Nilotinib in Treating Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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RATIONALE: Nilotinib 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 nilotinib works in treating patients with newly diagnosed chronic phase chronic myelogenous leukemia.

Detailed Description
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OBJECTIVES: Primary To establish the complete cytogenetic response rate at 6 months in patients with newly diagnosed Philadelphia chromosome-positive chronic phase chronic myelogenous leukemia treated with nilotinib. Secondary To establish the complete cytogenetic response rate at 3, 9, 12, 18, and 24 months in these patients. To establish the molecular response rate at 3, 6, 9, 12, 18, and 24 months in these patients. To establish the safety of this drug in these patients. To correlate pharmacokinetic data with response rate and toxicity. To correlate Bcr-Abl results using GeneXpert with Bcr-Abl results using international standardized quantitative PCR. To estimate the prevalence of Bcr-Abl mutations prior to and during treatment. OUTLINE: This is a multicenter study. Patients receive oral nilotinib twice daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Peripheral blood and bone marrow samples are collected periodically for mutation analysis, Bcr-Abl analysis by quantitative PCR, metaphase cytogenetics, and pharmacokinetic analysis. After completion of study therapy, patients are followed every 3 months for 2 years.

Official Title
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A Phase II Multi-center, Open-label, Study of Nilotinib at a Dose of 300mg Twice Daily in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: nilotinib
* Genetic: cytogenetic analysis
* Genetic: mutation analysis
* Genetic: polymerase chain reaction
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Cytogenetically confirmed chronic myelogenous leukemia (CML) by standard conventional cytogenetic analysis of bone marrow* Newly diagnosed disease (within the past 6 months) NOTE: *FISH cannot be used In chronic phase, as defined by the following: Less than 15% blasts in peripheral blood and bone marrow Less than 30% blasts plus promyelocytes in peripheral blood and bone marrow Less than 20% basophils in peripheral blood Platelet count ≥ 100,000/mm^3 No evidence of extramedullary leukemic involvement, except for hepatosplenomegaly Philadelphia chromosome-positive disease as demonstrated by (9;22) translocation (presence of Bcr-Abl) A review of ≥ 20 metaphases is required No previously documented T315I mutations PATIENT CHARACTERISTICS: ECOG performance status 0-2 Total bilirubin < 1.5 times upper limit of normal (ULN) AST and ALT < 2.5 times ULN Estimated glomerular filtration rate ≥ 30 mL/min Serum amylase and lipase ≤ 1.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN (unless related to CML) Potassium ≥ lower limit of normal (LLN) Magnesium ≥ LLN Phosphorous ≥ LLN Total calcium ≥ LLN (corrected for serum albumin) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No impaired cardiac function including, but not limited to, any of the following: LVEF < 45% or < LLN by ECHO Inability to determine the QT interval on ECG Complete left bundle branch block Congenital long QT syndrome or a known family history of long QT syndrome History of or presence of clinically significant ventricular or atrial tachyarrhythmias Clinically significant resting bradycardia (< 50 beats/min) QTc > 450 msec on an average of 3 serial baseline ECGs (using the QTcF formula) Clinically documented myocardial infraction within the past 12 months Unstable angina within the past 12 months Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension) No severe or uncontrolled medical condition (e.g., uncontrolled diabetes or active or uncontrolled infection) No history of significant congenital or acquired bleeding disorder unrelated to CML No history of non-compliance to medical regimens No other primary malignancy unless it is neither currently clinically significant nor requiring active intervention No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) No acute pancreatitis within the past year No history of chronic pancreatitis No acute or chronic liver, pancreatic, or severe renal disease considered unrelated to CML PRIOR CONCURRENT THERAPY: No prior therapy for CML other than hydroxyurea and/or anagrelide Prior imatinib mesylate allowed provided it was administered for ≤ 14 days More than 30 days since prior and no other concurrent investigational agents More than 4 weeks since prior major surgery and recovered No other concurrent anticancer agents, including chemotherapy and biologic agents No concurrent strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) No concurrent strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's wort) No concurrent medications that have the potential to prolong QT interval No concurrent grapefruit, star fruit, Seville oranges, or their derivatives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br> | Drug: nilotinib<br> <br> Genetic: cytogenetic analysis<br> <br> Genetic: mutation analysis<br> <br> Genetic: polymerase chain reaction<br> <br> Other: pharmacological study<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete cytogenetic response rate at 6 months as assessed by metaphase analysis |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular response rate at 3, 6, 9, 12, 18, and 24 months as assessed by quantitative PCR |  | 6 months | 
| Time to disease progression |  | 6 months | 
| Duration of event-free survival |  | 6 months | 
| Overall toxicity rate |  | 6 months | 
| Correlation of pharmacokinetic data with response rate and toxicity |  | 6 months | 
| Correlation of Bcr-Abl results using GeneXpert with Bcr-Abl results using international standardized quantitative PCR |  | 6 months | 
| Prevalence of Bcr-Abl mutations prior to and during treatment |  | 6 months | 

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