Clinical Trial Results:
Open-Label Single Arm Phase 2 Study Evaluating Dasatinib Therapy Discontinuation In Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML) With Stable Complete Molecular Response (CMR) DASFREE
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Summary
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EudraCT number |
2012-001421-27 |
Trial protocol |
FI ES IT DE |
Global end of trial date |
08 Oct 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Oct 2022
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First version publication date |
21 Oct 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CA180-406
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Bristol-Myers Squibb
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Sponsor organisation address |
Chaussee de la Hulpe 185, Brussels, Belgium, 1170
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Public contact |
EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
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Scientific contact |
Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Dec 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Oct 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to assess the rate of major molecular response (MMR), defined as the proportion of subjects who maintain MMR (BCR-ABL transcripts < 0.1% on International Scale (IS) at 12 months after dasatinib discontinuation, without re-starting dasatinib treatment.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
22 Jan 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 12
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
Italy: 11
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Country: Number of subjects enrolled |
Spain: 23
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Country: Number of subjects enrolled |
United States: 26
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Worldwide total number of subjects |
84
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EEA total number of subjects |
46
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
64
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From 65 to 84 years |
20
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
110 participants were screened. 26 failed to meet eligibility and 84 participants proceeded to receive study treatment. | ||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||
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Arms
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Arm title
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Total | ||||||||||||||||||||||||||||
Arm description |
At study entry, dasatinib will be discontinued in all enrolled participants. Dasatinib will be restarted if major molecular response is lost during the off-treatment period at the dose level received before study entry. The participant will remain on treatment for the duration of the study. Dose adjustment for toxicity and response is permitted during the retreatment period based on protocol guidelines. Dosing above 180 mg per day of dasatinib is prohibited. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Dasatinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
20 mg, 50 mg, 80 mg, 100 mg, and 140 mg Tablets
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: This number reflects the number of participants who restarted treatment after failure to maintain major molecular response. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: This number reflects the number of participants who restarted treatment after failure to maintain major molecular response. |
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Baseline characteristics reporting groups
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Reporting group title |
Total
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Reporting group description |
At study entry, dasatinib will be discontinued in all enrolled participants. Dasatinib will be restarted if major molecular response is lost during the off-treatment period at the dose level received before study entry. The participant will remain on treatment for the duration of the study. Dose adjustment for toxicity and response is permitted during the retreatment period based on protocol guidelines. Dosing above 180 mg per day of dasatinib is prohibited. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Total
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Reporting group description |
At study entry, dasatinib will be discontinued in all enrolled participants. Dasatinib will be restarted if major molecular response is lost during the off-treatment period at the dose level received before study entry. The participant will remain on treatment for the duration of the study. Dose adjustment for toxicity and response is permitted during the retreatment period based on protocol guidelines. Dosing above 180 mg per day of dasatinib is prohibited. | ||
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End point title |
Major Molecular Response (MMR) Rate [1] | ||||||||
End point description |
Major Molecular Response (MMR) rate at 12 months is the percentage of participants who maintain MMR (BCR-ABL transcripts < 0.1% on the International Scale [IS]) at 12 months after Dasatinib discontinuation without restarting Dasatinib
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End point type |
Primary
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End point timeframe |
At 12 months after Dasatinib discontinuation (assessed up to approximately June 4, 2018)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Event-Free Survival (EFS) Rate | ||||||||||||||||||
End point description |
Event-free survival (EFS) rate is defined as the percentage of surviving participants with no loss of Major Molecular Response (MMR) at the specified timepoints after dasatinib discontinuation. MMR is defined as BCR-ABL transcripts < 0.1% IS. Loss of MMR is defined per the European LeukemiaNet (ELN) definition of progression. Progression is defined as Transformation to Accelerated Phase or Blast Crisis (AP/BC):
Accelerated Phase (AP)
Blasts in PB or BM 15–29%; Blast + promyelocytes ≥ 30% with blasts < 30% or ACA in Ph+ cells (clonal progression), or basophils in blood ≥ 20%,or platelets < 100 x 10^9 /L unrelated to therapy
Blastic Phase or Crisis (BP/BC)
Blasts in PB or BM ≥ 30%, or extramedullary blast cell involvement (with exception of spleen and liver)
The date of progression is defined as the date any of the above criteria is first met. Participants who have not progressed will be censored on the date of last examination.
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End point type |
Secondary
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End point timeframe |
From 12 months after Dasatinib treatment discontinuation to every 12 months thereafter (up to approximately 60 months)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Relapse-Free Survival (RFS) Rate | ||||||||||||||||||||||||||||
End point description |
RFS is the percentage of participants who did not relapse at the specified timepoints. Participants who did not relapse were censored on the date of their last molecular assessment. Relapse is defined as any of the following events while on study: the loss of Major Molecular Response (MMR), loss of Complete Cytogenetic Response (CCyR), loss of Complete Hematologic Response (CHR) or progression to advanced/blastic phase.
MMR is defined as BCR-ABL transcripts < 0.1% IS. Cytogenetic response (CyR) is based on the prevalence of Ph+ cells in metaphase from bone marrow (BM) sample based on evaluation of at least 20 metaphases. CCyR is defined as 0% Ph+ cells in metaphase in BM. CHR is obtained when all the following criteria are met in peripheral blood (PB) sampling: white blood cell ≤10,000/mm3; Platelets < 450,000/mm3; PB basophils <5%; No blasts or promyelocytes in PB; <5% myelocytes plus metamyelocytes in PB; No extramedullary involvement (including no hepatomegaly or splenomegaly).
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End point type |
Secondary
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End point timeframe |
From 12 months after Dasatinib treatment discontinuation to every 6 months thereafter (up to approximately 60 months)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Progression Free Survival (PFS) Rate | ||||||||||||||||||||||||||||
End point description |
Progression free survival (PFS) is defined as the percentage of participants who experienced death (due to any cause) or accelerated phase, or blast crisis. Participants who neither progress nor die will be censored on the date of their last molecular assessment. Progression is defined as Transformation to Accelerated Phase or Blast Crisis (AP/BC) Accelerated Phase (AP) Blasts in PB or BM 15–29%; Blast + promyelocytes >= 30% with blasts < 30% or ACA in Ph+ cells (clonal progression), or basophils in blood >= 20%,or platelets < 100 x 109 /L unrelated to therapy Blastic Phase or Crisis (BP/BC) Blasts in PB or BM >= 30%, or extramedullary blast cell involvement (with the exception of spleen and liver)
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End point type |
Secondary
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End point timeframe |
From 12 months after Dasatinib treatment discontinuation to every 6 months thereafter (up to approximately 60 months)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Number of participants who experience intermittent loss of complete molecular response (CMR) (MR4.5) but no loss of major molecular response (MMR) | ||||||
End point description |
The number of participants who did not lose major molecular response (MMR) 60 months after discontinuing study treatment who were in MR4.5 at the time of discontinuation and lost MR4.5. Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (Q-PCR). MMR is defined as BCR-ABL transcripts < 0.1% Internal Standard (IS). CMR (MR4.5) defined as ≤ 0.0032% (IS) or ≥ 4.5 log reduction of BCR-ABL transcript levels molecular response.
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End point type |
Secondary
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End point timeframe |
60 months after last dose
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| No statistical analyses for this end point | |||||||
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End point title |
Number of participants who did not experience loss of complete molecular response (CMR) (MR4.5) and major molecular response (MMR) | ||||||
End point description |
Assessment of BCR-ABL kinetics in patients who are in CMR (MR4.5) or less when transcript levels are still measurable. CMR (MR4.5) defined as ≤ 0.0032% (IS) or ≥ 4.5 log reduction of BCR-ABL transcript levels molecular response.
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End point type |
Secondary
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End point timeframe |
From 12 months after Dasatinib treatment discontinuation to 5 years after the first visit of the last enrolled participant (up to approximately 82 months)
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| No statistical analyses for this end point | |||||||
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End point title |
Time to transformation to accelerated phase/blast crisis (AP/BC) | ||||||||
End point description |
Time to Transformation to AP/BC is defined as the rate at which participants experienced transformation to accelerated phase/blast crisis (AP/BC) since discontinuation. Participants who did not develop to AP, late phase, or BC phase were censored on their last molecular measurement date.
"99999"=N/A
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End point type |
Secondary
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End point timeframe |
From 12 months after Dasatinib treatment discontinuation to 5 years after the first visit of the last enrolled participant (up to approximately 82 months)
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
Time to Transformation to AP/BC is defined as the rate at which participants experienced transformation to accelerated phase/blast crisis (AP/BC) since discontinuation. Participants who did not develop to AP, late phase, or BC phase were censored on their last molecular measurement date.
"99999"=N/A
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End point type |
Secondary
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End point timeframe |
From 12 months after Dasatinib treatment discontinuation to the date of death or last known alive date (up to approximately 82 months)
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression Free Survival | ||||||||
End point description |
Progression-free survival (PFS) is defined as the time from treatment discontinuation to the date of progression or death (due to any cause), whichever occurs first. Participants who neither progress nor die will be censored on the date of their last molecular assessment.
"99999"=N/A
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End point type |
Secondary
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End point timeframe |
From treatment discontinuation to the date of progression or death due to any cause, whichever occurs first (up to 82 months)
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Participants were assessed for all-cause mortality from their enrollment to study completion, (up to approximately 87 months). SAEs and Other AEs were assessed from first dose to 30 days following last dose (up to approximately 85 months).
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Adverse event reporting additional description |
The number at Risk for All-Cause Mortality represents all enrolled Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication during re-treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
DASATINIB
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Reporting group description |
At study entry, dasatinib will be discontinued in all enrolled participants. Dasatinib will be restarted if major molecular response is lost during the off-treatment period at the dose level received before study entry. The participant will remain on treatment for the duration of the study. Dose adjustment for toxicity and response is permitted during the retreatment period based on protocol guidelines. Dosing above 180 mg per day of dasatinib is prohibited. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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19 Nov 2013 |
Edits to requirements for women of childbearing age; correction of EudraCT number |
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02 Mar 2015 |
Updates to eligibility criteria; second level of dose escalation to 180 mg dasatinib added; updates to ECG monitoring; bone marrow biopsy or aspirate or peripheral blood (FISH) for cytogenetic assessment no longer required as part of the baseline assessments; changes in the study stopping rule incorporated; corrections to assessment of response free survival and frequency of safety and efficacy review. |
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22 Mar 2016 |
Hepatitis B serology status now required; revised method of contraception guidelines; destruction of study drug now permitted per protocol requirements |
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24 Jul 2017 |
Added new exploratory endpoint; updated event free survival definition and timeframe; BCR-ABL kinetics analysis updated; clarification in the frequency of complete blood count (CBC) and platelet assessments; statistical section updated for consistency with the statistical analysis plan |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
