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) concentrationEffect 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 μmol/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
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