Venetoclax, Ponatinib, and Dexamethasone in Participants With Philadelphia Chromosome or BCR-ABL Positive Relapsed or Refractory Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of venetoclax, ponatinib, and dexamethasone
in patients with relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia
(ALL) or lymphoid blastic phase (BP)-chronic myelogenous leukemia (CML). (Phase I) II. To
determine the efficacy of the regimen, as defined by the rate of complete remission (CR) or
CR with incomplete count recovery (CRi). (Phase II)

SECONDARY OBJECTIVES:

I. To determine efficacy outcomes, including rate of minimal residual disease negativity by
polymerase chain reaction (PCR) for BCR-ABL1 transcripts, median relapse-free survival (RFS),
and median overall survival (OS).

II. To determine the proportion of patients proceeding to allogeneic stem cell transplant
(ASCT).

III. To preliminarily determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of single-agent ponatinib on apoptotic proteins and Bcl-2
dependency.

II. To correlate apoptotic protein expression and Bcl-2 dependency on response and resistance
to the combination regimen.

III. To assess impact of baseline genomics on outcomes with the combination regimen.

OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.

INDUCTION (COURSE 1): Participants who have not received ponatinib within 2 weeks of the
anticipated start date receive ponatinib orally (PO) daily on days 1-35, venetoclax PO daily
on days 8-35, and dexamethasone PO or intravenously (IV) over 15 minutes on days 8-11.
Participants who have received ponatinib within 2 weeks of the anticipated start date receive
ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes
on days 1-4. Participants with CD20 expression receive rituximab IV over 2-6 hours on days 14
and 21 at the discretion of the treating physician after the maximum dose of venetoclax has
been reached.

CONSOLIDATION (COURSES 2-4): Participants receive ponatinib PO and venetoclax PO daily on
days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Participants with CD20
expression receive rituximab IV over 2-6 hours for up to 2 doses each course at the
discretion of the treating physician after the maximum dose of venetoclax has been reached.
Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE (COURSES 5+): Participants receive ponatinib PO and venetoclax PO daily on days
1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Treatment repeats every 28 days
for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Participants achieving remission undergo ASCT at the discretion of the treating physician.

After completion of study treatment, participants are followed up at 30 days.

Inclusion Criteria:

- Patients with relapsed/refractory Ph-positive ALL or lymphoid blast phase CML (either
t(9;22) and/or BCR-ABL1 positive by fluorescent in situ hybridization or polymerase
chain reaction), including prior therapy with at least one Bcr-Abl tyrosine kinase
inhibitor

- Performance status =< 3 Eastern Cooperative Oncology Group (ECOG scale)

- Total serum bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's
syndrome, hemolysis or the underlying leukemia approved by the principal investigator
(PI)

- Alanine aminotransferase (ALT) =< 1.5 x ULN, unless due to the underlying leukemia
approved by the PI

- Aspartate aminotransferase (AST) =< 1.5 x ULN unless due to the underlying leukemia
approved by the PI

- Creatinine clearance >= 30 mL/min

- Serum lipase and amylase =< 1.5 x ULN

- Ability to swallow

- Signed informed consent

Exclusion Criteria:

- Prior history of treatment with venetoclax. Prior ponatinib is allowed

- Active serious infection not controlled by oral or intravenous antibiotics (e.g.
persistent fever or lack of improvement despite antimicrobial treatment)

- History of acute pancreatitis within 1 year of study or history of chronic
pancreatitis

- Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

- Active secondary malignancy that in the investigator's opinion will shorten survival
to less than 1 year

- Active grade III-V cardiac failure as defined by the New York Heart Association
criteria

- Clinically significant, uncontrolled, or active cardiovascular disease, specifically
including, but not restricted to: any history of myocardial infarction (MI), stroke,
revascularization, unstable angina or transient ischemic attack prior to enrollment;
left ventricular ejection fraction (LVEF) less than lower limit of normal per local
institutional standards prior to enrollment; diagnosed or suspected congenital long QT
syndrome; any history of clinically significant atrial or ventricular arrhythmias
(such as uncontrolled atrial fibrillation, ventricular tachycardia, ventricular
fibrillation, or Torsades de pointes) as determined by the treating physician;
prolonged corrected QT interval (QTc) interval on pre-entry electrocardiogram (> 480
msec) unless corrected after electrolyte replacement; history of venous
thromboembolism including deep venous thrombosis or pulmonary embolism within the past
3 months; uncontrolled hypertension (diastolic blood pressure > 100 mmHg; systolic >
150 mmHg)

- Patients currently taking drugs that are generally accepted to have a high risk of
causing Torsades de Pointes (unless these can be changed to acceptable alternatives)

- Received strong or moderate CYP3A inhibitors or inducers within 3 days of study entry

- Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days
prior to starting venetoclax

- Treatment with any investigational antileukemic agents or chemotherapy agents in the
last 7 days before study entry, unless full recovery from side effects has occurred or
patient has rapidly progressive disease judged to be life-threatening by the
investigator. Prior recent treatment with corticosteroids and hydroxyurea is permitted

- Pregnant and lactating women will not be eligible; women of childbearing potential
should have a negative pregnancy test prior to entering on the study and be willing to
practice methods of contraception throughout the study period. Women do not have
childbearing potential if they have had a hysterectomy or are postmenopausal without
menses for 12 months. In addition, men enrolled on this study should understand the
risks to any sexual partner of childbearing potential and should practice an effective
method of birth control. Appropriate birth control will be determined by the treating
physician