Metformin And Chloroquine in IDH1/2-mutated Solid Tumors

NCT02496741 | Completed Phase 1

• 1 other identifier: TBA
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 3

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.

Conditions

Glioma; Cholangiocarcinoma; Chondrosarcoma

Keywords

isocitrate dehydrogenase 1/2 mutation; metformin; chloroquine

Outcome Measures

Primary Outcomes (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.

  1 year

Secondary Outcomes (4)

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

  1 year

• Effect of metformin + chloroquine on intratumoral D2HG concentration

  1 year

• Effect of metformin + chloroquine on tumor response

  1 year

• Recommended dose of metformin + chloroquine

  1 year

Study Arms (1)

Metformin and chloroquine combination

EXPERIMENTAL

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

Drug: Metformin and chloroquine combination

Interventions

Metformin and chloroquine combination DRUG

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

Also known as: Aralen, Glucophage

Metformin and chloroquine combination

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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.

You may not qualify if:

• 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,
• cardiac arrhythmias,
• pulmonary insufficiency,
• epilepsy (interaction with chloroquine),
• severe gastrointestinal, neurological or hematological diseases (interaction with chloroquine).
• 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,

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead

Study Sites (3)

VU University Medical Center

Amsterdam, North Holland, 1081 HZ, Netherlands

Location

Academic Medical Center

Amsterdam, North Holland, 1105AZ, Netherlands

Location

Leiden University Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 28601826 DERIVED

MeSH Terms

Conditions

Glioma; Cholangiocarcinoma; Chondrosarcoma

Interventions

Metformin; Chloroquine

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Adenocarcinoma; Carcinoma; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Hanneke W Wilmink, M.D., Ph.D.

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 30, 2015
• First Posted: July 14, 2015
• Study Start: November 1, 2015
• Primary Completion: November 18, 2019
• Study Completion: November 18, 2019
• Last Updated: January 9, 2020

Record last verified: 2020-01

Locations

NL (3)