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 : Unknown
Verified November 2015 by J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA).
Recruitment status was: Recruiting
First Posted : July 14, 2015
Last Update Posted : November 17, 2015
|Condition or disease||Intervention/treatment||Phase|
|Glioma Cholangiocarcinoma Chondrosarcoma||Drug: Metformin and chloroquine combination||Phase 1 Phase 2|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase Ib Study of Metformin and Chloroquine in IDH1/2-mutated Patients With Glioma, Intrahepatic Cholangiocarcinoma or Chondrosarcoma|
|Study Start Date :||November 2015|
|Estimated Primary Completion Date :||August 2016|
|Estimated Study Completion Date :||December 2016|
Experimental: Metformin and chloroquine combination
Metformin will be administered in a 3+3 dose-escalation schedule.
Chloroquine will be administered in a fixed dose.
Drug: Metformin and chloroquine combination
Metformin and chloroquine are two oral medications. Metformin is to be taken twice daily, chloroquine once daily.
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02496741
|Contact: Hanneke W Wilmink, M.D., Ph.D.||+31(20)email@example.com|
|Contact: Remco J Molenaar, M.Sc.||+31(20)firstname.lastname@example.org|
|VU University Medical Center||Not yet recruiting|
|Amsterdam, Noord-Holland, Netherlands, 1081 HZ|
|Contact: Myra E Van Linde, M.D. +31(20)4441412 email@example.com|
|Academic Medical Center||Recruiting|
|Amsterdam, Noord-Holland, Netherlands, 1105AZ|
|Contact: Hanneke W Wilmink, M.D., Ph.D. +31(20)5662895 firstname.lastname@example.org|
|Contact: Remco J Molenaar, M.Sc. +31(20)5668587 email@example.com|
|Principal Investigator: Hanneke W Wilmink, M.D., Ph.D.|
|Leiden University Medical Center||Not yet recruiting|
|Leiden, Zuid-Holland, Netherlands, 2333 ZA|
|Contact: Hans J Gelderblom, M.D., Ph.D. +31(71)5269111 A.J.Gelderblom@lumc.nl|
|Principal Investigator:||Hanneke W Wilmink, M.D., Ph.D.||Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)|