| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) with stable Complete Molecular Response (CMR) who have received dasatinib as first or second-line treatment for a minimum of 2 years at the time of enrollment and have confirmed dasatinib induced complete molecular remission |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients affected by Chronic Phase Chronic Myeloid Leukemia treated by dasatinib and with stable complete molecular response |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to assess the rate of major molecular response (MMR), defined as BCR-ABL transcripts <0.1% on International Scale (IS) at 12 months after dasatinib discontinuation in patients who have maintained MMR without re-starting dasatinib treatment |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study include assessment of the following:
- event-free survival (EFS) (defined as no molecular relapse including no loss of MMR) at 12 months after dasatinib discontinuation;
- relapse-free survival (RFS) at 6, 18, 24 months and every 6 months thereafter;
- BCR-ABL kinetics in those patients who experience intermittent loss of CMR (MR4.5) but no loss of MMR (ie, BCR-ABL blips);
- assessment of BCR-ABL kinetics in patients who are in CMR (MR4.5) or less when transcript levels are still measurable;
- rate of transformation to accelerated phase/blast crisis (AP/BC);
- overall survival |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Signed Written Informed Consent
- Patients diagnosed with CP-CML, on treatment with dasatinib for a minimum of 2 years at the time of enrollment and in dasatinib-induced complete molecular remission (CMR defined as ≤ 0.0032% or 4.5 log reduction of BCR-ABL transcript as determined by local standards) ongoing for at least 1 year prior to study entry
- Patients are eligible for the screening assessment from the central lab if they have been in stable dasatinib induced CMR for a minimum of nine months, documented by at least three assessments, conducted 2.5 - 3.5 months apart, at a local lab. The first screening assessment conducted at the central lab will be repeated after three months, if the first assessment confirms CMR (MR 4.5). Patients are eligible for enrollment if both assessments from the central lab confirm MR4.5
- Patients with CP CML treated with dasatinib as first line treatment or second-line treatment after a TKI-based therapy
- Eligible patients must have achieved a 1-log reduction in BCR-ABL transcript levels compared to baseline as determined by local standards or less than or equal to 10% IS at 3 months for current dasatinib therapy (first or second line)
- ECOG PS of 0-1
- Life expectancy of > 1 year
- Adequate renal function defined as serum creatinine ≤ 3.0 times the institutional ULN
- 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)
- 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. Patients with low K, Mg levels, total serum Ca and/or ionized Ca must be replete to allow for protocol entry
- Subject Re-enrollment: This study does not permit the re-enrollment of a subject that has discontinued the study as a pre-treatment failure
- Men and women, ages 18 or older years, inclusive
- Women of childbearing potential (WOCBP) must use method(s) of contraception throughout the entire study period (i.e., during the study periods of dasatnib discontinuation and during re-initiation of dasatinib)
- Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to study entry, at each study visit, and 72 hours prior to re-initiation of dasatinib
- Women must not be breastfeeding
- Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year
- Women who are not of childbearing potential (i.e,, who are postmenopausal or surgically sterile) and azoospermic men do not
require contraception |
|
| E.4 | Principal exclusion criteria |
- Subjects with more than one CML treatment before dasatinib
- Lack of a 1-log reduction in BCR-ABL transcript levels compared to baseline as determined by local standards or > 10% IS at 3 months since beginning dasatinib therapy (first or second line).
- Patients who have previously undergone hematopoietic stem cell transplantation (SCT) or who are scheduled for SCT
- Any prior treatment with interferon
- Previous diagnosis of CML accelerated phase or blast crisis
- Prior or concurrent malignancy, except the following:
i) Curatively treated basal cell or squamous cell skin cancer
ii) Cervical carcinoma in situ
iii) Adequately treated Stage I or II cancer from which the subject is currently in complete remission
iv) Any other cancer from which the subject has been disease free for 3 years
- A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy
- Uncontrolled or significant cardiovascular disease, including any of the following:
i. Congestive cardiac failure (NYHA > 2) within 3 months
ii. Diagnosed or suspected congenital long QT syndrome
iii. Any history of clinically significant ventricular arrhythmias
iv. Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
v. Any history of second- or third-degree heart block (may be eligible if the subject
currently has a pacemaker)
vi. Uncontrolled angina within 3 months
vii. Prior myocardial infarction within 6 months
viii. Uncontrolled hypertension
- Pulmonary arterial hypertension
- Subjects with pericardial effusion of any grade at study entry are excluded. Subjects previously diagnosed with pleural/pericardial effusion of any grade resolved at the time of study entry are allowed
- History of significant bleeding disorder unrelated to CML, including
i. Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease)
ii. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
- Physical and Laboratory Test Findings
- Subjects with known hypersensitivity to excipients of dasatinib tablets (Tablet core: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium; hydroxypropyl cellulose, magnesium stearate; Film-coating: hypromellose titanium dioxide macrogol 400)
- Patients with a history of non-compliance to CML treatment and monitoring requirements
- Patients who are pregnant or breastfeeding or likely to become pregnant
- Men whose partner is unwilling or unable to avoid pregnancy
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint, the MMR rate at 12 months, is the proportion of enrolled subjects who maintain MMR 12 months after dasatinib discontinuation compared with the enrolled
subjects in the study |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after dasatinib discontinuation |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include:
- event-free survival at 12 months after dasatinib discontinuation
- relapse-free survival at 6, 18, 24 months and every 6 months thereafter after dasatinib discontinuation
- assessment of BCR-ABL kinetics for subjects who experience loss of CMR but not MMR
- assessment of BCR-ABL kinetics in subjects in CMR with measurable levels
- the rate of transformation to AP/BC, and overall survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- event-free survival at 12 months after dasatinib discontinuation
- relapse-free survival at 6, 18, 24 months and every 6 months thereafter after dasatinib discontinuation
|
|
| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| 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 | 4 |
| 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 |
| Canada |
| Finland |
| France |
| Italy |
| Spain |
| United States |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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