Randomized Phase Lll Study of Imatinib Dose Optimization vs Nilotinib in CML Patients With Suboptimal Response to Imatinib

Study Overview
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Brief Summary
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There is no available data on the clinical benefit of dose escalation for patients with suboptimal response to imatinib, and patients may still improve their response with continuation of therapy at the standard dose as shown in the IRIS trial after 5 years of follow-up. However, there is no data yet regarding the potential benefit of using nilotinib in the group of patients with suboptimal response. In this study, the efficacy of nilotinib 400mg BID will be compared to imatinib 600mg QD.

Detailed Description
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The comparative efficacy between imatinib dose escalation (600 mg QD) and nilotinib (400 mg BID), in terms of CCyR after 6 months, for patients with CML in chronic phase with suboptimal response to imatinib standard dose will be determined.

Official Title
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A Randomized Phase Lll Study of Imatinib Dose Optimization Compared With Nilotinib in Patients With Chronic Myelogenous Leukemia and Suboptimal Response to Standard-dose Imatinib

Conditions
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Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: nilotinib
* Drug: imatinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female ≥ 18 years old; ECOG of 0, 1, or 2; Ph+ CML in CP defined as: <15% blasts in peripheral blood or bone marrow; <30% blasts + promyelocytes in peripheral blood or bone marrow; <20% basophils in the peripheral blood; •≥100x109/L (≥ 100,000/mm3) platelets; no evidence of extramedullary leukemia involvement, with the exception of hepatosplenomegaly; SoR to 400 mg imatinib, defined as (min of 20 metaphases): No cytogenetic response at ≥ 3 to <6 months (> 95% Ph+ metaphases);or No PCyR at ≥ 6 to <12 months (36 to 95% Ph+ metaphases on bone marrow); or No CCyR at ≥ 12 to <18 months (1 to 35% Ph+ metaphases on bone marrow); Confirmation of SoR by FISH is allowed if BMK is done outside the screening window up to 4 wks. 400mg/daily imatinib (no higher doses) for at least 3months but no longer than 18 months; Previous use of IFN, taken prior to imatinib treatment, is allowed at a maximum of 90 days unless reason for switch from IFN to imatinib was intolerance. Parameters must be present: Creatinine <2.0 X ULN Total bilirubin <1.5 X ULN (< 3.0 X ULN if related to disease); SGOT and SGPT < 2.5 X ULN; Serum lipase ≤1.5 X ULN; Alkaline phosphatase ≤2.5 X ULN Serum potassium, phosphorus, magnesium and calcium ≥ LLN or corrected to WNL with supplements prior to first dose of study drug; Written informed consent prior to any study procedures being performed. Exclusion criteria: Prior accelerated phase including clonal evolution or blast crisis CML; Prior therapy with imatinib in combination with any other CML drug other than Hydroxyurea and/or Anagrelide; 4.Imatinib therapy started more than 12 months after the date of the original diagnosis; 5.Unable to tolerate imatinib at 400mg; 6.Previous treatment with any other tyrosine kinase inhibitor except Glivec and/or CML therapy other than IFN, hydroxyurea, and /or anagrelide; 7.Myelotoxicity ≥ Grade 2 present at the time of randomization, 8.Previously documented T315I mutations; 9.Impaired cardiac function including one of these: Long QT syndrome or family history of long QT syndrome Clinically significant resting brachycardia (<50 bpm) QTcF >450 msec on screening ECG (using the QTcF formula). If QTc >450 and electrolytes are not with normal ranges, electrolytes should be corrected and then the patient rescreened for QTc to certify QTc <450 msec; Myocardial infarction ≤ 12 months prior to the first dose of study drug; Other clinically significant heart disease (e.g., CHF, uncontrolled hypertension, unstable angina, significant ventricular or atrial tachyarrhythmias) 10. Impairment of GI function or disease that may significantly alter the absorption of study drug; 11. Treated with strong CYP3A4 inhibitors that cannot be either discontinued or switched to a different medication prior to starting study drug; 12.Currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug; 13.History of previous acute pancreatitis within one year of study entry or medical history of chronic pancreatitis; 14.Known cytopathologically confirmed CNS 15.Women who are pregnant, breast feeding or of a childbearing potential without a negative urine pregnancy test at screening. Female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial and for 3 months post trial end. Post-menopausal women must be ammenorrheic for at least 12 months to be considered of non-childbearing potential; 16. History of another primary malignancy that is currently clinically significant or currently requires active intervention; 17.Any other clinically significant medical or surgical condition which, according to investigators' discretion, should preclude participation; 18.Use of investigational agent within 28 days prior to enrollment; 19.Patients unwilling or unable to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 16 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br>Participants received 400 mg nilotinib twice daily (BID). | Drug: nilotinib<br>* Supplied as 200 mg tablets<br>* Other names: Tasigna;|
| Active Comparator: Imatinib<br>Participants received 600 mg imatinib once daily (QD). | Drug: imatinib<br>* Supplied as 100 mg and 400 mg tablets<br>* Other names: Gleevec/Glivec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Cytogenetic Response (CCyR) | CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Major Molecular Response (MMR) | MMR was defined as having a fusion gene of the Bcr and Abl genes of (BCR-ACL) less than or equal to 0.1% on the International Scale (IS). | 12 and 24 months | 
| Percentage of Participants With CCyr | CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow. | 12 and 24 months | 
| Time to CCyR | Time to CCyR was defined as time from date of randomization to date of first documented CCyR. | 24 months | 
| Duration of CCyR | Duration of CCyR was defined as time from the date of ransomization to the date of first loss of CCyR or death, whichever came first. | 24 months | 
| Progression-Free Survival (PFS) | PFS was defined as the time from the date of randomization to the date of documented disease progression to accelerated phase or blast crisis (AP/BC), or death due to any cause. | 24 months | 
| Event-Free Survival (EFS) | EFS was defined as the time from the date of randomization to the date of the first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of Partial Cytogenetic Response (PCyR), loss of CCyR, death on treatment or progression to AP/BC. | 24 months | 
| Overall Survival (OS) | OS was defined as time from date of randomization to the date of the death. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic, Myelogenous, Leukemia, CML, Chronic Phase, Suboptimal Response