Glioma Clinical Trial
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.
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.
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