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A Phase II Study of Dasatinib in Children and Adolescents With Newly Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or Intolerant to Imatinib

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ClinicalTrials.gov Identifier: NCT00777036
Recruitment Status : Active, not recruiting
First Posted : October 22, 2008
Results First Posted : January 5, 2018
Last Update Posted : January 29, 2018
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Brief Summary:
The purpose of this study is to determine whether dasatinib is safe and effective in children and adolescents with newly diagnosed chronic myeloid leukemia (CML), or in children with Ph+ acute lymphoblastic leukemia (ALL), accelerated or blast phases CML who relapse after imatinib or who are resistant or intolerant to imatinib. The side effects of this oral investigational drug in children and adolescents will be evaluated

Condition or disease Intervention/treatment Phase
Leukemia Drug: Dasatinib Phase 2

Detailed Description:
Cohort 2 was closed early to enrollment based on insufficient treatment response and poor enrollment

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 145 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Dasatinib in Children and Adolescents With Newly Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or Intolerant to Imatinib
Actual Study Start Date : February 19, 2009
Actual Primary Completion Date : September 1, 2016
Estimated Study Completion Date : September 23, 2021


Arm Intervention/treatment
Experimental: Cohort 1: Imatinib-resistant/intolerant CP-CML

Dasatinib 60 mg/m² tablet every day (QD) [with a maximum dose of 100 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit

OR

Dasatinib 72 mg/m² powder for oral suspension (PFSO) QD [with a maximum dose of 120 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit

Drug: Dasatinib
Other Name: Sprycel (BMS-354825)

Experimental: Cohort 2: Ph+ALL or AP- or BP-CML

Dasatinib 80 mg/m² tablet QD [with a maximum dose of 140 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit

OR

Dasatinib 96 mg/m² PFSO QD [with a maximum dose of 170 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit

Drug: Dasatinib
Other Name: Sprycel (BMS-354825)

Experimental: Cohort 3: Newly diagnosed, treatment naïve CP-CML

Dasatinib 60 mg/m² tablet QD [with a maximum dose of 100 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit

OR

Dasatinib 72 mg/m² PFSO QD [with a maximum dose of 120 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit

Drug: Dasatinib
Other Name: Sprycel (BMS-354825)




Primary Outcome Measures :
  1. Major Cytogenetic Response (MCyR) Rate [ Time Frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) ]
    Major Cytogenetic Response (MCyR) rate is defined as the proportion of all treated participants who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response, expressed as percentage. The denominator of the MCyR response rate consists of all treated participants in Cohort 1, and the numerator is all participants in Cohort 1 achieving MCyR. 95% confidence interval was calculated by Clopper-Pearson exact method.

  2. Complete Hematologic Response (CHR) Rate [ Time Frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) ]
    Complete Hematologic Response (CHR) rate is defined as the proportion of all treated participants who achieve a confirmed CHR while on-study, expressed as percentage. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood, expressed as percentage. The denominator of the CHR response rate consists of all treated participants in Cohort 2, and the numerator is all participants in Cohort 2 achieving CHR. 95% confidence interval was calculated by Clopper-Pearson exact method.

  3. Complete Cytogenetic Response (CCyR) Rate [ Time Frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) ]
    Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated participants who achieve a CCyR while on-study, expressed as a percentage. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The denominator of the CCyR response rate consists of all treated participants in Cohort 3, and the numerator is all participants in Cohort 3 achieving CCyR. 95% confidence interval was calculated by Clopper-Pearson exact method.


Secondary Outcome Measures :
  1. Major Cytogenetic Response (MCyR) Rate in Cohort 2 [ Time Frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) ]
    Major Cytogenetic Response (MCyR) rate was defined as the proportion of all treated participants who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response. The percentage of treated participants in each arm with MCyR is reported.

  2. Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3 [ Time Frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) ]
    Complete Hematologic Response (CHR) rate defined as the proportion of all treated participants who achieve a confirmed CHR while on-study. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood. The percentage of treated participants in each arm with CHR is reported.

  3. Rate of Best Cytogenetic Response [ Time Frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) ]
    The number of participants achieving their best on-study cytogenetic response was reported as a percentage of all treated participants in that arm.

  4. Time to Major Cytogenetic Response (MCyR) [ Time Frame: From first dose until MCyR criteria are met (assessed up to September 2016, approximately 90 months) ]
    Time to MCyR is defined as the time from first dose of dasatinib until the first day MCyR criteria are met, computed only for participants whose best response is MCyR.

  5. Duration of Major Cytogenetic Response (MCyR) [ Time Frame: From first day criteria are met for MCyR until the date PD is reported or death (assessed up to September 2016, approximately 90 months) ]
    Duration of MCyR will be computed from the first day criteria are met for MCyR until the date PD is reported (or treatment is discontinued for PD) or death. Participants who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last.

  6. Time to Complete Cytogenetic Response (CCyR) [ Time Frame: From first dose until CCyR criteria are met, assessed up to September 2016 (approximately 90 months) ]
    Time to CCyR is defined as the time from first dose of dasatinib until the first day CCyR criteria are met, computed only for participants whose best response is CCyR.

  7. Duration of Complete Cytogenetic Response (CCyR) [ Time Frame: From first day criteria are met for CCyR until the date of progressive disease or death (assessed up to September 2016, approximately 90 months) ]
    Duration of CCyR will be computed from the first day criteria are met for CCyR until the date PD is reported (or treatment is discontinued for PD) or death. Participants who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last.

  8. Progression-Free Survival (PFS) Rate at 2 Years [ Time Frame: 2 years ]

    PFS is defined as time from the first dosing date until the time PD is first documented by the investigator or death. Participants who die without a reported date of progression will be considered to have progressed on the date of death. Participants who neither progress nor die will be censored on the date of their last cytogenetic or hematologic assessment. The percentages of progression-free participants at 2 years are based on Kaplan-Meier estimation.

    Disease Progression was defined as any of the following criteria:

    • For CP-CML, progression to AP-CML or BP-CML while at highest tolerated dose
    • Increasing WBC
    • Loss of CHR (defined as any of the following: WBC count rises to >20.0x10^9/L; Platelet count rises to >600x10^9/L; appearance of extramedullary disease; appearance of >5% myelocytes+metamyelocytes in blood; appearance of blasts/promyelocytes in peripheral blood)
    • Loss of MCyR or increase in Ph+ bone marrow cells by >=30% from nadir
    • Death from any case during treatment

  9. Time to Complete Hematologic Response (CHR) [ Time Frame: From first dose until CHR criteria are met, assessed up to September 2016 (approximately 90 months) ]
    Time to CHR is defined as the time from first dose of dasatinib until the first day CHR criteria are met, provided they are confirmed 4 weeks later, computed only for participants whose best response is CHR.

  10. Duration of Complete Hematologic Response (CHR) [ Time Frame: From first day criteria are met for CHR until date of disease progression or death (assessed up to September 2016, approximately 90 months) ]
    Duration of CHR will be computed from the first day all criteria are met for CHR, provided they are confirmed 4 weeks later, until the date progressive disease (PD) is reported (or treatment is discontinued for PD) or death. Participants who neither discontinue due to PD nor die will be censored on the date of their last hematologic assessment.

  11. Disease-Free Survival Rate at 2 Years [ Time Frame: 2 years ]
    Disease free survival is defined as time from CCyR for participants with newly diagnosed chronic phase CML and for participants with chronic phase CML who are resistant or intolerant to imatinib (cohort 3 and cohort 1), and as time from CHR for participants with advanced phase CML and PH + ALL (cohort 2) until the time progression is first documented by the investigator or death from any cause. The percentages of disease-free participants at 2 years are based on Kaplan-Meier estimation.

  12. Overall Survival (OS) Rate at 2 Years [ Time Frame: 2 years ]
    OS is defined as time from the first dosing date until the time of death. All participants will be followed yearly for survival for up to 5 years after treatment discontinuation. Participants who have not died or who are lost to follow-up will be censored on the last date the participant is known to be alive. The percentages of surviving participants at 2 years are based on Kaplan-Meier estimation.

  13. Major Molecular Response (MMR) Rate [ Time Frame: From date of first treatment to date of MMR (assessed up to September 2016, approximately 90 months) ]
    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). MMR for participants with the p210 BCR-ABL transcript variant was defined as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale. In this study, ABL was used as the control-gene. For a participant with the p190 BCR-ABL transcript variant (occurring in Cohort 2 only), on-study assessments were compared to the participant's individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline was considered an MMR.

  14. Complete Molecular Response (CMR) Rate [ Time Frame: From date of first treatment to date of CMR (assessed up to September 2016, approximately 90 months) ]
    Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). (CMR) is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated participants with CMR is reported by arm.

  15. Major Cytogenetic Response (MCyR) Rate up to 2 Years [ Time Frame: 24 months ]
    Major Cytogenetic Response (MCyR) rate is defined as the proportion of all treated participants who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response. The percentage of treated participants with MCyR is reported by arm.

  16. Complete Cytogenetic Response (CCyR) Rate up to 2 Years [ Time Frame: 24 months ]
    Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated participants who achieve a CCyR while on-study. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The percentage of treated participants with CCyR is reported by arm.

  17. Major Molecular Response (MMR) Rate up to 2 Years [ Time Frame: 24 months ]
    Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time qPCR. MMR for participants with the p210 BCR-ABL transcript variant is defined according to the recommendations of Hughes et al. as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale proposed by the authors. The standardized baseline, as established in the IRIS trial, is taken to represent 100% on the international scale and a 3-log reduction in ratio (BCR-ABL transcripts/ABL or BCR) from the standardized baseline (MMR) is fixed at 0.1%. In this study, ABL or other housekeeping gene, will be used as the control-gene. For a participant with the p190 BCR-ABL transcript variant, on-study assessments will be compared to the participant's individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline will be considered an MMR. The percentage of treated participants with MMR is reported by arm.

  18. Complete Molecular Response (CMR) Rate up to 2 Years [ Time Frame: 24 months ]
    Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). (CMR) is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated participants with CMR is reported by arm.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

  • CP-CML who prove resistant or intolerant to imatinib (Cohort 1)
  • Ph+ ALL, AP-CML, or BP-CML who are resistant or intolerant to or who relapse after imatinib therapy (Cohort 2)
  • Newly diagnosed, treatment naive CP-CML (Cohort 3)
  • Lansky or Karnofsky scale >50
  • Life expectancy ≥12 weeks
  • Adequate hepatic and renal function
  • Written informed consent

Exclusion Criteria:

  • Eligibility for potentially-curative therapy including hematopoietic stem-cell transplantation
  • Symptomatic CNS involvement (other than signs and symptoms caused by leptomeningeal disease)
  • Isolated extramedullary disease
  • Prior therapy with Dasatinib

