Study of Dasatinib (BMS-354825) in Patients With Accelerated Phase Chronic Myeloid Leukemia

A Phase II Study of BMS-354825 in Subjects With Accelerated Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate

The purpose of this clinical research study is to learn if BMS-354825 will have activity, defined by hematologic response, in subjects who have accelerated phase chronic myeloid leukemia (CML) who are resistant to or intolerant to imatinib mesylate. The safety of this treatment will also be studied.

Study Overview

• Status: Completed
• Conditions: Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: Dasatinib

• Study Type: Interventional
• Enrollment (Actual): 197
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Local Institution
  • Cordoba, Argentina
    • Local Institution
• Australia
  • Wien, Australia
    • Local Institution
  • New South Wales
    • St. Leonards, New South Wales, Australia
      • Local Institution
  • Queensland
    • South Brisbane, Queensland, Australia
      • Local Institution
  • Victoria
    • East Melbourne, Victoria, Australia
      • Local Institution
    • Parkville, Victoria, Australia
      • Local Institution
• Belgium
  • B-Leuven, Belgium
    • Local Institution
  • Edegem, Belgium
    • Local Institution
• Brazil
  • Campinas, Brazil
    • Local Institution
  • Rio De Janeiro, Brazil
    • Local Institution
  • Sao Paulo, Brazil
    • Local Institution
• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Local Institution
• Denmark
  • Aarhus, Denmark
    • Local Institution
• Finland
  • Helsinki, Finland
    • Local Institution
• France
  • LIlle, France
    • Local Institution
  • Lyon Cedex 03, France
    • Local Institution
  • Nantes, France
    • Local Institution
  • Paris, France
    • Local Institution
  • Pessac, France
    • Local Institution
  • Poitiers Cedex, France
    • Local Institution
  • Strasbourg Cedex, France
    • Local Institution
• Germany
  • Hamburg, Germany
    • Local Institution
  • Mainz, Germany
    • Local Institution
  • Mannheim, Germany
    • Local Institution
• Israel
  • Ramat-Gan, Israel
    • Local Institution
• Italy
  • Bologna, Italy
    • Local Institution
  • Napoli, Italy
    • Local Institution
  • Orbassano, Italy
    • Local Institution
  • Roma, Italy
    • Local Institution
• Korea, Republic of
  • Jeollanam-Do, Korea, Republic of
    • Local Institution
  • Kyunggi-Do, Korea, Republic of
    • Local Institution
  • Seoul, Korea, Republic of
    • Local Institution
• Netherlands
  • Nijmegen, Netherlands
    • Local Institution
  • Rotterdam, Netherlands
    • Local Institution
• Norway
  • Trondheim, Norway
    • Local Institution
• Peru
  • Lima, Peru
    • Local Institution
• Philippines
  • Quezon City, Philippines
    • Local Institution
• Singapore
  • Singapore, Singapore
    • Local Institution
• Sweden
  • Gothenburg, Sweden
    • Local Institution
  • Lund, Sweden
    • Local Institution
  • Umea, Sweden
    • Local Institution
  • Uppsala, Sweden
    • Local Institution
• Switzerland
  • Basel, Switzerland
    • Local Institution
• Taiwan
  • Taipei, Taiwan
    • Local Institution
  • Taoyuan, Taiwan
    • Local Institution
• Thailand
  • Bangkok, Thailand
    • Local Institution
• United Kingdom
  • Central
    • Glasgow, Central, United Kingdom
      • Local Institution
  • Greater London
    • London, Greater London, United Kingdom
      • Local Institution
• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Local Institution
  • California
    • Anaheim, California, United States
      • Local Institution
    • Los Angeles, California, United States
      • Local Institution
    • Stanford, California, United States
      • Local Institution
    • Vallejo, California, United States
      • Local Institution
  • Florida
    • Jacksonville, Florida, United States
      • Local Institution
    • Tampa, Florida, United States
      • Local Institution
  • Georgia
    • Atlanta, Georgia, United States
      • Local Institution
  • Illinois
    • Chicago, Illinois, United States
      • Local Institution
  • Kansas
    • Kansas City, Kansas, United States
      • Local Institution
  • Maryland
    • Baltimore, Maryland, United States
      • Local Institution
  • Massachusetts
    • Boston, Massachusetts, United States
      • Local Institution
  • Michigan
    • Detroit, Michigan, United States
      • Local Institution
  • Missouri
    • St. Louis, Missouri, United States
      • Local Institution
  • New Jersey
    • Hackensack, New Jersey, United States
      • Local Institution
  • New York
    • New York, New York, United States
      • Local Institution
  • Oregon
    • Portland, Oregon, United States
      • Local Institution
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States
      • Local Institution
  • Tennessee
    • Nashville, Tennessee, United States
      • Local Institution
  • Texas
    • Dallas, Texas, United States
      • Local Institution
    • Houston, Texas, United States
      • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with Philadelphia chromosome positive (PH+) or the fused gene BCR/ABL positive (BCR/ABL+) accelerated phase chronic myeloid leukemia (CML) whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate.
• Subjects must have had prior exposure to imatinib. However, imatinib mesylate does not need to be their most recent CML treatment prior to coming on this study.
• Men and women, 18 years of age or older.
• Adequate hepatic function.
• Adequate renal function.
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of least 1 month before and at least 3 months after the study in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

