| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid
Leukemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 | 10054352 |
| E.1.2 | Term | Chronic phase chronic myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 best confirmed complete cytogenetic response (CCyR) rates within 12 months in newly diagnosed chronic phase CML subjects treated with dasatinib 100 mg QD versus imatinib 400 mg QD;
Data collection for the response rates at 12 months has been completed. |
|
| E.2.2 | Secondary objectives of the trial |
To compare in rank order the following:
• Time in confirmed CCyR overall
• Major molecular response (MMR) rate at any time
• Time to confirmed CCyR overall
• Time to MMR overall
• Progression-free survival (PFS)
• Overall survival (OS)
Data collection for the response rates at 12 months has been completed. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Subjects able to provide written informed consent.
2) Patients must have Ph+ CML in CP which is defined by the presence of all of the
following criteria:
< 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 10E9/L platelets.
No evidence of extramedullary leukemic involvement, with the exception of
hepatosplenomegaly. Ph+ or variants must be demonstrated by BM cytogenetics.
3) Previously untreated chronic CML.
4) Subjects must be enrolled in this study within approximately 3 months (90 days) after the date of first being diagnosed with CML, based on cytogenetic test results of bone marrow, demonstrating the presence of the Philadelphia chromosome or variants of the (9;22) translocation. Subjects are allowed to have secondary chromosomal abnormalities (i.e., clonal evolution) in addition to the Philadelphia chromosome and remain eligible.
5) ECOG Performance Status (PS) Score 0 - 2.
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 upper limit of normal (ULN).
7) Adequate renal function defined as serum creatinine ≤ 3 times the institutional ULN.
8) Men and women, ages 18 years and older.
9) 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 (4 weeks) before and at least 1 month (4 weeks) after the last dose of
investigational product in such a manner that the risk of pregnancy is minimized.
10) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug Dasatinib plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion
11) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from
contraceptive requirements. However they must still undergo pregnancy testing as described in section 6.1 of the protocol |
|
| E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for at least one month (4 weeks) before and for at least 1 month (4 weeks) after the last dose of study medication.
2) WOCBP using a prohibited contraceptive method (Not applicable for this study).
3) Women who are pregnant or breastfeeding.
4) Women with a positive pregnancy test at enrollment or prior to administration of
study medication.
5) Men whose sexual partners are WOCBP, who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 90 days (duration of sperm turnover) after completion of study medication
6) A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy.
7) Known pleural effusion at baseline.
8) Uncontrolled or significant cardiovascular disease, including any of the following:
A myocardial infarction within 6 months; Uncontrolled angina within 3 months; Congestive heart failure within 3 months; Diagnosed or suspected congenital long QT syndrome; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe); Prolonged QTcF interval > 450 msec on pre-entry ECG
9) History of significant bleeding disorder unrelated to CML, including:
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease);
Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
VIII antibodies).
10) Prior chemotherapy for peripheral stem cell mobilization. (Prior collection of
unmobilized peripheral blood stem cells is permitted).
11) Prior or concurrent malignancy, except for the following:
adequately treated basal cell or squamous cell skin cancer; cervical carcinoma in situ;
adequately treated Stage I or II cancer from which the subject is currently in
complete remission; or any other cancer from which the subject has been disease-free for three years.
12) Evidence of digestive dysfunction that would prevent administration of study therapy by mouth.
13) Any prior treatment with interferon
14) Any prior treatment with dasatinib
15) Any prior treatment with imatinib
16) Any other prior systemic treatments, with anti-CML activity [except for anagrelide,
or hydroxyurea (HU)].
17) Subjects currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes. 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 study therapy. Amiodarone must be discontinued for at least 14 days prior to randomization.
18) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the rate of best confirmed CCyR within 12 months.
CCyR will be assessed via cytogenetic analysis of bone marrow biopsy/aspirate specimens. Cytogenetic analysis will occur at the local institutions and be reported via CRF.
Toxic effects will be assessed continuously and reported for all treated subjects. Adverse events and other symptoms will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Time in, duration and time to confirmed CCyR Time in duration and time to confirmed CCyR within 12 months |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 3 months during first 12 months of treatment, every 12 months thereafter |
|
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| 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 | No |
| 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 |
| Australia |
| Austria |
| Brazil |
| Chile |
| China |
| Colombia |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Spain |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| Singapore |
| Turkey |
|
| 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
|
| Last follow up visit of the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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 | 7 |
| 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 |
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