Open-Label Study Evaluating Dasatinib Therapy Discontinuation in Patients With Chronic Phase Chronic Myeloid Leukemia With Stable Complete Molecular Response

Study Overview
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Brief Summary
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The study purpose is to test the hypothesis that Chronic Phase Chronic Myeloid Leukemia (CP-CML) patients with stable Complete Molecular Response (CMR) who discontinue Dasatinib treatment are able to maintain a sustained remission in the long-term, with undetectable or minimally detectable BCR-ABL residual disease.

Detailed Description
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Primary Purpose: Protocol designed to evaluate remission of disease after treatment discontinuation. Treatment re-started if relapse occurs

Official Title
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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

Conditions
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Chronic Phase Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria Signed Written Informed Consent 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 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: 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 Medical History and Concurrent Diseases 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 Allergies and Adverse Drug Reaction a. Subjects with known hypersensitivity to excipients of Dasatinib tablets 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 Other Exclusion Criteria Patients with a history of non-compliance to CML treatment and monitoring requirements Prisoners or subjects who are involuntarily incarcerated 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib<br>Dasatinib 50, 80, 100, 140, 180 mg tablets by mouth, once daily, up to 60 months | Drug: Dasatinib<br> <br> * Other names: Sprycel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Molecular Response (MMR) Rate | 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 | At 12 months after Dasatinib discontinuation (assessed up to approximately June 4, 2018) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) Rate | 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. | From 12 months after Dasatinib treatment discontinuation to every 12 months thereafter (up to approximately 60 months) | 
| Relapse-Free Survival (RFS) Rate | 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). | From 12 months after Dasatinib treatment discontinuation to every 6 months thereafter (up to approximately 60 months) | 
| Progression Free Survival (PFS) Rate | 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) | From 12 months after Dasatinib treatment discontinuation to every 6 months thereafter (up to approximately 60 months) | 
| Number of Participants Who Experience Intermittent Loss of Complete Molecular Response (CMR) (MR4.5) But no Loss of Major Molecular Response (MMR) | 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. | 60 months after last dose | 
| Number of Participants Who Did Not Experience Loss of Complete Molecular Response (CMR) (MR4.5) and Major Molecular Response (MMR) | 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. | 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 Accelerated Phase/Blast Crisis (AP/BC) | 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. | From 12 months after Dasatinib treatment discontinuation to 5 years after the first visit of the last enrolled participant (up to approximately 82 months) | 
| Overall Survival (OS) | 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. | From 12 months after Dasatinib treatment discontinuation to the date of death or last known alive date (up to approximately 82 months) | 
| Progression Free Survival | 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. | From treatment discontinuation to the date of progression or death due to any cause, whichever occurs first (up to 82 months) |