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

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 for 3 years in the absence of disease progression or unacceptable
toxicity (patients enrolled prior to 4/1/2018 receive only dasatinib).

Inclusion Criteria:

- Diagnosis of Philadelphia chromosome (Ph)-positive or BCR-ABL positive CML in early
chronic phase CML (i.e., time from diagnosis is 12 months); except for hydroxyurea
and/or 1 to 2 doses of cytarabine patients, patients must have received no or minimal
prior therapy, defined as < 1 month (30 days) of prior Food and Drug Administration
(FDA) approved tyrosine kinase inhibitor (TKI)

- 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)

- 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 corrected QT (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 investigational product 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