• Women who are pregnant or breastfeeding.
• Subjects who are eligible and willing to undergo transplantation during the screening period.
• A serious uncontrolled medical disorder or active infection that would impair the ability of the subjects to receive protocol therapy.
• Uncontrolled or significant cardiovascular disease.
• Medications that increase bleeding risk.
• Medications that change heart rhythms.
• Dementia or altered mental status that would prohibit the understanding or rendering of informed consent.
• History of significant bleeding disorder unrelated to CML.
• Concurrent incurable malignancy other than CML.
• Evidence of organ dysfunction or digestive dysfunction that would prevent administration of study therapy.
• Prior therapy with dasatinib (BMS-354825).
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: Dasatinib; Tablets, Oral, 70 mg, twice daily, until disease progression or intolerable toxicity, switch to the roll-over study or study closure; Other Names: BMS-354825; Sprycel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major and Overall Hematologic Response (MaHR and OHR)	MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). OHR=best confirmed response of MaHR or minor hematologic response (MiHR). Confirmed hematologic response=response confirmed ≥4 weeks after first documented event with no concomitant use of anagrelide or hydroxyurea. Maintaining a response=no 2 consecutive records of nonresponse at assessment. Criteria for CHR and NEL specified in Outcome Measure 2 and criteria for MiHR in Outcome Measure 4.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF)	The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.
Population PK of Dasatinib	Population pharmacokinetic analysis was not done because it is not meaningful for this single study	Day 8 immediately prior to the first daily dose and between 30 minutes to 3 hours following this dose.
Percentage of Participants Who Achieved MaHR and Did Not Progress at 12 Months (Based on the Kaplan-Meier Estimate of the Duration of Response)	MaHR=best response of CHR or NEL. CHR=white blood cells ≤institutional upper limit of normal (iULN); absolute neutrophil count (ANC) ≥1000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes in peripheral blood (PB); bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement. NEL=WBC ≤iULN; no blasts/promyelocytes in PB; bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤iULN; no extramedullary involvement; at least 1 of: ANC ≥500/mm3 & <1000/mm3; platelets ≥20,000/mm3 & <100,000/mm3.	12 months
Percentage of Participants Who Achieved MaHR and Did Not Progress at 24 Months in the Imatinib-Resistant Group (Based on the Kaplan-Meier Estimate of the Duration of Response)	Percentage of participants in the Imatinib-Resistant Group who achieved MaHR and did not progress at Month 24, based on the Kaplan-Meier estimate of the duration of response. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR and NEL are specified in Outcome Measure 2.	24 months
Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months	Percentage of participants who achieved OHR and did not progress at specified timepoints, based on the Kaplan-Meier estimate of the duration of response. OHR=best confirmed response of MaHR or MiHR. MaHR criteria in Outcome Measure 2. MiHR= <15% blasts in bone marrow and <15% blasts in peripheral blood (PB); <30% blasts+promyelocytes in bone marrow and <30% blasts+promyelocytes in PB; <20% basophils in PB; no extramedullary disease other than spleen and liver. Confirmed hematologic response= confirmed ≥4 weeks after 1st documented event with no concomitant use of anagrelide or hydroxyurea.	12 months, 24 months
Median Time in Days From First Dosing Date to Date of MaHR	MaHR=best response of CHR or NEL. CHR=white blood cells ≤institutional upper limit of normal (iULN); absolute neutrophil count (ANC) ≥1000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes in peripheral blood (PB); bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement. NEL=WBC ≤iULN; no blasts/promyelocytes in PB; bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤iULN; no extramedullary involvement; at least 1 of: ANC ≥500/mm3 & <1000/mm3; platelets ≥20,000/mm3 & <100,000/mm3.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment
Time to OHR	Median time (in months) from first dosing date to date of OHR. OHR=best confirmed response of MaHR or MiHR. Criteria for MaHR specified in Outcome Measure 2. MiHR= <15% blasts in bone marrow and <15% blasts in peripheral blood (PB); <30% blasts+promyelocytes in bone marrow and <30% blasts+promyelocytes in PB; <20% basophils in PB; no extramedullary disease other than spleen and liver. Confirmed hematologic response = response confirmed ≥4 weeks after 1st documented event with no concomitant use of anagrelide or hydroxyurea.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment
