Imatinib Mesylate With or Without Hydroxychloroquine in Treating Patients With Chronic Myeloid Leukemia

CHOICES: A Randomized Phase II Trial of Imatinib (IM) Versus Hydroxychloroquine (HCQ) and IM for Patients With Chronic Myeloid Leukemia (CML) in Major Cytogenetic Response (MCyR) With Residual Disease Detectable by Quantitative Polymerase Chain Reaction (Q-PCR).

RATIONALE: Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as hydroxychloroquine, may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether imatinib mesylate is more effective when given with or without hydroxychloroquine in treating patients with chronic myeloid leukemia.

PURPOSE: This randomized phase II trial is studying the side effects of giving imatinib mesylate with or without hydroxychloroquine and to see how well it works in treating patients with chronic myeloid leukemia.

Study Overview

• Status: Unknown
• Conditions: Leukemia
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Drug: imatinib mesylate; Genetic: cytogenetic analysis; Genetic: polymerase chain reaction; Drug: hydroxychloroquine

Detailed Description

OBJECTIVES:

Primary

• To determine if imatinib mesylate versus hydroxychloroquine (HCQ) and imatinib mesylate is more effective in terms of BCR/ABL levels in patients with chronic myeloid leukemia in major cytogenetic response (MCyR) with residual BCR/ABL-positive cells detectable by quantitative polymerase chain reaction after at least one year of imatinib mesylate treatment.
• To determine the safety and tolerability of this regimen in these patients.

Secondary

• To determine whether the introduction of HCQ influences imatinib mesylate plasma levels.
• To determine if whole blood HCQ levels achieved in combination with imatinib mesylate are in the expected range.
• To determine if HCQ inhibits autophagy in vivo.
• To evaluate the effects of this regimen on residual BCR/ABL-positive primitive progenitors.

OUTLINE: This is a multicenter study. Patients are stratified according to baseline polymerase chain reaction (PCR) level (< 3 logs below baseline vs ≥ 3 logs below baseline), time on imatinib mesylate (12 to < 24 months vs 24 to < 36 months), imatinib mesylate dose (< 400 mg vs 400 mg to < 600 mg vs 600 mg to 800 mg), and center. Patients are randomized to 1 of 2 treatment arms.

• Arm A: Patients receive oral imatinib mesylate daily. Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.
• Arm B: Patients receive oral imatinib mesylate daily and oral hydroxychloroquine (HCQ) twice daily. Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.

In both arms, patients may then receive oral imatinib mesylate daily for another 12 months during the follow up period of this study.

Consenting patients undergo blood sample and bone marrow collection at baseline, during, and after completion of study therapy for pharmacologic and other laboratory studies.

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months.

Peer Reviewed, Funded by MRC and supported by Cancer Research UK

• Study Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • Liverpool, England, United Kingdom, L7 8XP
      • Recruiting
      • Royal Liverpool University Hospital
      • Contact: Contact Person; Phone Number: 44-151-706-4297; Email: r.e.clark@liverpool.ac.uk
    • London, England, United Kingdom, W12 0HS
      • Recruiting
      • Imperial College London
      • Contact: Contact Person; Phone Number: 44-20-8383-1627; Email: d.marin@imperial.ac.uk
  • Scotland
    • Glasgow, Scotland, United Kingdom, G12 0YN
      • Recruiting
      • Gartnavel General Hospital
      • Contact: Contact Person; Phone Number: 44-141-301-7881; Email: t.holyoake@clinmed.gla.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of chronic myeloid leukemia (CML) in chronic phase (CP)

• Has been treated with imatinib mesylate for at least 1 year

  • Receiving a stable dose for ≥ 6 months prior to randomization
• Achieved at least major cytogenetic response (MCyR) and continues to be BCR/ABL-positive by quantitative polymerase chain reaction (Q-PCR)
• Must have a fusion gene present that can be monitored by Q-PCR

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm³ (stable and within normal range for ≥ 2 months)
• Platelet count ≥ 100,000/mm³ (stable and within normal range for ≥ 2 months)
• Serum albumin > 3 g/dL
• AST and/or ALT ≤ 2.5 times upper limit of normal (ULN)
• Serum bilirubin ≤ 1.5 times ULN
• Serum creatinine ≤ 1.5 times ULN OR 24-hour creatinine clearance ≥ 50 mL/min
• Serum potassium ≥ lower limit of normal with or without replacement therapy
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double-method contraception (including a barrier method [i.e., condom]) during and for 3 months after completion of study therapy

• No impaired cardiac function, including any of the following:

  • QTc > 450 msec on screening ECG
  • Congenital long QT syndrome
  • History or presence of sustained ventricular tachycardia
  • History of ventricular fibrillation or Torsades de pointes
  • NYHA class III-IV congestive heart failure
  • Uncontrolled hypertension
• No severe gastrointestinal (GI) disorder, uncontrolled epilepsy, known glucose-6-phosphate dehydrogenase (G6PD) deficiency, known porphyria, moderate or severe psoriasis, known myasthenia gravis, or other concurrent severe and/or uncontrolled medical conditions
• No preexisting maculopathy of the eye
• No significant history of noncompliance to medical regimens or the inability to grant a reliable informed consent

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy, investigational drug, or major surgery and recovered
• More than 6 months since change in imatinib mesylate dose
• No other concurrent anticancer therapy or radiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Proportion of treatment "successes" defined as patients who have at least 0.5 log reductions or more in their 12-month PCR level from baseline

Secondary Outcome Measures

Outcome Measure
Proportion of treatment "successes" at 24 months
Molecular response at 12 and 24 months (complete response, major response, or no response)
Proportion of patients with progression at 12 and 24 months

Collaborators and Investigators

• Sponsor: Lynn McMahon
• Collaborators: Medical Research Council; CRUK Trials unit Glasgow
• Investigators: Principal Investigator: Tessa Holyoake, MD, Gartnavel General Hospital

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Anticipated): March 1, 2012

Study Registration Dates

• First Submitted: October 21, 2010
• First Submitted That Met QC Criteria: October 22, 2010
• First Posted (Estimate): October 25, 2010

Study Record Updates

• Last Update Posted (Estimate): November 30, 2011
• Last Update Submitted That Met QC Criteria: November 29, 2011
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Keywords: chronic phase chronic myelogenous leukemia; chronic myelogenous leukemia, BCR-ABL1 positive
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia, Myeloid; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Protein Kinase Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Imatinib Mesylate; Hydroxychloroquine
• Other Study ID Numbers: CDR0000686729; CRUK-H135; ISRCTN-61568166; EUDRACT-2009-014373-41; EU-21078