Metformin And Chloroquine in IDH1/2-mutated Solid Tumors
Metformin And Chloroquine in IDH1/2-mutated Solid Tumors
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.
Inclusion Criteria:

 1. Presence of a glioma, IHCC or WHO grade ≥ II CS (both newly-diagnosed and
 refractory/relapsed tumors)

 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
 (circulating) tumor material.

 3. 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.

 4. ECOG/WHO performance 0-2 (see Appendix D).

 5. Age > 18 years.

 6. Adequate renal function (creatinine < 150 μmol/L and/ or a creatinine clearance > 60
 ml/ L).

 7. 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).

 8. Adequate bone marrow function (WBC > 3.0 x 109/L, platelets > 100 x 109/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:

 -  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).

 4. 6 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,

 -  severely impaired lung function.

 5. Patients that use digoxin, MAO inhibitors, fenylbutazone, oxygenbutazone, gold
 preparations or cimetidine (known pharmaco interaction with chloroquine) or loop
 diuretics (known pharmaco interaction with metformin) for which no good alternative is
 available.

 6. Patients that have a known history of alcohol abuse (interaction with metformin).

 7. Patients with known glucose-6-phosphate dehydrogenase deficiency, porphyria,
 myasthenia gravis or ocular/retinal aberrations (interaction with chloroquine).

 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. Long-term use of chloroquine (>5 years or cumulative dose >300 grams) in the past.

 12. Use of other anti-cancer therapy (i.e. surgical resection, chemotherapy, targeted
 therapy, radiation therapy, surgery). Palliative therapy is permitted, such as:

 -  palliative radiotherapy for symptomatic bone metastases;

 -  dexamethasone for symptom relief in patients with glioma and cerebral edema;

 -  non-enzyme inducing antiepileptic drugs (with the exception of topiramate) in
 patients with glioma and epileptic seizures.