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

Leukemia Clinical Trial

Official title:

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).

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01227135
• Other study ID #: CDR0000686729
• Secondary ID: CRUK-H135ISRCTN-
• Status: Recruiting
• Phase: Phase 2
• First received: October 21, 2010
• Last updated: November 29, 2011
• Start date: March 2010

Study information

• Verified date: November 2011
• Source: University of Glasgow
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• hydroxychloroquine

• imatinib mesylate

Genetic:
• cytogenetic analysis

• polymerase chain reaction

Other:
• laboratory biomarker analysis

• pharmacological study

Locations

Country	Name	City	State
United Kingdom	Gartnavel General Hospital	Glasgow	Scotland
United Kingdom	Royal Liverpool University Hospital	Liverpool	England
United Kingdom	Imperial College London	London	England

Sponsors (3)

Lead Sponsor	Collaborator
Lynn McMahon	CRUK Trials unit Glasgow, Medical Research Council

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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			No
Secondary	Proportion of treatment "successes" at 24 months			No
Secondary	Molecular response at 12 and 24 months (complete response, major response, or no response)			No
Secondary	Proportion of patients with progression at 12 and 24 months			No