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Trial record 3 of 158 for:    Chloroquine phosphate

Metformin And Chloroquine in IDH1/2-mutated Solid Tumors (MACIST)

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ClinicalTrials.gov Identifier: NCT02496741
Recruitment Status : Unknown
Verified November 2015 by J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA).
Recruitment status was:  Recruiting
First Posted : July 14, 2015
Last Update Posted : November 17, 2015
Sponsor:
Information provided by (Responsible Party):
J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.

Condition or disease Intervention/treatment Phase
Glioma Cholangiocarcinoma Chondrosarcoma Drug: Metformin and chloroquine combination Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib Study of Metformin and Chloroquine in IDH1/2-mutated Patients With Glioma, Intrahepatic Cholangiocarcinoma or Chondrosarcoma
Study Start Date : November 2015
Estimated Primary Completion Date : August 2016
Estimated Study Completion Date : December 2016


Arm Intervention/treatment
Experimental: Metformin and chloroquine combination

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

Chloroquine will be administered in a fixed dose.

Drug: Metformin and chloroquine combination
Metformin and chloroquine are two oral medications. Metformin is to be taken twice daily, chloroquine once daily.
Other Names:
  • Aralen
  • Glucophage




Primary Outcome Measures :
  1. Maximum tolerated dose of metformin + chloroquine [ Time Frame: 1 year ]
    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.


Secondary Outcome Measures :
  1. Effect of metformin + chloroquine on serum/urine/bile D-2-hydroxyglutarate (D2HG) concentration [ Time Frame: 1 year ]
    D-2HG concentration will be measured by mass spectrometry (MS) in serum/urine/bile, at the beginning and end of the study.

  2. Effect of metformin + chloroquine on intratumoral D2HG concentration [ Time Frame: 1 year ]
    Intratumoral D-2HG concentration will be measured by magnetic resonance spectroscopy (MRS), at the beginning and end of the study.

  3. Effect of metformin + chloroquine on tumor response [ Time Frame: 1 year ]
    Tumor size will be measured using a MRI/CT scan before and after treatment.

  4. Recommended dose of metformin + chloroquine [ Time Frame: 1 year ]
    The recommended dose is the dose of chloroquine plus metformin is the dose level one step below the maximum tolerated dose.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02496741


Contacts
Contact: Hanneke W Wilmink, M.D., Ph.D. +31(20)5662895 j.w.wilmink@amc.uva.nl
Contact: Remco J Molenaar, M.Sc. +31(20)5668587 r.j.molenaar@amc.nl

Locations
Netherlands
VU University Medical Center Not yet recruiting
Amsterdam, Noord-Holland, Netherlands, 1081 HZ
Contact: Myra E Van Linde, M.D.    +31(20)4441412    m.vanlinde@vumc.nl   
Academic Medical Center Recruiting
Amsterdam, Noord-Holland, Netherlands, 1105AZ
Contact: Hanneke W Wilmink, M.D., Ph.D.    +31(20)5662895    j.w.wilmink@amc.uva.nl   
Contact: Remco J Molenaar, M.Sc.    +31(20)5668587    r.j.molenaar@amc.nl   
Principal Investigator: Hanneke W Wilmink, M.D., Ph.D.         
Leiden University Medical Center Not yet recruiting
Leiden, Zuid-Holland, Netherlands, 2333 ZA
Contact: Hans J Gelderblom, M.D., Ph.D.    +31(71)5269111    A.J.Gelderblom@lumc.nl   
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
Principal Investigator: Hanneke W Wilmink, M.D., Ph.D. Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: J.W. Wilmink, Principal Investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT02496741     History of Changes
Other Study ID Numbers: TBA
First Posted: July 14, 2015    Key Record Dates
Last Update Posted: November 17, 2015
Last Verified: November 2015

Keywords provided by J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
isocitrate dehydrogenase 1/2 mutation
metformin
chloroquine

Additional relevant MeSH terms:
Chloroquine
Chloroquine diphosphate
Glioma
Cholangiocarcinoma
Chondrosarcoma
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
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents