| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Subjects with Ph+ chronic phase Chronic Myeloid leukemia (CML).
Sujetos con Leucemia Mieloide Crónica en fase crónica con cromosoma Philadelphia Positivo. |
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| MedDRA Classification |
| 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 compare the rate of major molecular response of dasatinib (100 mg QD) to high-dose imatinib (800 mg, i.e. 400 mg BID) therapy at 12 months in chronic phase CML subjects, who had achieved only a suboptimal response after at least 3 months imatinib (400 mg) monotherapy prior to enrollment. A suboptimal response is defined as a hematologic response but less than Complete HR after at least 3 months; a cytogenetic response but less than a partial cytogenetic response (PCgR) after at least 6 months; a partial cytogenetic response after at least 12 months, or less than a major molecular response with complete cytogenetic response after at least 18 months.
Additional 12 months of treatment:
The primary objective is to collect longer term efficacy on dasatinib in terms of duration of major molecular response.
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| E.2.2 | Secondary objectives of the trial |
• To estimate the rates of Complete Cytogenetic Response (CCgR) at months 6 and 12 in both treatment arms
• To estimate the time to Major Molecular Response (MMolR) and TTF, PFS in both treatment arms
• To assess the safety of dasatinib and high-dose imatinib
• To establish BCR/ABL kinase domain mutation rate
• To investigate causes and mechanisms of resistance
• To evaluate the quality of life (QOL) in each treatment arm
Additional 12 months of treatment:
The secondary objective is to provide access to study treatment for those patients who are benefiting from 800 mg imatinib and to obtain further safety data. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Subjects able to provide written informed consent
2) Available for periodic follow up
3) Life expectancy of at least approximately 3 months
Target population
4) Subjects with Ph+ chronic phase CML who achieved only a suboptimal response (defined as a HR which is <CHR after at least 3 months therapy with imatinib 400 mg
monotherapy; a CgR which is <PCgR after at least 6 months therapy with imatinib
400 mg monotherapy; a PCgR after at least 12 months therapy with imatinib 400 mg monotherapy or less than MMolR with CCgR after at least 18 months therapy with imatinib 400 mg monotherapy). Only subjects who started treatment with imatinib 400 mg monotherapy within 6 months of initial CML diagnosis will be eligible.
5) ECOG performance status (PS) score 0 - 2 (See Protocol Appendix 1)
6) Adequate hepatic function defined as:
- total bilirubin ≤2.0 times the institutional ULN;
- alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the institutional ULN
7) Adequate renal function defined as: serum creatinine ≤3 times the institutional ULN.
8) Serum Na, K, Mg and total serum Ca or ionized Ca levels must be greater than or equal to the institutional lower limit of normal. Subjects with low K, Mg levels, total serum Ca and/or ionized Ca must be repleted to allow for protocol entry.
Age and Sex
9) Men and women, 18 years of age and older
10) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 1 month before and at least 3 months after the study in such a manner that the risk of pregnancy is minimized.
11) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication.
The following subjects are considered to be eligible for the additional 12 months of
treatment:
• Subjects with a MMolR after initial 12 months of treatment on either dasatinib or
800 mg imatinib. Subjects who obtain their first MMolR at month 12, should have
this response confirmed at month 13 in order to be eligible to the second year of the study.
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| E.4 | Principal exclusion criteria |
Sex and Reproductive Status
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period of at least one month before and for at least 3 months after completion of study medication.
2) Women who are pregnant or breastfeeding
3) Women with a positive pregnancy test on enrollment or prior to study drug administration.
4) Men whose sexual partners are WOCBP, who are unwilling or unable to use an acceptable method to avoid pregnancy of his partner for the entire study period and for at least 3 months after completion of study medication.
Target Disease Exceptions
5) Subjects eligible for immediate autologous or allogeneic stem cell transplantation.
6) Previous diagnosis of accelerated phase or blast crisis CML
7) Subjects who have previously documented T315I mutation.
Screening for mutation is not required for enrollment onto the protocol.
8) Subjects with a MMolR
9) Subjects with no hematologic response
10) Subjects who lost previously documented CHR, PCgR or CCgR
Medical History and Concurrent Diseases
11) A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy
12) Uncontrolled or significant cardiovascular disease, including:
a) A myocardial infarction within 6 months
b) Uncontrolled angina within 3 months
c) Congestive heart failure within 3 months
d) Diagnosed or suspected congenital long QT syndrome
e) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe)
f) Prolonged QTc interval > 500 msec on pre-entry ECG according to Fridericia formula
g) Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker)
h) Heart rate consistently < 50 beats/minute on pre-entry ECG
i) Uncontrolled hypertension
13) History of significant bleeding disorder unrelated to CML, including:
a) Diagnosed congenital bleeding disorders
b) Diagnosed acquired bleeding disorder within one year
c) Clinically significant bleeding from the GI tract within 6 months
14) Concurrent other malignancies other than CML
Physical and Laboratory Test Findings
15) Intolerance to imatinib 400 mg. Intolerance is defined as occurrence of any of the following at any time during treatment
a) Imatinib-related grade 3 or greater non-hematologic toxicity
b) Imatinib-related grade 4 hematologic toxicity lasting more than 7 days
c) Imatinib-related toxicity leading to imatinib discontinuation or disruption in dosing for >4 weeks
Prohibited Therapies and/or Medications
16) Prior treatment with imatinib at a dose > 400 mg
17) Less than 3 months of prior treatment with imatinib
18) Time from initial diagnosis of CML to start of first imatinib dose > 6 months
19) Subjects with prior stem cell transplantation and/or high dose chemotherapy for CML
20) Subjects currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes including:
- quinidine, procainamide, disopyramide
- amiodarone, sotalol, ibutilide, dofetilide
- erythromycins, clarithromycin
- chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, zyprasidone
- cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
Subjects who have discontinued any of these medications must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is greater) prior to the first dose of dasatinib.
21) Subjects taking medications that inhibit platelet function or anticoagulants (Low-dose warfarin for prophylaxis to prevent catheter thrombosis, and heparin-flushes for IV lines is permitted);
22) Prior therapy with dasatinib or other experimental agent for CML
Other Exclusion Criteria
23) Prisoners or subjects who are involuntarily incarcerated. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
• Primary endpoint: proportion of subjects achieving a MMolR rate at 12 months
• Secondary endpoints: CCgR rate at 6 and 12 months, time to MMolR, TTF and PFS.
Subjects who have a confirmed MMolR at 12 months on treatment will be counted as responders (if first MMolR is at month 12, the confirmed MMolR should occur at month 13). Treatment failure will be defined as failure to complete 12 months of treatment or failure to achieve a MMolR at 12 months of study treatment. Subjects who achieved a MMolR earlier than 12 months, but have lost this response at evaluation at 12 months, will not be considered responders.
Safety:
Safety and tolerability of dasatinib and imatinib will be reported for all randomized subjects. Adverse events will be assessed continuously and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Mutation and resistance analysis:
Mutation analysis will be performed in all subjects at baseline, at the time of progression during study treatment or after 12 months of treatment. |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| BCR/ABL kinase mutation rate analysis; Health Utility Assessment (QoL) |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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
| 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 | 7 |
| 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 |
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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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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