E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nilotinib vs. Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response for CML-CP Patients with Evidence of Persistent Leukemia by RQ-PCR |
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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 | 10009012 |
E.1.2 | Term | Chronic myelogenous leukemia |
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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 compare the rate of confirmed best cumulative CMR within the first year of study therapy with nilotinib or imatinib |
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E.2.2 | Secondary objectives of the trial |
• To characterize kinetics of CMR achieved in both treatment arms • To compare progression-free survival between the two arms |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
After 4 years all patiens will be followed annually and an annual blood sample for PCR will be collected for a futher 6 years as part of standard of care.
Title: An Open Label, Randomized Study of Nilotinib vs. Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response for CML-CP Patients with Evidence of Persistent Leukemia by RQ-PCR.
Primary Objective: To compare the rate of confirmed best cumulative CMR within the first year of study therapy with nilotinib or imatinib |
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E.3 | Principal inclusion criteria |
1. Patients ≥18 years old 2. Diagnosis of chronic myeloid leukemia in chronic phase (CML-CP) associated with BCR-ABL quantifiable by RQ-PCR (IS) 3. Documented CCyR* by bone marrow (standard cytogenetic test) or peripheral blood BCR-ABL<1% IS as defined in Appendix 1 of protocol 4. Persistent disease demonstrated by two PCR positive tests (ie., BCR-ABL level <1% IS) which have been performed during the past nine months and are at least 10 weeks apart. One of these should be performed within 3 months of randomization (see definition of persistent disease in Appendix 1). 5. Treatment with imatinib for at least 2 years with 400 mg or 600 mg and a stable dose (the dose has not changed in the previous 6 months.) Patients who received imatinib 800 mg/day in the past, but the dose was subsequently reduced to 600 mg or 400 mg/day more than 6 months before the randomization are also eligible for this study. 6. Must have been treated with Glivec®/Gleevec® 7. No other current or planned anti-leukemia therapies 8. ECOG Performance status 0,1, or 2 9. Adequate end-organ function as defined by: a. Total bilirubin < 1.5 x ULN (ULN = upper limit of normal in a local institution lab). Does not apply to patients with isolated hyperbilirubinemia (e.g., Gilbert’s disease) grade <3. b. AST (SGOT) and ALT (SGPT) < 2.5 x ULN c. Serum amylase and lipase ≤ 1.5 x ULN d. Alkaline phosphatase ≤ 2.5 x ULN 10. Patients must have the following laboratory values (WNL = within normal limits at the local institution lab) or corrected to within normal limits with supplements prior to the first dose of study medication a. Potassium (WNL) b. Magnesium (WNL) c. Phosphorus (WNL) d. Calcium (WNL) 11. Life expectancy of more than 12 months in the absence of any intervention 12. Patient has given written, informed consent to participate in the study *Note: One of the PCR tests used to document persistent disease may also serve to document CCyR, if <1% on IS (see Inclusion criteria #4) |
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E.4 | Principal exclusion criteria |
1. Prior accelerated phase or blast crisis 2. Patient has evidence of rising PCR (a confirmed >1 log increase in previous 6 months) 3. Patient has received another investigational agent within last 6 months or TKIs other than imatinib 4. Prior stem cell transplantation 5. Impaired cardiac function including any one of the following: a. Inability to monitor the QT/QTc interval on ECG b. Long QT syndrome or a known family history of long QT syndrome c. Clinically significant resting brachycardia (<50 beats per minute) d. QTc > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patientre-screened for QTc e. Myocardial infarction within 12 months prior to starting study f. Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension) g. History of or presence of clinically significant ventricular or atrial tachyarrhythmias 6. Administration of cytokine therapy (e.g. G-CSF, GM-CSF or SCF) within 4 weeks prior to study entry 7. Atypical BCR-ABL transcript not quantifiable by standard RQ-PCR. 8. Another primary malignant disease, which requires systemic treatment (chemotherapy or radiation) 9. Acute liver disease 10. Acute or chronic pancreatic disease 11. Another severe and/or life-threatening medical disease 12. History of significant congenital or acquired bleeding disorder unrelated to cancer 13. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug 14. Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug 15. Patients who are 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 16. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential) 17. Interruption of imatinib therapy for a cumulative period in excess of 21 days in the preceding 3 months 18. Major toxicity on imatinib in past 3 months 19. History of non-compliance or inability to grant informed consent |
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of confirmed best cumulative CMR within the first year of study therapy with nilotinib or imatinib |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
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 | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |