| 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 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 | 20.0 |
| 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 | 100000013009 |
|
| 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 the proportion of subjects who maintain MMR (BCR-ABL transcripts < 0.1% on International Scale (IS) at 12 months after dasatinib discontinuation 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 survival with no loss of MMR) at 12, 24, 36, 48 and 60 months after dasatinib discontinuation;
- relapse-free survival (RFS) at 6, 12, 18, 24 months and every 6 months thereafter;
- BCR-ABL kinetics in those patients who experience loss of CMR (MR4.5) but no loss of MMR (BCR-ABL kinetics are any changes in residual level that do not have clinical relevance);
- 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);
- progression free survival
- 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 (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 - 6.5 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. For any patient not eligible for enrollment on the basis of a central laboratory test that does not confirm CMR, rescreening is allowed 9 months after (or longer) from the last central lab screening failure. These patients must have documented stable CMR at the local lab, and must meet all other criteria, before rescreening
- Subjects who have received dasatinib beyond first or second line treatment and meet other enrollment criteria are eligible for the study provided prior TKIs were discontinued due to intolerance or lack efficacy, although only one instance of lack of efficacy to TKI is allowed
- 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 ≤ 3.0 times the institutional ULN;alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 times the institutional upper limit of normal (ULN). In cases where the patient needs to restart dasatinib therapy, caution will be used in case of hepatic impairment
- 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 may be repleted to allow for protocol entry. Rescreening is permitted in the event of temporary biochemical abnormalities.
- Men and women ≥ 18
- Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the restart of study drug
- Women must not be breastfeeding
-WOCBP must agree to follow instructions for method(s) of contraception at the restart of treatment with drug and for the duration treatment plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion
- Men who are sexually active with WOCBP agree to follow instructions for method(s) of contraception for 90 days after study entry (withdrawal of dasatinib), at restart of study drug (dasatinib) and for the duration of treatment with study drug (dasatinib) plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion
-Male subjects whose partners are WOCBP must use condoms, including
male subjects who are azoospermic. WOCBP who are continuously not
heterosexually active are exempt from contraceptive requirements but
still must undergo pregnancy testing as described in this section
-Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBPon the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception |
|
| E.4 | Principal exclusion criteria |
- Patients who have not achieved 1-log reduction in BCR-ABL transcript levels compared to baseline as determined by local standards or > 10% IS documented at 3.0-6.5 months since the initial start of dasatinib therapy
- Patients who have previously undergone hematopoietic stem cell transplantation (SCT) or who are scheduled for SCT
- 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 in case reinitiation of dasatinib is needed
- Although subjects with acute hepatitis B virus (HBV) infection are
excluded, subjects with chronic or resolved hepatitis B infection may be
enrolled if they meet all other eligibility criteria. See Section 5.3 for
recommendations regarding subjects with positive HBV serology
- Uncontrolled or significant cardiovascular disease, including any of the following:
i. not applicable per amendment 02
ii. Diagnosed or suspected congenital long QT syndrome
iii. Any history of clinically significant ventricular arrhythmias
iv. Prolonged QTc interval on pre-entry electrocardiogram that is considered clinically significant according to investigator's criteria
v. Any history of second- or third-degree heart block (may be eligible if the subject currently has a pacemaker)
- Subjects with prior history of pericardial effusion or pleural effusion that requires thoracentesis are excluded. Subjects with prior history of pericardial or pleural effusion that was clically manageable and a maintaines CMR ≥1 year on a sable dose of dasatinib 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)
- 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
- Additional Criteria for Patients Eligible to Re-start Dasatinib - Any
patient who has lost MMR and is eligible for re-starting dasatinib therapy must not have developed a condition that precludes dasatinib use, e.g., pulmonary arterial hypertension. Such a subject will be dropped from treatment with dasatinib and treated according to the investigator's choice. |
|
| 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 (EFS) (defined as survival with no loss of MMR) at 12, 24, 36, 48 and 60 months after dasatinib discontinuation
- relapse-free survival at 6, 12, 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, PFS and overall survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- event-free survival at 12, 24, 36, 48 and 60 months after dasatinib discontinuation
- relapse-free survival at 6, 12, 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Germany |
| 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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