Chronic Myelogenous Leukemia or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemic Study

Leukemia Clinical Trial

Official title:

Long-Term Safety and Efficacy of Dasatinib (BMS-354825) in Chronic Myelogenous Leukemia or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in Subjects Who Experienced Clinical Benefit on Protocol CA180-002

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00978731
• Other study ID #: CA180-039
• Status: Completed
• Phase: Phase 1
• First received: September 16, 2009
• Last updated: April 25, 2011
• Start date: December 2005
• Est. completion date: September 2008

Study information

• Verified date: April 2011
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

To determine the long term safety and tolerability of dasatinib exposure in subjects previously treated in CA180-002.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

This study enrolled participants with Philadelphia chromosome positive (Ph+)chronic myelogenous leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) who had demonstrated hematologic resistance or intolerance to imatinib mesylate (Gleevec) and had experienced clinical benefit (in Investigator's opinion) on protocol CA180002.

Inclusion Criteria:

• Signed written informed consent

• Previous treatment with dasatinib on protocol CA180-002 and receiving clinical benefit in the opinion of the investigator

• Completed a minimum of 3 months on protocol CA180-002

• Eastern Cooperative Oncology Group (ECOG)performance status 0, 1, or 2 (See Appendix 1)

• Prior history of Ph+ chronic, accelerated, or blast phase CML or Ph+ ALL

Exclusion Criteria:

• Women of childbearing potential(WOCBP)who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the study

• WOCBP using a prohibited contraceptive method

• Women who are pregnant or breastfeeding

• Met the criteria as defined in protocol CA180-002 for discontinuation of therapy which includes:

• Withdrawal of informed consent (subject's decision to withdraw for any reason)

• Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion of the investigator, indicates that continued treatment with dasatinib is not in the best interest of the subject

• Imprisonment or the compulsory detention for treatment of either a psychiatric or physical (e.g., infectious disease) illness

Medical History and Concurrent Diseases

• A serious uncontrolled medical disorder or active infection which would impair the ability of the patient to receive protocol therapy;

• Uncontrolled angina 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 pointes)

• Prolonged corrected QT(QTc) interval on pre-entry electrocardiogram (> 450 msec)

• Uncontrolled hypertension

• Dementia or altered mental status that would prohibit the understanding or rendering of informed consent;

• History of significant bleeding disorder unrelated to CML, including:

1. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

2. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)

Physical and Laboratory Test Findings

• Total bilirubin = 1.5 mg/dl

• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2 times the institutional upper limits of normal

• Serum creatinine = 1.5 times the institutional upper limits of normal

Prohibited Therapies and/or Medications

• Patients currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes including:

• quinidine, procainamide, disopyramide

• amiodarone, sotalol, ibutilide, dofetilide

• erythromycins, clarithromycin

• chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

• cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.

• Medications that inhibit platelet function and any non-steroidal anti-inflammatory drug) or anticoagulants are prohibited unless a previous exception on CA180-002 was granted by the medical monitor. Subjects taking anagrelide for thrombocytosis due to CML are eligible for this protocol

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Abnormal Karyotype
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Philadelphia Chromosome

Intervention

Drug:
• Dasatinib
Tablets, Oral, The dosing ranges from 50mg to a total of 240mg daily with the following 3 schedules: 5 days on, 2 days off 6 days on, 1 day off Continuous daily dosing Once Daily (QD) or Twice Daily (BID) dosing, Subjects will be treated until progression of disease despite escalation/reductions of dose to the level deemed safe by available data, until intolerable/unacceptable toxicity or until subject withdrawal from the study or discontinuation of the study

