Methods and analysis We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.

Ethics and dissemination This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal.

Trial registration number This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.

  • Adult oncology
  • Hepatobiliary tumours
  • Neurological oncology
  • Sarcoma
  • Magnetic resonance imaging
  • Clinical trials

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjopen-2016-014961

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    Footnotes

    • Contributors RJM and JWW conceived and designed the study. RJSC, MK, MEvL, JAMB, JVMGB, RAM, HWMvL, CJFvN, WPV, HG and TMvG guided the study design. RJM wrote the manuscript. All authors read and approved the final manuscript.

    • Funding This study is funded by the Dutch Cancer Society (KWF grant 10460). RJM is supported by an AMC PhD Scholarship. RJM, MK and CJFvN are supported by the Dutch Cancer Society (KWF grant UVA 2014-6839). These funders have no role in the study.

    • Competing interests None declared.

    • Ethics approval The clinical trial protocol with version number 1.2 (22 September 2015) received approval from the Medical-Ethical Committee of the Academic Medical Centre, Amsterdam (MEC-AMC), the Netherlands, and the Dutch national competent authority (CCMO) on 22 October 2015 and 13 January 2016, respectively.

    • Provenance and peer review Not commissioned; externally peer reviewed.