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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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).

Conditions
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Leukemia

Intervention / Treatment
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* Drug: hydroxychloroquine
* Drug: imatinib mesylate
* Genetic: cytogenetic analysis
* Genetic: polymerase chain reaction
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: hydroxychloroquine|nan|
|Drug: imatinib mesylate|nan|
|Genetic: cytogenetic analysis|nan|
|Genetic: polymerase chain reaction|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic phase chronic myelogenous leukemia, chronic myelogenous leukemia, BCR-ABL1 positive