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GliomaPhase 1/2MACISTNCT02496741

Metformin And Chloroquine in IDH1/2-mutated Solid Tumors

A Phase 1/2 study testing Metformin and chloroquine combination in people with Glioma and Cholangiocarcinoma, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 3 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Glioma, Cholangiocarcinoma, Chondrosarcoma
What is being tested?
Metformin and chloroquine combination
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
15 participants
Where
3 sitesNetherlands
Study dates
Nov 2015to 18 Nov 2019
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Presence of a glioma, IHCC or WHO grade ≥ II CS (both newly-diagnosed and refractory/relapsed tumors)
  • 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.
  • 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.
  • ECOG/WHO performance 0-2 (see Appendix D).
  • Age > 18 years.
  • Adequate renal function (creatinine < 150 μmol/L and/ or a creatinine clearance > 60 ml/ L).
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  • 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).
  • Adequate bone marrow function (WBC > 3.0 x 109/L, platelets > 100 x 109/L).
  • If patient is eligible for resection, surgery is (already) planned at least 4 weeks away from start study treatment.
  • Mentally, physically, and geographically able to undergo treatment and follow up.
  • Signed informed content obtained prior to treatment.

Who cannot join

  • Pregnancy (positive serum pregnancy test) and lactation.
  • Serious concomitant systemic disorder that would compromise the safety of the patient, at the discretion of the investigator.
  • Patients who have any severe and/or uncontrolled medical conditions such as:
  • unstable angina pectoris,
  • symptomatic congestive heart failure,
  • myocardial infarction,
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  • cardiac arrhythmias,
  • pulmonary insufficiency,
  • epilepsy (interaction with chloroquine),
  • severe gastrointestinal, neurological or hematological diseases (interaction with chloroquine).
  • 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.
  • 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.
  • Patients that have a known history of alcohol abuse (interaction with metformin).
  • Patients with known glucose-6-phosphate dehydrogenase deficiency, porphyria, myasthenia gravis or ocular/retinal aberrations (interaction with chloroquine).
  • Patients with a known hypersensitivity to metformin or chloroquine.
  • Patients that are lactose intolerant.
  • Use of metformin or chloroquine in the previous 6 months.
  • Long-term use of chloroquine (>5 years or cumulative dose >300 grams) in the past.
  • 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.

Trial locations and contacts

3 sites in 1 country.

Netherlands3 sites

  • VU University Medical Center

    Amsterdam, North Holland, 1081 HZ

  • Academic Medical Center

    Amsterdam, North Holland, 1105AZ

  • Leiden University Medical Center

    Leiden, South Holland, 2333 ZA

Other trials in Netherlands

About this study

Official title: Phase Ib Study of Metformin and Chloroquine in IDH1/2-mutated Patients With Glioma, Intrahepatic Cholangiocarcinoma or Chondrosarcoma

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.

Read the 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.

Being tested
Metformin and chloroquine combination
Keywords
isocitrate dehydrogenase 1/2 mutation, metformin, chloroquine
Medical subject headings
Glioma, Cholangiocarcinoma, Chondrosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Metformin and chloroquine combinationDrug

    Also called Aralen, Glucophage

    Metformin and chloroquine are two oral medications. Metformin is to be taken twice daily, chloroquine once daily.

Study groups in NCT02496741
Study groupRoleWhat they receive
Metformin and chloroquine combinationExperimentalMetformin will be administered in a 3+3 dose-escalation schedule. Chloroquine will be administered in a fixed dose.
Receives: Drug: Metformin and chloroquine combination

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose of metformin + chloroquine

    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.

    Measured: 1 year

Secondary outcomes (4)

  1. Effect of metformin + chloroquine on serum/urine/bile D-2-hydroxyglutarate (D2HG) concentration

    D-2HG concentration will be measured by mass spectrometry (MS) in serum/urine/bile, at the beginning and end of the study.

    Measured: 1 year

  2. Effect of metformin + chloroquine on intratumoral D2HG concentration

    Intratumoral D-2HG concentration will be measured by magnetic resonance spectroscopy (MRS), at the beginning and end of the study.

    Measured: 1 year

  3. Effect of metformin + chloroquine on tumor response

    Tumor size will be measured using a MRI/CT scan before and after treatment.

    Measured: 1 year

  4. Recommended dose of metformin + chloroquine

    The recommended dose is the dose of chloroquine plus metformin is the dose level one step below the maximum tolerated dose.

    Measured: 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jul 2015 (estimated)
  2. Study startNov 2015
  3. Primary completion18 Nov 2019
  4. Study completion18 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02496741
Sponsor's protocol ID
TBA
Acronym
MACIST
Status last verified
Jan 2020
First submitted
30 Jun 2015
Last updated
9 Jan 2020
Results posted
No
Data monitoring committee
No

Publications

  • Molenaar RJ, Coelen RJS, Khurshed M, Roos E, Caan MWA, van Linde ME, Kouwenhoven M, Bramer JAM, Bovee JVMG, Mathot RA, Klumpen 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.

    PubMed 28601826

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Metformin and chloroquine combination in people with Glioma and Cholangiocarcinoma, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 3 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose of metformin + chloroquine (time frame: 1 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02496741, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2020.

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