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Metformin And Chloroquine in IDH1/2-mutated Solid Tumors (MACIST)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02496741
Recruitment Status : Completed
First Posted : July 14, 2015
Last Update Posted : January 9, 2020
Sponsor:
Information provided by (Responsible Party):
J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information
First Submitted Date  ICMJE June 30, 2015
First Posted Date  ICMJE July 14, 2015
Last Update Posted Date January 9, 2020
Study Start Date  ICMJE November 2015
Actual Primary Completion Date November 18, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2015)
Maximum tolerated dose of metformin + chloroquine [ Time Frame: 1 year ]
The maximum tolerated dose is the chloroquine plus metformin dose in which no more than 1 in 3 patients (of a 3+3 dose-escalation schedule) observe serious adverse effects.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02496741 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2015)
  • Effect of metformin + chloroquine on serum/urine/bile D-2-hydroxyglutarate (D2HG) concentration [ Time Frame: 1 year ]
    D-2HG concentration will be measured by mass spectrometry (MS) in serum/urine/bile, at the beginning and end of the study.
  • Effect of metformin + chloroquine on intratumoral D2HG concentration [ Time Frame: 1 year ]
    Intratumoral D-2HG concentration will be measured by magnetic resonance spectroscopy (MRS), at the beginning and end of the study.
  • Effect of metformin + chloroquine on tumor response [ Time Frame: 1 year ]
    Tumor size will be measured using a MRI/CT scan before and after treatment.
  • Recommended dose of metformin + chloroquine [ Time Frame: 1 year ]
    The recommended dose is the dose of chloroquine plus metformin is the dose level one step below the maximum tolerated dose.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2015)
  • Effect of metformin + chloroquine on serum/urine/bile D2HG concentration [ Time Frame: 1 year ]
    D-2HG concentration will be measured by mass spectrometry in serum/urine/bile, at the beginning and end of the study.
  • Effect of metformin + chloroquine on intratumoral D2HG concentration [ Time Frame: 1 year ]
    Intratumoral D-2HG concentration will be measured by magnetic resonance spectroscopy, at the beginning and end of the study.
  • Effect of metformin + chloroquine on tumor response [ Time Frame: 1 year ]
    Tumor size will be measured using a MRI/CT scan before and after treatment.
  • Recommended dose of metformin + chloroquine [ Time Frame: 1 year ]
    The recommended dose is the dose of chloroquine plus metformin is the dose level one step below the maximum tolerated dose.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metformin And Chloroquine in IDH1/2-mutated Solid Tumors
Official Title  ICMJE Phase Ib Study of Metformin and Chloroquine in IDH1/2-mutated Patients With Glioma, Intrahepatic Cholangiocarcinoma or Chondrosarcoma
Brief Summary This phase Ib, open-label, single-center, non-randomized clinical trial will evaluate the toxicity and efficacy of metformin and chloroquine in isocitrate dehydrogenase 1/2-mutated (IDH1/2MT) patients with a glioma, intrahepatic cholangiocarcinoma or chondrosarcoma.
Detailed Description

Glioma, intrahepatic cholangiocarcinoma (IHCC) and chondrosarcoma (CS) are aggressive, malignant cancers with a dismal outcome, the two latter types especially in the locally-advanced or metastasized setting. This is due to a lack of effective treatment strategies and highlights the dire need for novel therapies.

A subset of these cancer types are characterized by the presence of mutations in the genes encoding for isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2). These mutations occur in 80% of world health organization (WHO) grade II and III glioma and secondary glioblastoma, 20% of IHCC and 60% of CS and, besides their oncogenic function, induce metabolic vulnerabilities to IDH1/2MT cancer cells that can be exploited in vitro by the oral antidiabetic metformin and the oral antimalarial drug chloroquine.

In the present study protocol, the investigators describe a phase Ib single-center clinical trial in which patients with glioma, IHCC or CS are being screened for IDH1/2MT using the surrogate marker D-2-hydroxyglutarate (D-2HG), which is exclusively produced in IDH1/2MT cancers, or DNA sequencing of tumor material. Eligible IDH1/2MT patients are then treated with a combination of metformin and chloroquine.

The study protocol uses a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose in order to establish a recommended dose for a phase II trial. Secondary objectives of the study include (1) to investigate the pharmacokinetics of the combination therapy of metformin plus chloroquine, (2) whether or not IDH1/2MT status can be determined by magnetic resonance spectroscopy and/or mass spectrometry of the serum, urine and/or bile or next-generation sequencing of circulating tumor DNA in glioma, IHCC or CS patients and to (3) investigate the tumor response and D-2HG concentration response to metformin plus chloroquine in IDH1/2MT cancers.

This study may open a novel treatment avenue for IDH1/2MT glioma, IHCC and CS by investigating two relatively safe drugs for these highly malignant tumors. In addition, this study may present novel therapies for other cancers that are regularly affected by IDH1/2MT, such as acute myeloid leukemia, acute lymphocytic leukemia and T-cell lymphoma.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioma
  • Cholangiocarcinoma
  • Chondrosarcoma
Intervention  ICMJE Drug: Metformin and chloroquine combination
Metformin and chloroquine are two oral medications. Metformin is to be taken twice daily, chloroquine once daily.
Other Names:
  • Aralen
  • Glucophage
Study Arms  ICMJE Experimental: Metformin and chloroquine combination

Metformin will be administered in a 3+3 dose-escalation schedule.

Chloroquine will be administered in a fixed dose.

Intervention: Drug: Metformin and chloroquine combination
Publications * Molenaar RJ, Coelen RJS, Khurshed M, Roos E, Caan MWA, van Linde ME, Kouwenhoven M, Bramer JAM, Bovée JVMG, Mathôt RA, Klümpen HJ, van Laarhoven HWM, van Noorden CJF, Vandertop WP, Gelderblom H, van Gulik TM, Wilmink JW. Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours. BMJ Open. 2017 Jun 10;7(6):e014961. doi: 10.1136/bmjopen-2016-014961.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 7, 2020)
15
Original Estimated Enrollment  ICMJE
 (submitted: July 10, 2015)
20
Actual Study Completion Date  ICMJE November 18, 2019
Actual Primary Completion Date November 18, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Presence of a glioma, IHCC or WHO grade ≥ II CS (both newly-diagnosed and refractory/relapsed tumors)
  2. Tumor carries a neomorphic D-2HG generating mutation in IDH1 or IDH2 as determined by MS of serum and urine (optional: bile), MRS of the tumor or DNA sequencing of (circulating) tumor material.
  3. Measurable lesion according to RECIST 1.1 criteria (see Appendix B) in IHCC and CS patients and RANO criteria (see Appendix C) in glioma patients.
  4. ECOG/WHO performance 0-2 (see Appendix D).
  5. Age > 18 years.
  6. Adequate renal function (creatinine < 150 μmol/L and/ or a creatinine clearance > 60 ml/ L).
  7. Adequate liver function (bilirubin < 1.5 times upper limit of normal, ALAT or ASAT < 5.0 times upper limit of normal in case of liver metastases and < 2.5 the upper limit of normal in absence of liver metastases).
  8. Adequate bone marrow function (WBC > 3.0 x 109/L, platelets > 100 x 109/L).
  9. If patient is eligible for resection, surgery is (already) planned at least 4 weeks away from start study treatment.
  10. Mentally, physically, and geographically able to undergo treatment and follow up.
  11. Signed informed content obtained prior to treatment.

Exclusion Criteria:

  1. Pregnancy (positive serum pregnancy test) and lactation.
  2. Serious concomitant systemic disorder that would compromise the safety of the patient, at the discretion of the investigator.
  3. Patients who have any severe and/or uncontrolled medical conditions such as:

    • unstable angina pectoris,
    • symptomatic congestive heart failure,
    • myocardial infarction,
    • cardiac arrhythmias,
    • pulmonary insufficiency,
    • epilepsy (interaction with chloroquine),
    • severe gastrointestinal, neurological or hematological diseases (interaction with chloroquine).
  4. 6 months prior to randomization:

    • serious uncontrolled cardiac arrhythmia,
    • uncontrolled diabetes as defined by fasting serum glucose >2X ULN,
    • active or uncontrolled severe infection, including malaria,
    • cirrhosis, chronic active hepatitis or chronic persistent hepatitis,
    • severely impaired lung function.
  5. Patients that use digoxin, MAO inhibitors, fenylbutazone, oxygenbutazone, gold preparations or cimetidine (known pharmaco interaction with chloroquine) or loop diuretics (known pharmaco interaction with metformin) for which no good alternative is available.
  6. Patients that have a known history of alcohol abuse (interaction with metformin).
  7. Patients with known glucose-6-phosphate dehydrogenase deficiency, porphyria, myasthenia gravis or ocular/retinal aberrations (interaction with chloroquine).
  8. Patients with a known hypersensitivity to metformin or chloroquine.
  9. Patients that are lactose intolerant.
  10. Use of metformin or chloroquine in the previous 6 months.
  11. Long-term use of chloroquine (>5 years or cumulative dose >300 grams) in the past.
  12. Use of other anti-cancer therapy (i.e. surgical resection, chemotherapy, targeted therapy, radiation therapy, surgery). Palliative therapy is permitted, such as:

    • palliative radiotherapy for symptomatic bone metastases;
    • dexamethasone for symptom relief in patients with glioma and cerebral edema;
    • non-enzyme inducing antiepileptic drugs (with the exception of topiramate) in patients with glioma and epileptic seizures.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02496741
Other Study ID Numbers  ICMJE TBA
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study Sponsor  ICMJE Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hanneke W Wilmink, M.D., Ph.D. Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
PRS Account Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP