| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| IMATINIB DOSE OPTIMIZATION COMPARED WITH NILOTINIB IN PATIENTS WITH CML AND SUBOPTIMAL RESPONSE TO STANDARD-DOSE IMATINIB |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients with Philadelphia-chromosome-positive CML in chronic phase
who have suboptimally responded to 400 mg daily imatinib at specific
timepoints during the first year of imatinib treatment |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009012 |
| E.1.2 | Term | Chronic myelogenous leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the rate of major molecular response (MMR) between the 2
arms
- To evaluate safety and tolerability of imatinib 600mg/daily and
nilotinib 400mg twice a day
- to evaluate the rate of CCyR at 12, 18 and 24 months on study and
MMR at 18 and 24 months on study in the two treatment arms
- To evaluate the time to and duration of CCyR in the two arms;
- To evaluate progression-free survival (PFS), event-free survival (EFS)
and overall survival (OS) up to 2 years on study;
- To investigate predictors of response to imatinib dose escalation
among patients with CML in chronic phase with suboptimal response to
400mg imatinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, aged ≥ 18 years;
2. ECOG Performance Status of 0, 1, or 2 (see Appendix A);
3. Ph-positive CML in chronic phase (CP) at study enrollment is defined
as follows:
• <15% blasts in peripheral blood and bone marrow;
• <30% blasts plus promyelocytes in peripheral blood or 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, defined as follows (cytogenetic analysis to document suboptimal response must have been done within 6 weeks of randomization):
• No cytogenetic response at ≥ 3 to <6 months (more than 95% Ph+ metaphases)
• 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; Confirmation of suboptimal response (SoR) by FISH is allowed if BMK is done outside the screening window up to 4 weeks.
5. Patients receiving 400mg/daily imatinib standard dose for at least 3
months but no longer than 18 months;
6. No prior use of imatinib dose higher than 400 mg daily;
7. Previous use of IFN, taken prior to imatinib treatment, is allowed at a
maximum of 90 days. There is no time limit if the reason for switch from
IFN to imatinib was intolerance.
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;
• Serum lipase ≤1.5 X ULN;
• Alkaline phosphatase ≤2.5 X ULN
• Serum potassium, phosphorus, magnesium and calcium ≥ lower limit of normality (LLN) or corrected to within normal limits with supplements prior to first dose of study drug;
11. Written informed consent prior to any study procedures being performed (see Appendix C).
|
|
| E.4 | Principal 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;
3. More than 18 months of imatinib therapy;
4. Patients who started imatinib therapy more than 12 months after the date of the original diagnosis
5. Unable to tolerate imatinib at standard dose (400mg);
6. Previous treatment with any other tyrosine kinase inhibitor except Glivec and/or CML therapy other than INF, hydroxyurea, and/or anagrelide
7. Patients with myelotoxicity ≥ Grade 2 at the time of randomization,
8. Previously documented T315I mutations;
9. Achieved prior PCyR or CCyR on imatinib therapy and lost that response before entering the study;
10. Impaired cardiac function including one of the following:
• 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., congestive heart failure, uncontrolled hypertension, unstable angina, significant ventricular or atrial tachyarrhythmias)
11. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug;
12. 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;
13. 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;
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 urine pregnancy test at screening. 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 nonchildbearing 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 investigational agent within 28 days prior to enrollment in the study or foreseen use of an investigational agent during the study;
20. Patients unwilling or unable to comply with the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Rate of CCyR (CCyR defined as 0% Ph+ metaphases) at 6 months.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
- Rate of a MMR (MMR is defined as BCR-ABL less than or equal to 0.1% on international scale) at 12 months
- Safety profile of nilotinib and imatinib treatment arms Other secondary timepoints:
- Rate of CCyR at 12, 18 and 24 months and MMR 18 and 24 months
- Time to CCyR defined as the time from the date of andomization to the date of the first documented CCyR
- Duration of CCyR defined as the time from the date of the first documented CCyR to the date of the first loss of CCyR or death,which ever occurs first;
- Rate of durable CCyR at 24 months; defined as the proportion of patients who achieved CCyR at 6 months and maintained CCyR at the 24-month visit without a documented loss of CCyR
- Progression-Free Survival (PFS), Event-Free Survival (EFS), Overall Survival (OS) |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Argentina |
| Brazil |
| China |
| Colombia |
| Germany |
| Guatemala |
| India |
| Mexico |
| Panama |
| Poland |
| Russian Federation |
| Venezuela, Bolivarian Republic of |
|
| 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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