A RANDOMIZED PHASE III STUDY OF IMATINIB DOSE OPTIMIZATION COMPARED WITH NILOTINIB IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA AND SUBOPTIMAL RESPONSE TO STANDARD-DOSE IMATINIB

• Conditions: IMATINIB DOSE OPTIMIZATION COMPARED WITH NILOTINIB IN PATIENTS WITH CML AND SUBOPTIMAL RESPONSE TO STANDARD-DOSE IMATINIB; MedDRA version: 9.1Level: LLTClassification code 10009012Term: Chronic myelogenous leukemia

• Registration Number: EUCTR2008-007054-35-FI
• Lead Sponsor: ovartis Pharma Services AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2009-06-16
• Last Update Posted: 29 May 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 188

Inclusion Criteria

1.Male or female, aged = 18 years;
2.ECOG Performance Status of 0, 1, or 2 (see Appendix A);
3.Diagnosis of Ph-positive CML in chronic phase (CP) at the start of therapy with imatinib 400mg. CP is defined as follows:
•<15% blasts in peripheral blood and bone marrow;
•<30% blasts plus promyelocytes in peripheral blood and bone marrow;
•<20% basophils in the peripheral blood;
•=100x 109/L (= 100,000/mm3) platelets;
•no evidence of extramedullary leukemia involvement, with the exception of hepatosplenomegaly;

4.Patients with a suboptimal cytogenetic response to 400 mg of imatinib, as follows25 (cytogenetic analysis to document suboptimal response must have been done a maximum of 6 weeks before the first dose of study drug):
•No partial cytogenetic response at = 6 to <12 months of treatment (and at least 36% to 95% Ph+ metaphases on bone marrow); or
•No complete cytogenetic response at = 12 to <18 months of treatment (and have at least 1% to 35% Ph+ metaphases on bone marrow);
•Bone marrow karyotyping (BMK) is required on a minimum of 20 metaphases;
5.Patients receiving 400mg/daily imatinib standard dose for at least 6 months and no more than 18 months;
6.No prior use of imatinib dose higher than 400 mg daily;
7.Previous use of IFN-? is allowed at a maximum of 1 month;
8. Female patients of childbearing potential must have a negative urine pregnancy test within 7 days prior to registration;
9.Adults must agree to use an acceptable method of contraception to avoid pregnancy for the duration of the study and for 3 months after study termination;
10.The following laboratory result 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 (< 5.0 X ULN if related to disease);
•Serum lipase =1.5 X ULN;
•Alkaline phosphatase =2.5 X ULN (< 5.0 X ULN if related to disease)
•Serum potassium, phosphorus, magnesium and calcium = LLN [lower limit of normality] or correctable with supplements prior to first dose of study drug;

11.Written informed consent prior to any study procedures being performed (see Appendix C).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1.Prior accelerated phase or blast crisis CML;
2.Prior therapy with imatinib in combination to any other drug;
3.More than 18 months (+ 8 weeks) of therapy with 400mg/daily imatinib;
4.Patients receiving imatinib dose of 300 mg daily;
5.Patients with myelotoxicity > Grade 2 (receiving 400mg or less) at the time of randomization,
6.Previously documented T315I mutations;
7.Achieved prior PCyR or CCyR on imatinib and lost that response before entering the study;
8.Previous treatment with any other tyrosine kinase inhibitor except imatinib;
9.Impaired cardiac function including one of the following:
•LVEF <45% by echocardiography
•Long QT syndrome or family history of long QT syndrome
•Clinically significant resting brachycardia (<50 bpm)
•QTcF >480 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 and within 20 msec of baseline)
•Myocardial infarction within one year of the first dose of study drug;
•Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, unstable angina, significant ventricular or atrial tachyarrhythmias)
10.Treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St John’s Wort), and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. See link in Section 7.1.10 for complete list of these medications;
11.Treatment with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. See link in Section 7.1.10 or complete list of these medications;
12.Patients using medication that have been documented to prolong QT interval (see Section 7.1.10) should be avoided. In case it is not possible to avoid or switch to other medication, patient should be followed with caution and ECG test should be requested every 3 months after starting study, or if any dose changing, or if clinical symptoms appeared;
13.Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery).
14.History of previous acute pancreatitis within one year of study entry or medical history of chronic pancreatitis;
15.Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture is not required).
16.Women who are pregnant, breast feeding or of a childbearing potential without a negative serum pregnancy test at screening. Male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial. Post-menopausal women must be ammenorrheic for at least 12 months to be considered of non-childbearing potential;
17.Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention;
18.Patients with any other clinically significant medical or surgical condition which, according to investigators’ discretion, should preclude participation;
19.Use of any investigational agent within

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is to determine the comparative efficacy between imatinib dose escalation and nilotinib, in terms of CCyR (CCyR defined as the proportion of patients has 0% Ph+ metaphases) after 6 months of treatment, for patients with CML in chronic phase with suboptimal response to imatinib standard dose.;Secondary Objective: •to compare the rate of major molecular response (MMolR defined as = to 3 log reduction in BCR-ABL transcript levels from standardized baseline at 12 months) between the 2 arms;<br>•to correlate the dose administered with plasma levels of imatinib and with response to therapy;<br>•to establish predictors of response to imatinib dose escalation among patients with CML in chronic phase with suboptimal response to 400mg imatinib;<br>•to evaluate safety and tolerability of imatinib 600mg/daily and nilotinib 400mg twice daily;<br>;Primary end point(s): Rate of CCyR (CCyR defined as 0% Ph+ metaphases) at 6 months.<br><br>