| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nilotinib will be evaluated in patients having showed a suboptimal cytogenetic response to imatinib |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009700 |
| E.1.2 | Term | CML |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the complete cytogenetic response (CCyR) rate at 12 months of nilotinib compared to imatinib in adult patients with Ph+ CML in CP who have a suboptimal cytogenetic response to imatinib. |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the rate of durable CCyR at 24 mts (patients who have achieved CCyR by 12 mts, and maintain continuous CCyR until the 24 mts timepoint).
•To evaluate the rate of major molecular response (MMR) of nilotinib vs. Imatinib*.
•To evaluate the rate of durable CCyR over the initial 24 mts of this study*.
•To evaluate the CCyR rate of nilotinib vs. imatinib* at 24 mts.
•To evaluate the time to and duration of CCyR of nilotinib vs. imatinib*.
•To evaluate the time to, rate of, and duration of a ≥ 4 log reduction in BCR-ABL transcript levels a from the standardized baseline (as established in the IRIS study), or ≤ 0.01% BCR-ABL/control gene% by international scale of nilotinib vs. imatinib*.
•To evaluate the time to and duration of MMR of nilotinib vs. imatinib*.
•To describe overall survival, progression free survival and event-free survival up to 5 years*.
•To evaluate the safety profile of nilotinib and vs. imatinib*.
*in adult patients with Ph+ CML in CP
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male and female patients ≥ 18 years of age.
ECOG performance status of 0,1, or 2.
Diagnosis of Ph+ CML-CP defined as:
<15% blasts in peripheral blood and bone marrow,
< 30% blasts plus promyelocytes in peripheral blood and bone marrow
< 20% basophils in the peripheral blood
≥100 x 109 /L (>/ 100,000 /mm3) platelets
No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
Patients with suboptimal cytogenetic response to a dose of 400 mg imatinib (1st line therapy) defined as ≥ 6 to < 12 months of treatment and have 36 - 95% Ph+ metaphases, or ≥ 12 to < 18 months of treatment and have 1 - 35% Ph+ metaphases. Bone marrow karyotyping is rquired on a min. of 20 metaphases. FISh analysis is not allowed.
The following laboratory results must be present:
Total bilirubin <1.5XULN; SGOT and SGPT <2.5XULN; Creatinine < 1.5XULN, Serum potassium, phosphorus, magnesium and calcium ≥ LLN or correctable with supplements prior to the first doese of study drug. Serum amylase and lipase ≤ 1.5xULN, alkaline phosphatase ≤ 2.5XULN unless considered tumor related.
|
|
| E.4 | Principal exclusion criteria |
Prior accelerated phase or blast phase CML.
Previously documented T315I mutation.
Achieved prior PCyR or CCyR on imatinib and lost that response prior to entering the study.
• Prior treatment with > 400 mg/day of imatinib.
• Patients who have received more than 18 months of imatinib therapy.
• Intolerance to imatinib ≥ 400 mg/day defined as the inability to maintain dosing of 400 mg daily for the previous 3 months.
• Previous treatment with any other tyrosine kinase inhibitor except imatinib.
• Patients who had any other treatment for CML (e.g. interferon, transplant) except
hydroxyurea and/or anagrelide.
•Impaired cardiac function including any one of the following:
• LVEF < 45% by echocardiography
• Complete left bundle branch block
• Congenital long QT syndrome or family history of long QT syndrome
• History of or presence of significant ventricular or atrial tachyarrhythmias
• 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
• Use of a ventricular-paced pacemaker
• 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).
• Treatment with strong 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 6.6.4 for complete list of these medications.
• 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 6.6.4 for complete list of these medications.
• Treatment with medications that have been well documented to prolong the QT interval is contraindicated. See Section 6.6.4 for further guidance.
• 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).
• History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis.
• Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS
involvement, lumbar puncture not required).
• Any other malignancy that is clinically significant or requires active intervention.
• Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or chronic liver disease, pancreatic, or severe renal disease unrelated to tumor, active or uncontrolled infection).
• History of significant congenital or acquired bleeding disorder unrelated to cancer.
• Previous radiotherapy to ≥ 25% of the bone marrow.
• Patients who have had major surgery within 4 weeks prior to the first dose of study drug or who have not recovered from prior surgery.
• Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon).
• Treatment with other investigational agents within 28 days of Day 0 (first dose of
study drug).
• History of non-compliance to medical regimens or inability to grant consent.
• Women who are pregnant, breast feeding, or of 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. Postmenopausal women must be ammenorrheic for at least 12 months to be considered of nonchildbearing potential. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy
Complete cytogenetic Response (CCyR) rate at 12 months (CCyR is defined as 0% Ph+ metaphases)
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Imatinib mesylate (Glivec®) |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Therapy with nilotinib or imatinib will be continued for up to 5 years while on study, until progression or the development of intolerance of treatment, whichever occurs first.
Patients will receive nilotinib as long as they have not discontinued from this study up to the 5 year study duration.
Patients will receive imatinib as long as they have not discontinued from this study (or crossed over to nilotinib) for up to the 5 year study duration. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
Print
