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

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

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.

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.

Inclusion criteria:

1. Male or female ≥ 18 years old;

2. ECOG of 0, 1, or 2;

3. 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;

4. 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.

5. 400mg/daily imatinib (no higher doses) for at least 3months but no longer than 18 months;

6. 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.

7. 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;

8. Written informed consent prior to any study procedures being performed.

Exclusion criteria:

1. Prior accelerated phase including clonal evolution or blast crisis CML;
2. 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.