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation.	AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to AEs were recorded. These data differ from that in the Participant Flow section. This is because the data were collected on 2 different pages of the Case Report Form and were not reconciled.	From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.	Yes
Primary	Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs.	Drug-related AEs are those events with a relationship to the study therapy of certain; probable; or possible or missing. Drug-related SAEs are those events with any relationship to the study therapy.	From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.	Yes
Primary	Number of Participants With Grade 3-4 Hematology Abnormalities	Abnormalities were graded per the National Cancer Institute(NCI)Common Toxicity Criteria (CTC), v3.0(Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Hemoglobin: Grade 3:6.5 - <8.0g/dL, Grade 4: <6.5g/dL. Platelets: Grade 3: 25.0 - <50.0*10^9/L, Grade 4: <25.0*10. Absolute Neutrophil Count (ANC): Grade 3: 0.5 - <1.0*10^9/L, Grade 4: <0.5*10^9/L.White Blood Cells (WBC) : Grade 3: 1.0 - <2.0*10^9/L, Grade 4: <1.0*10^9/L.	From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.	Yes
Primary	Number of Participants With Grade 3-4 Serum Chemistry Abnormalities	Abnormalities were graded per the NCI (CTC), v3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Alanine aminotransferase (ALT): Grade 3: 5.0-20.0 * ULN (upper limit of normal), Grade 4: >20.0 * ULN; Calcium: Grade 3: 6.0-<7.0 or >12.5-13.5 mg/dL, Grade 4: <0.6->13.5 mg/dL; Bilirubin: Grade 3: >3-10 * ULN, Grade 4: >10 * ULN; Creatinine: Grade 3: >3.0-6.0 * ULN, Grade 4: >6.0 * ULN; Albumin: Grade 3: <2g/dL (Grade 4 not defined in NCI CTC); Magnesium: Grade 3: 0.6-<0.8 or >2.46-6.6mEq/L, Grade 4: <0.6 or >6.6mEq/L.	From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.	Yes
Primary	Number of Participants With Dose Interruptions and Dose Reductions	Dose interruptions and reductions were allowed, in order to optimize individual participant's hematologic, cytogenetic, and molecular response while maintaining and evaluating safety and tolerability of long-term exposure to dasatinib. A dose reduction is defined as the administration of a dose at a lower level compared to previous dose and such that reduced dose, or a lower dose, is given at least 4 consecutive times. In determining the reductions, dose level would be compared to the previous non-null dose. Dose interruption is defined as a complete omission of dosing for 4 consecutive times.	From start of study to final assessment (up to 32.2 months).	Yes
Secondary	Number of Participants With Complete Hematologic Response (CHR)	CHR should meet all of the following criteria: WBC <= Institutional ULN; ANC >= 1000/mm^3 ; Platelets < 450 000/mm^3 , no blasts or promyelocytes in peripheral blood; < 5% myelocytes plus metamyelocytes in peripheral blood; basophils in peripheral blood < 20% and no extramedullary involvement (including no hepatomegaly or splenomegaly). CHR can begin only 14 days after the start of treatment.	Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.	No
Secondary	Median Number of Months of CHR (Kaplan Meier Method)	CHR: WBC<=ULN (range: 9.29-12.5*10^3 c\uL); ANC >=1000/mm^3;Platelets <450000/mm^3,no blasts/promyelocytes in peripheral blood; <5% myelocytes+metamyelocytes in peripheral blood; basophils in peripheral blood <20% & no extramedullary involvement. Duration computed for chronic phase participants, measured in months from first day CHR criteria met, provided they are confirmed 4 weeks later, until progression of disease, treatment discontinuation due to progressive disease or death. Participants who neither discontinue due to progression, nor progress nor die censored on date of last assessment.	Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.	No
Secondary	Number of Participants With Major Cytogenetic Response (MCyR)	Cytogenetic responses are based on the prevalence of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a bone marrow sample. MCyR is defined as number of participants with Complete Cytogenetic Response (CCyR): 0% Ph+ cells in metaphase in bone marrow or Partial Cytogenetic Response (PCyR): >0% to 35% Ph+ cells in metaphase in bone marrow.	Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.	No
Secondary	Median Number of Months of Major Cytogenetic Response (MCyR)	MCyR: 0% Ph+ cells in metaphase in bone marrow or Partial Cytogenetic Response (PCyR): >0% to 35% Ph+ cells in metaphase in bone marrow.The duration of MCyR was computed for chronic phase participants whose best response is either CCyR or PCyR. It was measured in months from the time measurement criteria are first met for CCyR or PCyR (whichever status is recorded first) until the date of progression or death. Participants who neither progress nor die are censored on the date of their last cytogenetic assessment.	Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.	No
Secondary	Number of Participants With Best Cytogenetic Response	Cytogenetic responses are based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow sample. CCyR: 0% Ph+ cells in metaphase in bone marrow, PCyR: >0% to 35% Ph+ cells in metaphase in bone marrow, Minor CyR: >35% to 65% Ph+ cells in metaphase in bone marrow, Minimal CyR: >65% to 95% Ph+ cells in metaphase in bone marrow and No CyR: >95% to 100% Ph+ cells in metaphase in bone marrow.	Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.	No
Secondary	Median Number of Months of Progression-free Survival (PFS) (Kaplan Meier Method)	Interval between randomization date & earliest date of disease progression/death due to any cause, assessed by the Independent Radiology Review Committee (IRRC) using modified World Health Organization (WHO) criteria to define progressive disease (PD): >=25% increase in sum of products of diameters (SOPD) of lesions compared with smallest SOPD recorded for study period or progression of any non-index lesion/appearance of new lesion. If no progression/death, date of last tumor assessment used. For participants who had no on-study tumor assessments & were still alive, date of randomization used.	Baseline to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.	No
Secondary	Median Number of Months of Overall Survival (OS) (Kaplan Meier Method)	Overall survival was defined as the median number of months from baseline to death from any cause.	Baseline to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.	No

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm