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.
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
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.
- Conditions
- Glioma, Cholangiocarcinoma, Chondrosarcoma
- 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 group | Role | What they receive |
|---|---|---|
| Metformin and chloroquine combination | Experimental | Metformin 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.
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)
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
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
Effect of metformin + chloroquine on tumor response
Tumor size will be measured using a MRI/CT scan before and after treatment.
Measured: 1 year
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.
- First posted14 Jul 2015 (estimated)
- Study startNov 2015
- Primary completion18 Nov 2019
- Study completion18 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for GliomaStudies of the same condition, open and under way.
- More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- Hanneke W Wilmink, M.D., Ph.D., Principal investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
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
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase Ib Study of Metformin and Chloroquine in IDH1/2-mutated Patients With Glioma, Intrahepatic Cholangiocarcinoma or Chondrosarcoma
- ClinicalTrials.gov ID
- NCT02496741
- Acronym / sponsor ID
- MACIST / TBA
- Conditions
- Glioma, Cholangiocarcinoma, Chondrosarcoma
- Keywords
- isocitrate dehydrogenase 1/2 mutation, metformin, chloroquine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Study start
- Nov 2015
- Primary completion
- 18 Nov 2019 (actual)
- Study completion
- 18 Nov 2019 (actual)
- First posted
- 14 Jul 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Metformin and chloroquine combination | Experimental | Drug: Metformin and chloroquine combinationMetformin will be administered in a 3+3 dose-escalation schedule. Chloroquine will be administered in a fixed dose. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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.
Key exclusion criteria (27 listed)
- 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:
- 6 months prior to randomization:
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Metformin and chloroquine combinationAlso: Aralen, GlucophageMetformin and chloroquine are two oral medications. Metformin is to be taken twice daily, chloroquine once daily. | Drug | Metformin and chloroquine combination |
Primary outcome
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.
4 secondary outcomes
Effect of metformin + chloroquine on serum/urine/bile D-2-hydroxyglutarate (D2HG) concentration
Time frame: 1 year
Effect of metformin + chloroquine on intratumoral D2HG concentration
Time frame: 1 year
Effect of metformin + chloroquine on tumor response
Time frame: 1 year
Recommended dose of metformin + chloroquine
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2020.
- Derived from this study: PubMed 28601826Molenaar 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hanneke W Wilmink, M.D., Ph.D. principal investigator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
3 sites in 1 country: see every site and its status.
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.