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).
18 Years
N/A
Both
Leukemia
Trial Information
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).
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
Inclusion Criteria
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
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment
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
Safety Issue:
No
Principal Investigator
Tessa Holyoake, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Gartnavel General Hospital
Authority:
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Study ID:
CDR0000686729
NCT ID:
NCT01227135
Start Date:
March 2010
Completion Date:
Related Keywords:
- Leukemia
- chronic phase chronic myelogenous leukemia
- chronic myelogenous leukemia, BCR-ABL1 positive
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
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