Best Cytogenetic Response	Number of participants with complete, partial, minor, minimal, or no cytogenetic response. Determination of cytogenetic response based on the prevalence (percentage) of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase in a bone marrow sample (aspirates/biopsies).	Baseline (within 4 weeks of therapy start); Every month for Cycles 1-3; Every 12 weeks for Cycles 4+; end of treatment
Best Confirmed Hematologic Response	Number of participants with confirmed complete hematologic response (CHR) or No Evidence of Leukemia (NEL), minor hematologic response (MiHR), or no hematologic response. Confirmed hematologic response=response that is confirmed after at least 4 weeks with no concomitant use of anagrelide or hydroxyurea use during this interval. Criteria for CHR and NEL are specified in Outcome Measure 2; criteria for MiHR are specified in Outcome Measure 4.	Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment
Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period	Number of participants who achieved an MMR at any time during the treatment period. MMR was calculated by measuring BCR-ABL transcripts in blood during treatment using quantitative reverse transcription-polymerase chain reaction (RT-PCR). BCR-ABL=the fused gene found in subjects with this type of Chronic Myeloid Leukemia (CML).	Baseline, every 12 weeks throughout study (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations	Major hematologic and cytogenetic responses (MaHR and MCyR) to dasatinib in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). BCR-ABL=the fused gene found in subjects with this type of CML. Criteria for MaHR are specified in Outcome Measure 2. MCyR=combined complete cytogenetic and partial cytogenetic response rate. Complete Cytogenetic Response= 0% Ph+ Cells in Metaphase in Bone Marrow, Partial Cytogenetic Response > 0% to 35% Ph+ Cells in Metaphase in Bone Marrow.	Baseline, at time of disease progression. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G)	Number of subjects with minimally significant changes from baseline in the health-related quality of life questionnaire FACT-G. FACT-G=27 questions in 4 domains: physical, social/family, emotional, and functional well-being (PWB, SWB, EWB, FWB). Total score=0 to 108; higher score=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, and FWB score change of 3 or more, and SWB score change of 2 or more=minimal clinically important change.	Baseline, every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up.(treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation	AE=any new untoward medical occurrence or worsening of a pre-existing medical condition regardless of causal relationship with treatment. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)	Continuous from pretreatment through each 4-week cycle and at follow-up. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax)	The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.
Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 Hours (AUC[0-T])	The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were less than the lower limit of quantitation (LLQ) were assigned a value of zero.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.
Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax)	The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.	Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, Amadori S, de Souza CA, Lipton JH, Hochhaus A, Heim D, Larson RA, Branford S, Muller MC, Agarwal P, Gollerkeri A, Talpaz M. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007 May 15;109(10):4143-50. doi: 10.1182/blood-2006-09-046839. Epub 2007 Jan 30.
• Apperley JF, Cortes JE, Kim DW, Roy L, Roboz GJ, Rosti G, Bullorsky EO, Abruzzese E, Hochhaus A, Heim D, de Souza CA, Larson RA, Lipton JH, Khoury HJ, Kim HJ, Sillaber C, Hughes TP, Erben P, Van Tornout J, Stone RM. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol. 2009 Jul 20;27(21):3472-9. doi: 10.1200/JCO.2007.14.3339. Epub 2009 Jun 1.

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (Actual): August 1, 2006
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: January 12, 2005
• First Submitted That Met QC Criteria: January 12, 2005
• First Posted (Estimate): January 13, 2005

Study Record Updates

• Last Update Posted (Estimate): April 15, 2011
• Last Update Submitted That Met QC Criteria: April 13, 2011
• Last Verified: April 1, 2011

More Information

Terms related to this study

• Keywords: Chronic myelogenous leukemia (CML): Accelerated phase
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Accelerated Phase; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dasatinib
• Other Study ID Numbers: CA180-005