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00777036


  Hide Study Locations
Locations
United States, Arizona
Phoenix Children'S Hospital
Phoenix, Arizona, United States, 85016
United States, California
Jonathan Jaques Children'S Cancer Center
Long Beach, California, United States, 90801-1428
Children'S Hospital Of Orange County
Orange, California, United States, 92868
United States, Colorado
Children'S Hospital
Aurora, Colorado, United States, 80045
United States, Georgia
Children's Healthcare Of Atlanta - Egleston
Atlanta, Georgia, United States, 30322
United States, Illinois
Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Massachusetts
Dana Faber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New York
Stephen D. Hassenfeld Children'S Center
New York, New York, United States, 10016
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Oregon
Oregon Health & Sci Univ
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children'S Hospital Of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children'S Hospital Of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15224
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030-4009
Texas Children'S Cancer Center
Houston, Texas, United States, 77030
United States, Washington
Seattle Children'S
Seattle, Washington, United States, 98105
Argentina
Local Institution
Bunos Aires, Buenos Aires, Argentina, 1425
Hospital Nacional Profesor Alejandro Posadas
El Palomar, Buenos Aires, Argentina, 1684
Local Institution
Cordoba, Argentina, 5016
Australia, New South Wales
Local Institution
Randwick, New South Wales, Australia, 2031
Local Institution
Westmead, New South Wales, Australia, 2145
Australia, Queensland
Local Institution
Sth Brisbane, Queensland, Australia, 4101
Australia, South Australia
Local Institution
North Adelaide, South Australia, Australia, 5006
Australia, Victoria
Local Institution
Parkville, Victoria, Australia, 3052
Brazil
Local Institution
Curitiba, Parana, Brazil, 80060-900
Local Institution
Porto Alegre, RIO Grande DO SUL, Brazil, 90035-003
Local Institution
Campinas, Brazil, 13083-970
Local Institution
Sao Paulo, Brazil, 01401-000
Local Institution
Sao Paulo, Brazil, 04023-062
Canada, Alberta
Alberta Children'S Hospital
Calgary, Alberta, Canada, T3B 6A8
Stollery Children'S Hospital
Edmonton, Alberta, Canada, T6G 2B7
Canada, British Columbia
Bc Children'S Hospital
Vancouver, British Columbia, Canada, V6H 3V4
Canada, Nova Scotia
Iwk Health Centre
Halifax, Nova Scotia, Canada, B3K 6R8
Canada, Ontario
Children'S Hospital Of Eastern Ontario
Ottawa, Ontario, Canada, K1H 8L1
The Hospital For Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Chu Ste-Justine
Montreal, Quebec, Canada, H3T 1C5
France
Local Institution
Lyon, France, 69008
Local Institution
Nantes, France, 44093
Local Institution
Paris Cedex 12, France, 75571
Local Institution
Paris, France, 75935
Local Institution
Poitiers, France, 86000
Germany
Local Institution
Frankfurt, Germany, 60590
Local Institution
Hannover, Germany, 30625
India
Local Institution
Navrangpura, Ahmedabad, Gujarat, India, 380009
Local Institution
Bangalore, Karnataka, India, 560027
Local Institution
Pune, Maharashtra, India, 411001
Local Institution
Madurai, Tamil NADU, India, 625107
Local Institution
Vellore, Tamilnadu, India, 632004
Local Institution
Kolkatta, India, 700 016
Local Institution
Mumbai, India, 400010
Local Institution
Trivandrum, India, 695011
Italy
Local Institution
Bologna, Italy, 40138
Local Institution
Monza (MB), Italy, 20900
Local Institution
Roma, Italy, 00161
Local Institution
Roma, Italy, 00165
Local Institution
Torino, Italy, 10126
Korea, Republic of
Local Institution
Seoul, Korea, Republic of, 05505
Local Institution
Seoul, Korea, Republic of, 137-701
Mexico
Local Institution
Df, Distrito Federal, Mexico, 06720
Local Institution
Mexico, D. F., Distrito Federal, Mexico, 06726
Local Institution
Mexico, Distrito Federal, Mexico, 04530
Hospital Civil De Guadalajara - Nuevo Dr. Juan I. Menchaca
Guadalajara, Jalisco, Mexico, 44340
Local Institution
Monterrey, N.l., Nuevo LEON, Mexico, 64180
Local Institution
Monterrey, Nuevo LEON, Mexico, 64460
Netherlands
Local Institution
Rotterdam, Netherlands, 3015 GJ
Romania
Local Institution
Bucharest, Romania, 022322
Russian Federation
Local Institution
Moscow, Russian Federation, 115478
Local Institution
Moscow, Russian Federation, 117198
Local Institution
Saint-petersburg, Russian Federation, 197022
Singapore
Local Institution
Singapore, Singapore, 119228
South Africa
Local Institution
Bloemfontein, FREE State, South Africa, 9301
Local Institution
Pretoria, Gauteng, South Africa, 0001
Local Institution
Cape Town, Western CAPE, South Africa, 7925
Local Institution
Tygerberg, Western CAPE, South Africa, 7505
Spain
Local Institution
Barcelona, Spain, 08025
Local Institution
Barcelona, Spain, 08035
Local Institution
Madrid, Spain, 28009
Local Institution
Madrid, Spain, 28046
Local Institution
Malaga, Spain, 29010
Local Institution
Valencia, Spain
United Kingdom
Local Institution
Glasgow, Central, United Kingdom, G3 8SJ
Local Institution
Sutton, Surrey, United Kingdom, SM2 5PT
Local Institution
Birmingham, WEST Midlands, United Kingdom, B4 6NH
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb

Additional Information:
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00777036     History of Changes
Other Study ID Numbers: CA180-226
2008-002260-33 ( EudraCT Number )
First Posted: October 22, 2008    Key Record Dates
Results First Posted: January 5, 2018
Last Update Posted: January 29, 2018
Last Verified: January 2018

Keywords provided by Bristol-Myers Squibb:
Leukemia, Pediatric

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Chronic-Phase
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Imatinib Mesylate
Dasatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action