| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Chronic or Advanced Phase Chronic Myelogenous Leukemia (CML) or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (ALL) who are Resistant or Intolerant to Imatinib. |
|
| MedDRA Classification |
| 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 further assess the safety of dasatinib when administered 100 mg QD in CP CML subjects or 140 mg QD in AD CML or Ph+ ALL subjects as measured by the incidence and severity of adverse events, dose interruptions, dose reductions and treatment discontinuation due to drug-related adverse events. |
|
| E.2.2 | Secondary objectives of the trial |
In Chronic Phase (CP) CML subjects:
• To estimate the rate of Major Cytogenetic Response (MCyR) and Complete Hematologic Response (CHR)
• To measure the molecular response
• To estimate the time to, and duration of MCyR
• To explore the spectrum of BCR-ABL point mutations
In Advanced Phase (AD) CML and Ph+ ALL subjects:
• To estimate the rate of Major Hematologic Response (MaHR)
• To estimate the duration of MaHR
• To estimate the rate of Cytogenetic Response (CyR) - optional
In all subjects
• To evaluate Progression-Free Survival (PFS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Signed written informed consent
- Subjects must have had prior exposure to imatinib and have primary or acquired resistance or intolerance. Subjects can be pretreated with IFN, standard chemotherapy or high-dose chemotherapy and stem-cell transplantation. Imatinib may or may not be their most recent treatment prior to entering this study.
Target population:
1/ CP CML
Subjects with a myeloproliferative disorder defined as Ph+ CP CML must meet all the
following criteria:
• < 15% blasts in PB cells or BM
• < 30% blasts + promyelocytes in PB cells or BM
• < 20% basophils in PB cells
• Platelets ≥ 100,000/mm³ (or less if related to prior drug therapy)
• No extra-medullar involvement (except liver or spleen)
Subjects with previous history of AD CML and subjects with clonal evolution (e.g., trisomy 8, der Ph+, iso17q or trisomy 19) are not eligible in this category even if they still meet the criteria for CP as defined above. They are considered in cytogenetic accelerated phase (AP).
2/ AD CML and Ph+ ALL
Subjects with a myeloproliferative disorder defined as Ph+ or BCR-ABL+ AP CML or MyBP CML or LyBP CML or ALL.
- AP CML
Subjects are considered to have AP CML if they meet at least one of the following
criteria:
• At least 15% to < 30% blasts in PB or in BM
• A sum of the percent of blasts and promyelocytes in PB or the BM ≥ 30% (with
< 30% blasts alone)
• ≥ 20% basophils in PB or BM
• Platelets < 100,000/mm³ unrelated to prior drug therapy
Subjects may not have extra-medullary infiltrates of leukemic cells other than in spleen or liver.
In addition, the following subjects will be considered to be part of the AP CML
population even if they do not reach the above threshold values of % blasts in PB or BM for accelerated phase (i.e. chronic phase by hematologic criteria):
• Subjects with clonal evolution (e.g. +8, +19, der Ph+, iso17q, but not -Y only)
• Subjects with prior episode of AP who achieved a hematologic response and subsequently progressed
- MyBP and LyBP CML
Subjects are considered to have Myeloid or Lymphoid BP CML if they meet at least one of the following criteria:
• ≥ 30% myeloid or lymphoid blasts in PB or in BM
• Extra-medullary infiltrates of leukemic cells, other than in spleen or liver, with myeloid or lymphoid blast morphology
Subjects with prior episode of BP who achieved a hematologic response and subsequently progressed but do not meet the criteria for BP CML as described above (i.e. in CP or AP by hematologic criteria) will be considered to be part of the BP CML population.
Subjects with asymptomatic leptomeningeal leukemia are eligible. Concomitant intra-techal therapy is allowed.
- Ph+ ALL
Subjects must have received prior imatinib and at least one prior standard
induction ± consolidation chemotherapy regimen and not be eligible for immediate
autologous or allogeneic stem cell transplantation.
There is no minimum % blasts in PB or BM required for recurrent Ph+ ALL.
Subjects with asymptomatic leptomeningeal leukemia are eligible. Concomitant
intra-techal therapy is allowed.
Subjects characteristics
1) ECOG performance status (PS) score 0 – 2 in CP CML subjects
2) ECOG PS score 0 - 3 in AD CML and Ph+ ALL subjects (See protocol Appendix 1)
3) 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
4) Adequate renal function defined as:
− serum creatinine ≤ 1.5 times the institutional ULN
5) Serum Na, K, Mg, P and total serum Ca or ionized Ca levels must be ≥ grade 1.
Ideally, subjects with low K, Mg levels, total serum Ca and/or ionized Ca must be
repleted before protocol entry.
Age and Sex
6) Men and women, 18 years of age and older
7) 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.
8) 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. |
|
| 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 of at least one month before and for at least 3 months after completion of the study medication.
2) WOCBP using a non-effective contraceptive method
3) Women who are pregnant or breastfeeding
4) Women with a positive pregnancy test on enrollment or prior to study drug administration.
5) 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.
Medical History and Concurrent Diseases
6) A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy
7) Uncontrolled or significant cardiovascular disease, including:
• 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
• Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker)
• Heart rate consistently < 50 beats/minute on pre-entry ECG
• Uncontrolled hypertension
8) History of significant bleeding disorder unrelated to CML, including
• Diagnosed congenital bleeding disorder (e.g., von Willebrand’s disease)
• Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
• Clinically significant bleeding from the GI tract within 6 months
9) Dementia or altered mental status that would prohibit the understanding or rendering of informed consent
Physical and Laboratory Test Findings
10) Evidence of digestive dysfunction that would prevent administration of study therapy
Prohibited Therapies and/or Medications
11) Subjects who received any of the following:
− hydroxyurea within 2 days (unless WBC > 50,000/mm3)
− imatinib, interferon, 6-mercaptopurine or cytarabine within 7 days
− any investigational agent or other antineoplastic agent within 14 days
12) Subjects currently taking drugs that are generally accepted to have a risk of causing Torsade de Pointe (see Protocol Appendix 2)
13) Subjects currently taking drugs that are potent CYP3A4 substrates, inhibitors or inducers (see Protocol Appendixes 3, 4 and 5)
Other Exclusion Criteria
14) Prisoners or subjects who are compulsorily detained |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety/Toxicity
All subjects who receive any study drug will be evaluable for toxicity. Toxic effects will be assessed continuously. Adverse events and other symptoms will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. All subjects will be followed for 30 days after discontinuation of therapy.
Efficacy
Efficacy endpoints include Major Cytogenetic Response (MCyR) rate, complete hematologic response (CHR) rate, time to, and duration of MCyR and progression free survival (PFS) in CP CML subjects. Major HR rate (MaHR), duration of MaHR and PFS will be estimated in AD CML and Ph+ ALL subjects.
|
|
| 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 |
| For subjects with CP CML, BCR/ABL kinase mutation rate analysis and Molecular response monitoring |
|
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 47 |
| 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 |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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