| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subject with Ph Chronic phase Chronic Myeloid leukemia CML |
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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 | 10009013 |
| E.1.2 | Term | Chronic myeloid leukaemia |
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| E.1.3 | Condition being studied is a rare disease | No |
| 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 MMolR of dasatinib 100 mg QD to high-dose imatinib 800 mg; i.e. 400 mg BID therapy in CP CML patients with a suboptimal response after at least 12 months of therapy with imatinib 400 mg monotherapy. |
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| E.2.2 | Secondary objectives of the trial |
| To estimate the rates of CCgR in both treatment arms To estimate the time to MMolR and CCgR 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 |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
| Signed written informed consent 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 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 Appendix 1 6 Adequate hepatic function defined as total bilirubin 8804; 2.0 times the institutional ULN; alanine aminotransferase ALT and aspartate aminotransferase AST 8804; 2.5 times the institutional ULN 7 Adequate renal function defined as serum creatinine 8804; 3 times the institutional ULN. 8 Serum Na, K, Mg, P 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. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization hysterectomy, bilateral tubal ligation or bilateral oophorectomy or is not postmenopausal defined as amenorrhea 8805; 12 consecutive months; or women on hormone replacement therapy HRT with documented serum follicle stimulating hormone FSH level 35mIU/mL . Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods diaphragm, condoms, spermicides to prevent pregnancy or practicing abstinence or where partner is sterile e.g., vasectomy , should be considered to be of child bearing potential. 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. |
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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 less than a PCgR 10 Subjects who lost previously documented CCgR and have currently PCgR 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 450 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 e.g., von Willebrand s disease b Diagnosed acquired bleeding disorder within one year e.g., acquired anti-factor VIII antibodies 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 12 months of prior treatment with imatinib 18 Subject who received imatinib within the last 7 days wash-out period 19 Time from initial diagnosis of CML to start of first imatinib dose 6 months 20 Subjects with prior stem cell transplantation and/or high dose chemotherapy for CML 21 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 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. 22 Subjects taking medications that inhibit platelet function i.e., aspirin, dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab, ticlopidine, and any non-steroidal anti-inflammatory drug .. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy Primary endpoint MMolR rate at 12 months Secondary endpoints CCgR rate at 12 months, time to MMolR, CCgR 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 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 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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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) | 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 3 |
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