An Efficacy Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Participants With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

The drug being tested in this study is called ponatinib. Ponatinib is being tested to treat
people who have newly diagnosed Ph+ ALL. This study will look at the efficacy of ponatinib in
participants in addition to standard care.

The study will enroll approximately 230-320 patients. Patients will be randomized in a 2:1
ratio to receive oral ponatinib or imatinib (Cohort A and Cohort B, respectively) daily
throughout the study.

All participants will be asked to take ponatinib or imatinib at the same time each day with
reduced-intensity chemotherapy in induction phase (Cycles 1 to 3), consolidation phase
(Cycles 4 to 9) and maintenance phase (Cycles 10 to 20). At the end of the 20 cycles,
participants will remain on ponatinib or imatinib (administered as a single agent). The dose
of ponatinib in consolidation and maintenance phase will start with the last dose given in
the previous phase. The dose can be modified based on MRD-negative CR results.

This multi-center trial will be conducted worldwide. Participants including those who achieve
a clinical response, may receive study drug until they are deceased, have failed to achieve
the primary endpoint, have experienced relapse from CR or have progressive disease, have an
unacceptable toxicity, have withdrawn consent, have proceeded to HSCT, or until the sponsor
terminates the study, whichever occurs first. After disease progression, all participants
will be contacted every 3 months for survival follow-up. Participants will be followed until
completion of the study or until the participant's death has been reported.

Inclusion Criteria:

1. Newly diagnosed Philadelphia chromosome-positive (Ph+) or BCR-ABL1-positive ALL, as
defined by the 2017 national comprehensive cancer network (NCCN) guidelines.

2. Molecular assessment of BCR-ABL1 must demonstrate the presence of a p190 (that is
e1a2) or p210 (ie, e13a2 or e14a2 [also known as b2a2 or b3a2]) transcript type.

3. Eastern Cooperative Oncology Group (ECOG) performance status of <=2.

Exclusion Criteria:

1. With a history or current diagnosis of chronic phase, accelerated phase, or blast
phase chronic myeloid leukemia (CML).

2. Prior/current treatment with any systemic anticancer therapy (including but not
limited to any tyrosine kinase inhibitor [TKI]) and/or radiotherapy for cancer, with
the exception of an optional prephase therapy, which should be discussed with the
sponsor's medical monitor/designee.

3. Currently taking drugs that are known to have a risk of causing prolonged QTc or
torsades de pointes (TdP) (unless these can be changed to acceptable alternatives or
discontinued).

4. Taking any medications or herbal supplements that are known to be strong inhibitors or
strong inducers of cytochrome P450 (CYP)3A4 within at least 14 days before the first
dose of study drug.

5. Active serious infection requiring antibiotics within 14 days before the first dose of
study drug.

6. Major surgery within 28 days before randomization (minor surgical procedures such as
catheter placement or BM biopsy are not exclusionary criteria).

7. Ongoing or active systemic infection, known seropositive human immunodeficiency virus
(HIV), known active hepatitis B or C infection.

8. History of acute pancreatitis within 1 year of study screening or history of chronic
pancreatitis.

9. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).

10. Diagnosed and treated for another malignancy within 5 years before randomization or
previously diagnosed with another malignancy and have any evidence of residual
disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type
are excluded if they have not undergone complete resection.

11. History or presence of clinically relevant CNS pathology such as epilepsy, childhood
or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia,
Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.

12. Clinical manifestations of CNS or extramedullary involvement with ALL.

13. Autoimmune disease with potential CNS involvement.

14. Known significant neuropathy of Grade >=2 severity.

15. Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or
peripheral vascular disease, or history of or active venous thrombotic/embolic event.

16. Had a significant bleeding disorder unrelated to ALL.