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Metformin And Chloroquine in IDH1/2-mutated Solid Tumors

Information source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Glioma; Cholangiocarcinoma; Chondrosarcoma

Intervention: Metformin and chloroquine combination (Drug)

Phase: Phase 1/Phase 2

Status: Not yet recruiting

Sponsored by: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Official(s) and/or principal investigator(s):
Hanneke W Wilmink, M.D., Ph.D., Principal Investigator, Affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Overall contact:
Hanneke W Wilmink, M.D., Ph.D., Phone: +31(20)5662895, Email: j.w.wilmink@amc.uva.nl

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.

Clinical Details

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Maximum tolerated dose of metformin + chloroquine

Secondary outcome:

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

Effect of metformin + chloroquine on intratumoral D2HG concentration

Effect of metformin + chloroquine on tumor response

Recommended dose of metformin + chloroquine

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.

Eligibility

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Cytological or histological confirmed glioma, IHCC or CS (both newly diagnosed and refractory/relapsed). 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 tumor material. 3. Measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) 1. 1 criteria (IHCC and CS) or Response Assessment in Neuro-Oncology (RANO) criteria (glioma). 4. Eastern Cooperative Oncology Group (ECOG)/WHO performance 0-2 (see Appendix E). 5. Age > 18 years. 6. Adequate renal function (creatinine < 150 ╬╝mol/L and/ or a creatinine clearance > 60 ml/ L). 7. Adequate liver function (bilirubin < 1. 5 times upper limit of normal, alanine transaminase (ALAT) or aspartate transaminase (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 (white blood count > 3. 0 x 10^9/L, platelets > 100 x 10^9/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: i. unstable angina pectoris, ii. symptomatic congestive heart failure, iii. myocardial infarction, iv. cardiac arrhythmias. 4. 6 months prior to randomization: i. serious uncontrolled cardiac arrhythmia, ii. uncontrolled diabetes as defined by fasting serum glucose >2. 0 x upper limits of normal, iii. active or uncontrolled severe infection, including malaria, iv. cirrhosis, chronic active hepatitis or chronic persistent hepatitis, v. severely impaired lung function. 5. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. 6. Patients that use digoxin, monoamine oxidase (MAO) inhibitors, phenylbutazone, oxyphenbutazone, gold preparations (known pharmacological interaction with chloroquine). 7. Patients that have a known history of alcohol abuse (interaction with metformin). 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. Use of other anti-cancer therapy (i. e. chemotherapy, targeted therapy, radiation therapy, surgery).

Locations and Contacts

Hanneke W Wilmink, M.D., Ph.D., Phone: +31(20)5662895, Email: j.w.wilmink@amc.uva.nl

Academic Medical Center, Amsterdam, Noord-Holland 1105AZ, Netherlands; Not yet recruiting
Hanneke W Wilmink, M.D., Ph.D., Phone: +31(20)5662895, Email: j.w.wilmink@amc.uva.nl
Remco J Molenaar, M.Sc., Phone: +31(20)5668587, Email: r.j.molenaar@amc.nl
Hanneke W Wilmink, M.D., Ph.D., Principal Investigator

VU University Medical Center, Amsterdam, Noord-Holland 1081 HZ, Netherlands; Not yet recruiting
Myra E Van Linde, M.D., Phone: +31(20)4441412, Email: m.vanlinde@vumc.nl

Leiden University Medical Center, Leiden, Zuid-Holland 2333 ZA, Netherlands; Not yet recruiting
Hans J Gelderblom, M.D., Ph.D., Phone: +31(71)5269111, Email: A.J.Gelderblom@lumc.nl

Additional Information

Starting date: July 2015
Last updated: July 14, 2015

Page last updated: August 23, 2015

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