Open-Label Study Evaluating Dasatinib Therapy Discontinuation in Patients With Chronic Phase Chronic Myeloid Leukemia With Stable Complete Molecular Response (DASFREE)
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| ClinicalTrials.gov Identifier: NCT01850004 |
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Recruitment Status :
Completed
First Posted : May 9, 2013
Results First Posted : November 2, 2018
Last Update Posted : November 3, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Chronic Phase Chronic Myeloid Leukemia | Drug: Dasatinib | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 84 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Other |
| Official Title: | 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 |
| Actual Study Start Date : | January 22, 2014 |
| Actual Primary Completion Date : | September 20, 2017 |
| Actual Study Completion Date : | October 8, 2021 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Dasatinib
Dasatinib 50, 80, 100, 140, 180 mg tablets by mouth, once daily, up to 60 months
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Drug: Dasatinib
Other Name: Sprycel |
- Major Molecular Response (MMR) Rate [ Time Frame: At 12 months after Dasatinib discontinuation (assessed up to approximately June 4, 2018) ]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
- Event-Free Survival (EFS) Rate [ Time Frame: From 12 months after Dasatinib treatment discontinuation to every 12 months thereafter (up to approximately 60 months) ]
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.
- Relapse-Free Survival (RFS) Rate [ Time Frame: From 12 months after Dasatinib treatment discontinuation to every 6 months thereafter (up to approximately 60 months) ]
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).
- Progression Free Survival (PFS) Rate [ Time Frame: From 12 months after Dasatinib treatment discontinuation to every 6 months thereafter (up to approximately 60 months) ]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)
- Number of Participants Who Experience Intermittent Loss of Complete Molecular Response (CMR) (MR4.5) But no Loss of Major Molecular Response (MMR) [ Time Frame: 60 months after last dose ]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.
- Number of Participants Who Did Not Experience Loss of Complete Molecular Response (CMR) (MR4.5) and Major Molecular Response (MMR) [ Time Frame: From 12 months after Dasatinib treatment discontinuation to 5 years after the first visit of the last enrolled participant (up to approximately 82 months) ]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.
- Time to Transformation to Accelerated Phase/Blast Crisis (AP/BC) [ Time Frame: From 12 months after Dasatinib treatment discontinuation to 5 years after the first visit of the last enrolled participant (up to approximately 82 months) ]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.
- Overall Survival (OS) [ Time Frame: From 12 months after Dasatinib treatment discontinuation to the date of death or last known alive date (up to approximately 82 months) ]Overall survival (OS) is defined as the time from dasatinib treatment discontinuation to the date of death (due to any cause) or last known alive date. Participants who do not die will be censored on their last known alive date.
- Progression Free Survival [ Time Frame: From treatment discontinuation to the date of progression or death due to any cause, whichever occurs first (up to 82 months) ]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.
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: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com
Inclusion Criteria
- Signed Written Informed Consent
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Target Population
- Men and women diagnosed with CP-CML, on treatment with dasatinib for a minimum of 2 years at the time of enrollment and in dasatinib-induced complete molecular remission ongoing for at least 1 year prior to study entry.
- Patients are eligible if they have been in stable dasatinib induced CMR for a minimum of nine months, documented by at least three assessments, conducted 2 - 6.5 months apart, at a local lab.
- Subjects who have received dasatinib beyond first or second line treatment and meet other enrollment criteria are eligible for the study provided prior Tyrosine-kinase inhibitors (TKI) were discontinued due to intolerance or lack efficacy, although only one instance of lack of efficacy to TKI is allowed.
- Eastern Co-Operative Group (ECOG) Performance Status (PS) of 0-1
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Age and Reproductive Status
- Men and women, ages ≥18
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the restart of study drug
- Women must not be breastfeeding
- WOCBP must agree to follow instructions for method(s) of contraception at the restart of treatment with study drug (dasatinib) and for the duration treatment plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion
- Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for 90 days after study entry (withdrawal of dasatinib), at restart of study drug (dasatinib) and for the duration of treatment with study drug (dasatinib) plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion
Exclusion Criteria:
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Target Disease Exceptions
- Patients who have not achieved a 1-log reduction in BCR-ABL transcript levels compared with baseline as determined by local standards or > 10% IS [International Standard]) documented at 3.0-6.5 months since the initial start of dasatinib therapy.
- Patients who have previously undergone hematopoietic stem cell transplantation (SCT) or who are scheduled for SCT
- Previous diagnosis of CML accelerated phase or blast crisis
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Medical History and Concurrent Diseases
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Prior or concurrent malignancy, except the following:
- Curatively treated basal cell or squamous cell skin cancer
- Cervical carcinoma in situ
- Adequately treated Stage I or II cancer from which the subject is currently in complete remission
- Any other cancer from which the subject has been disease free for 3 years
- A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy in case re-initiation of dasatinib is needed.
- Uncontrolled or significant cardiovascular disease
- Subjects with prior history of pericardial effusion or pleural effusion that required thoracentesis are excluded. Subjects with prior history of pericardial or pleural effusion that was clinically manageable and a maintained CMR for ≥ 1 year on a stable dose of dasatinib are allowed.
- History of significant bleeding disorder unrelated to CML
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Allergies and Adverse Drug Reaction
a. Subjects with known hypersensitivity to excipients of Dasatinib tablets
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Sex and Reproductive Status
- Patients who are pregnant or breastfeeding or likely to become pregnant
- Men whose partner is unwilling or unable to avoid pregnancy
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Other Exclusion Criteria
- Patients with a history of non-compliance to CML treatment and monitoring requirements
- Prisoners or subjects who are involuntarily incarcerated
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Additional Criteria for Patients Eligible to Restart Dasatinib
- Any patient who has lost MMR and is eligible for re-starting dasatinib therapy must not have developed a condition that precludes dasatinib use.
Other protocol defined inclusion/exclusion criteria could apply
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): NCT01850004
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| Study Director: | Bristol-Myers Squibb | Bristol-Myers Squibb |
Documents provided by Bristol-Myers Squibb:
| Responsible Party: | Bristol-Myers Squibb |
| ClinicalTrials.gov Identifier: | NCT01850004 |
| Other Study ID Numbers: |
CA180-406 2012-001421-27 ( EudraCT Number ) |
| First Posted: | May 9, 2013 Key Record Dates |
| Results First Posted: | November 2, 2018 |
| Last Update Posted: | November 3, 2022 |
| Last Verified: | October 2022 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Neoplasms by Histologic Type Neoplasms Myeloproliferative Disorders |
Bone Marrow Diseases Hematologic Diseases Dasatinib Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |