Nilotinib and Imatinib Mesylate in Treating Patients With Early Chronic Phase Chronic Myelogenous Leukemia (CML0408)

• Complete cytogenetic response [ Time Frame: At at 6 and 24 months from study entry ] [ Designated as safety issue: No ]
• Major and complete molecular response rate [ Time Frame: At at 6, 12 and 24 months from study entry ] [ Designated as safety issue: No ]
• Development of BCR-ABL kinase domain mutations (number, timing, and type) [ Time Frame: At at 24 months during and for 3 years after study treatment ] [ Designated as safety issue: No ]
• Rate of failures and the time to failure [ Time Frame: At 12, 24, and 60 months from study entry ] [ Designated as safety issue: No ]
• Safety and tolerability [ Time Frame: At 24 months from study entry ] [ Designated as safety issue: Yes ]
• Frequency and type of adverse events (AE) and severe AE [ Time Frame: At 24 months from study entry ] [ Designated as safety issue: Yes ]
• Relationship between response, the gene expression profile, the biomarkers of leukemic cells, and plasma concentrations of nilotinib and imatinib mesylate [ Time Frame: At 24 months from study entry ] [ Designated as safety issue: No ]

• Complete cytogenetic response at 6 and 24 months [ Designated as safety issue: No ]
• Major and complete molecular response rate at 6, 12, and 24 months [ Designated as safety issue: No ]
• Development of BCR-ABL kinase domain mutations (number, timing, and type) at 24 months during and for 3 years after study treatment [ Designated as safety issue: No ]
• Rate of failures and the time to failure at 12, 24, and 60 months [ Designated as safety issue: No ]
• Safety and tolerability [ Designated as safety issue: Yes ]
• Frequency and type of adverse events (AE) and severe AE [ Designated as safety issue: Yes ]
• Relationship between response, the gene expression profile, the biomarkers of leukemic cells, and plasma concentrations of nilotinib and imatinib mesylate [ Designated as safety issue: No ]

RATIONALE: Nilotinib and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying how well giving nilotinib together with imatinib mesylate works in treating patients with early chronic phase chronic myelogenous leukemia.

OBJECTIVES:

Primary

• To assess the complete cytogenetic response rate at 12 months in patients with Philadelphia chromosome- and BCR-ABL-positive early chronic phase chronic myelogenous leukemia treated with nilotinib and imatinib mesylate.

Secondary

• To assess the complete cytogenetic response rate at 6 and 24 months in these patients.
• To assess the major and complete molecular response rate at 6, 12, and 24 months in these patients.
• To assess the frequency and the types of BCR-ABL kinase domain mutations at 24 months during and for 3 years after study treatment.
• To assess the rate of failures and the time to failure at 12, 24, and 60 months in these patients.
• To assess compliance, toxicity, and adverse events in these patients.
• To understand the relationship between response, gene expression profile, biomarkers, and drug plasma concentrations in these patients.

OUTLINE: This is a multicenter study.

Patients receive oral nilotinib twice daily in months 1-3, 7-9, 13-15, and 19-21 and oral imatinib mesylate once daily in months 4-6, 10-12, 16-18, and 22-24. Treatment continues for 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible to continue oral nilotinib and oral imatinib mesylate for up to another 36 months if it is in the interest of the patient.

Blood samples and bone marrow biopsies are collected periodically for cytogenetic response by chromosome banding analysis and FISH analysis; real-time quantitative PCR mutational analysis and single nucleotide polymorphism analysis of BCR-ABL transcripts; and gene expression profiling and correlative biomarker studies.

After completion of study therapy, patients are followed every 6 months for 3 years and then every 12 months for 5 years.

• Drug: imatinib mesylate
• Drug: nilotinib
• Genetic: cytogenetic analysis
• Genetic: fluorescence in situ hybridization
• Genetic: microarray analysis
• Genetic: mutation analysis
• Genetic: polymerase chain reaction
• Genetic: polymorphism analysis
• Other: laboratory biomarker analysis

DISEASE CHARACTERISTICS:

• Cytologically and cytogenetically confirmed chronic myelogenous leukemia meeting the following criteria:

  • Early chronic phase disease (< 6 months from diagnosis)
  • Philadelphia chromosome-positive disease
  • BCR-ABL-positive

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• ALT and AST = 2.5 times upper limit of normal (ULN) (5.0 times ULN if considered due to leukemia)
• Alkaline phosphatase = 2.5 times ULN (unless considered due to leukemia)
• Serum bilirubin = 1.5 times ULN
• Serum creatinine = 1.5 times ULN
• Serum amylase = 1.5 times ULN
• Serum lipase = 1.5 times ULN

• Normal serum levels of the following or correctable with supplements:

  • Potassium
  • Total calcium (corrected for serum albumin)
  • Magnesium
  • Phosphorus
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier method contraception during study and for up to 3 months following completion of study treatment

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

  • LVEF < 45% by MUGA scan or echocardiogram
  • Uncontrolled congestive heart failure
  • Uncontrolled hypertension
  • Uncontrolled angina pectoris
  • Myocardial infarction within the past 12 months

• No significant electric heart abnormalities, including any of the following:

  • History or active ventricular or atrial tachyarrhythmias
  • Congenital long QT syndrome and/or QTc > 450 msec on screening ECG
• No history of acute (within one year) or chronic pancreatitis
• No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• No acute or chronic liver or renal disease considered unrelated to leukemia
• No known diagnosis of HIV infection
• No other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
• No other primary malignancy that is currently clinically significant or requires active intervention

PRIOR CONCURRENT THERAPY:

• More than 2 weeks since prior major surgery and recovered
• More than 30 days since prior imatinib mesylate, with a washout period of ≥ 7 days
• More than 4 weeks since prior investigational drug
• No prior hematopoietic stem cell transplantation
• No concurrent therapeutic coumarin derivates (i.e., warfarin, acenocoumarol, phenprocoumon)
• No concurrent medications that would prolong the QT interval
• No concurrent chemotherapy, investigational agents, radiotherapy, or biologic therapy
• Prior treatment with hydroxyurea or anagrelide allowed