Metformin And Chloroquine in IDH1/2-mutated Solid Tumors
Condition: Glioma; Cholangiocarcinoma; Chondrosarcoma
MeSH terms: Glioma; Cholangiocarcinoma; Chondrosarcoma
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

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.
    

Intervention name(s): Metformin and chloroquine combination
Intervention type(s): Drug
Intervention description(s): Metformin and chloroquine are two oral medications. Metformin is to be taken twice daily, chloroquine once daily.
Other intervention name(s): Aralen; Glucophage
Intervention MeSH terms: Metformin; Chloroquine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: isocitrate dehydrogenase 1/2 mutation; metformin; chloroquine