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

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• Leukemia 5,441

Keywords

• Leukemia, Pediatric

Leukemia

5,441 studies on the registry are indexed under Leukemia; 636 are open to participants now.

This study's enrollment of 133 is above the median of 38 across 4,247 interventional studies indexed under Leukemia.

Lead sponsor

Bristol-Myers Squibb is the lead sponsor of 1,538 studies on the registry; 116 are open to participants now.

Of its 429 completed or terminated interventional studies of FDA-regulated products, 223 (52%) have results posted.

Study arms

• 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 (PFOS) 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

• 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 PFOS 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

• 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 PFOS 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

Interventions

• DrugDasatinib

  Also known as: Sprycel (BMS-354825)

Primary outcomes

1. Major Cytogenetic Response (MCyR) Rate

   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.

   Time frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

2. Complete Hematologic Response (CHR) Rate

   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.

   Time frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

3. Complete Cytogenetic Response (CCyR) Rate

   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.

   Time frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

Secondary outcomes

1. Major Cytogenetic Response (MCyR) Rate in Cohort 2

   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.

   Time frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

2. Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3

   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.

   Time frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

3. Rate of Best Cytogenetic Response

   The number of participants achieving their best on-study cytogenetic response was reported as a percentage of all treated participants in that arm. (Based on \>=20 Metaphases)

   Time frame: From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

4. Time to Major Cytogenetic Response (MCyR)

   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. (Based on \>=20 Metaphases)

   Time frame: From first dose until MCyR criteria are met (assessed up to September 2016, approximately 90 months)

5. Duration of Major Cytogenetic Response (MCyR)

   Duration of MCyR will be computed from the first day criteria are met for MCyR 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 or cytogenetic assessment, whichever comes last. (Based on \>=20 Metaphases)

   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)

6. Time to Complete Cytogenetic Response (CCyR)

   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. (Based on \>=20 Metaphases)

   Time frame: From first dose until CCyR criteria are met, assessed up to September 2016 (approximately 90 months)

7. Duration of Complete Cytogenetic Response (CCyR)

   Duration of CCyR will be computed from the first day criteria are met for CCyR 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 or cytogenetic assessment, whichever comes last. (Based on \>=20 Metaphases)

   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)

8. Progression-Free Survival (PFS)

   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. Based on Kaplan-Meier methodology. 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.

   Time frame: 174 Months

9. Time to Complete Hematologic Response (CHR)

   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.

   Time frame: From first dose until CHR criteria are met, assessed up to September 2016 (approximately 90 months)

10. Duration of Complete Hemotologic Response (CHR)

    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.

    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)

11. Disease-Free Survival

    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. Based on Kaplan-Meier methodology. (CML: Chronic Myeloid Leukemia).

    Time frame: 168 Months

12. Overall Survival (OS)

    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. Based on Kaplan-Meier methodology using graphs.

    Time frame: 174 Months

13. Major Molecular Response (MMR) Rate

    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.

    Time frame: From date of first treatment to date of MMR (assessed up to Jan 2025, approximately 15 years and 10 months)

14. Complete Molecular Response (CMR) Rate

    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.

    Time frame: From date of first treatment to date of CMR (assessed up to Jan 2025, approximately 15 years and 10 months)

15. Major Cytogenetic Response (MCyR) Rate up to 2 Years

    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.

    Time frame: 24 months

16. Complete Cytogenetic Response (CCyR) Rate up to 2 Years

    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.

    Time frame: 24 months

17. Major Molecular Response (MMR) Rate up to 7.5 Years

    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.

    Time frame: 90 months

18. Complete Molecular Response (CMR) Rate up to 7.5 Years

    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.

    Time frame: 90 months

Baseline characteristics

Publications

• Gore L, Kearns PR, de Martino ML, Lee, De Souza CA, Bertrand Y, Hijiya N, Stork LC, Chung NG, Cardos RC, Saikia T, Fagioli F, Seo JJ, Landman-Parker J, Lancaster D, Place AE, Rabin KR, Sacchi M, Swanink R, Zwaan CM. Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial. J Clin Oncol. 2018 May 1;36(13):1330-1338. doi: 10.1200/JCO.2017.75.9597. Epub 2018 Mar 2. PubMed 29498925 ↗

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