A Phase II Study of Dasatinib (BMS-354825) in Subjects with Chronic or Advanced Phase Chronic Myelogenous Leukemia or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia who are Resistant or Intolerant to Imatinib

• Conditions: 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.

• Registration Number: EUCTR2006-001279-39-CZ
• Lead Sponsor: Bristol-Myers Squibb International Corporation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2006-09-05
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 300

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 insti

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified