Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how well dasatinib and venetoclax work in treating patients with Philadelphia chromosome positive or BCR-ABL1 positive early chronic phase chronic myelogenous leukemia. Dasatinib and venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the proportion of patients with previously-untreated chronic phase chronic myeloid leukemia (CML) who achieve major molecular response by 12 months of treatment with dasatinib 50 mg orally daily (first 70 patients) and of dasatinib 50 mg daily in combination with venetoclax 200 mg daily starting after 3 months of dasatinib therapy (after protocol amendment). SECONDARY OBJECTIVES: I. To estimate the 12 months molecular response (MR)4.5 rate and the cumulative overall rate of MR4.5 (BCR-ABL transcripts [IS] =< 0.01%). II. To estimate the proportion of patients with MR4.5 at 6-, 12-, 18-, 24-, and 36-months of therapy. III. To estimate the proportion of patients with sustained MR4.5 of 3 years and more. IV. To estimate the treatment-free remission rate, time to progression, and overall survival. V. To assess the safety of this combination. OUTLINE: Patients receive dasatinib orally (PO) once daily (QD) for 15 years in the absence of disease progression or unacceptable toxicity. After 3 months of dasatinib treatment, patients also receive venetoclax PO QD on days 1-14 of each month for 3 years in the absence of disease progression or unacceptable toxicity (patients enrolled prior to 4/1/2018 receive only dasatinib).

Official Title
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Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) With Dasatinib and Venetoclax: A Phase II Study

Conditions
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Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Other: Laboratory Biomarker Analysis
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Ph-positive or BCR-ABL positive CML in early chronic phase CML (i.e., time from diagnosis ≤ 12 months). Except for hydroxyurea and/or 1 to 2 doses of cytarabine patients must have received no or minimal prior therapy, defined as <1 month (30 days) of prior FDA approved TKI. Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis, and when present at diagnosis may not impact the prognosis at all. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study. Eastern Cooperative Oncology Group (ECOG) performance of 0-2 Total bilirubin < 1.5 x upper limit normal (ULN) (unless secondary to Gilbert's disease, in which case should be < 2.5x ULN) Serum glutamate pyruvate transaminase (SGPT) < 3 x ULN Creatinine < 1.5 x ULN Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital Exclusion Criteria: New York Heart Association (NYHA) cardiac class 3-4 heart disease Patients meeting the following criteria are not eligible unless cleared by cardiology: Uncontrolled angina within 3 months Diagnosed or suspected congenital long QT syndrome Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) Prolonged QTc interval on pre-entry electrocardiogram (> 460 msec) History of significant bleeding disorder unrelated to cancer, including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) Patients with active, uncontrolled psychiatric disorders include: psychosis, major depression, and bipolar disorders Subject is known to be positive for human immunodeficiency virus (HIV); (HIV testing is not required) Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: Uncontrolled and/or active systemic infection (viral, bacterial or fungal) Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Women must continue birth control for the duration of the trial and at least 3 months after the last dose of study drug. Pregnant or breast-feeding women are excluded. All WOCBP must have a negative pregnancy test prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive study drug and must not be enrolled in the study. Patients in late chronic phase (i.e., time from diagnosis to treatment > 12 months), accelerated or blast phase are excluded; the definitions of CML phases are as follows: Early chronic phase: Time from diagnosis to therapy ≤12 months Late chronic phase: Time from diagnosis to therapy > 12 months Blastic phase: Presence of 30% blasts or more in the peripheral blood or bone marrow Accelerated phase CML: Presence of any of the following features: Peripheral or marrow blasts 15% or more Peripheral or marrow basophils 20% or more Thrombocytopenia < 100 x 10^9/L unrelated to therapy Documented extramedullary blastic disease outside liver or spleen

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (dasatinib, venetoclax)<br>Patients receive dasatinib PO QD for 15 years in the absence of disease progression or unacceptable toxicity. After 3 months of dasatinib treatment, patients also receive venetoclax PO QD on days 1-14 of each month for 3 years in the absence of disease progression or unacceptable toxicity (patients enrolled prior to 4/1/2018 receive only dasatinib). | Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major molecular response (MMR) defined as BCR-ABL transcripts (IS) =< 0.1% | MMR estimates will be presented with 95% credible intervals. MMR and patient and clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete cytogenetic response (CCR) defined as 0% Ph-positive metaphases, or fluorescence in situ hybridization =< 2%, or BCR-ABL transcripts (IS) =< 1% | CCR estimates will be presented with 95% credible intervals. | At 6 months | 
| Incidence of toxicities, defined as grade 3 or higher pleural effusion | Safety data of the patients will be summarized using descriptive statistics such as mean, standard deviation, median and range (i.e., duration of hematologic, cytogenetic and molecular response to the drug). | Up to 3 years | 
| Time to progression | Estimated using the Kaplan-Meier method. The two-sided log-rank test will be used to assess the differences of time to events between groups. | Up to 3 years | 
| Overall survival | Estimated using the Kaplan-Meier method. The two-sided log-rank test will be used to assess the differences of time to events between groups. | Up to 3 years |