A Study of Ponatinib With Chemotherapy in Children, Teenagers, and Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Inclusion Criteria:

1. Participants must have a diagnosis of Ph+ ALL, Philadelphia chromosome-positive plusmixed phenotype acute leukemia (Ph+ MPAL), or Ph-like ALL with: a) Involvement of BM with ALL, including one of the following: i. M2 BM (5%-24%lymphoblasts): by morphology with confirmatory testing consisting of at least one ofthe following: flow cytometry lymphoblasts ≥5%, or BCR-ABL1 fluorescence in situhybridization, or ≥10-2 leukemic clone identified by immunoglobulin heavychain-T-cell receptor polymerase chain reaction, OR ii. M3 BM (≥25% lymphoblasts):by morphology, OR iii. Participants with combined BM (as defined above) andextramedullary disease. b) Evidence of Ph+ ALL, MPAL, or Ph-like ALL: i. Definite evidence of BCR-ABL1fusion (Ph) for Ph+ ALL and MPAL, OR ii. Definite evidence of Ph-like ALL withtargetable kinase-activating lesions involving any of the following kinase genes:ABL1, ABL2, CSF1R, and PDGFRB. Ph-like ALL diagnosis requires the identification of specified targetablekinase-activating lesions preferably by ribonucleic acid (RNA) sequencing or byalternative accredited method used by the site. c) Disease status: (i) For non-US sites: participants who have relapsed (post 0 or 1HSCT) or are resistant or intolerant to at least one prior therapy that contained aBCR-ABL-targeted tyrosine kinase inhibitor (TKI), or for US sites: participants whohave relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at least oneprior therapy that contained a second-generation BCR-ABL1-targeted TKI (i.e,dasatinib, nilotinib, and bosutinib); OR (ii) Have a BCR-ABL1 T315I mutationirrespective of relapse, resistance/intolerance, or transplant status andirrespective of any prior TKI use. Notes: A participant will be defined as intolerant if they had a Grade ≥3 nonhematologictoxicity or a Grade 4 hematologic toxicity considered related to the last TKI andlasting for >2 weeks, and led to discontinuation of therapy.

2. Weight: Participants must be weighing at least 5 kg at the time of enrollment.

3. Performance Status: Karnofsky performance status ≥50% for participants ≥16 years ofage or Lansky Play Scale ≥50% for participants <16 years of age.

4. Have recovered to less than Grade 2 National Cancer Institute common terminologycriteria for adverse events (NCI CTCAE) Version 5.0, or to baseline, from anynonhematologic toxicities (except alopecia) due to previous therapy.

5. Participants must meet the following criteria related to prior therapies:

• Cytoreduction with hydroxyurea: Hydroxyurea can be initiated and continued forup to 24 hours before the start of protocol therapy.

• Participants who relapsed while receiving cytotoxic therapy: At least 14 daysmust have passed since the completion of the last dose of chemotherapy beforethe first dose of ponatinib can be given except for the following: intrathecal (IT) chemotherapy and/or maintenance therapy such as vincristine,mercaptopurine, methotrexate, or glucocorticoids. There is no waiting periodfor those relapsing on maintenance-like therapy.

• HSCT: Participants who have experienced relapse after a HSCT are eligible,provided they have no evidence of acute or chronic graft-versus-host disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90days posttransplant at the time of enrollment.

• Hematopoietic growth factors: Before the first dose of ponatinib, at least 7days must have passed since completion of therapy with granulocytecolony-stimulating factor or other growth factors, and at least 14 days musthave passed since completion of therapy with pegfilgrastim.

• Biologics and targeted therapies: Before the first dose of ponatinib, at least 7 days must have passed since the last dose of a biologic agent. For agentsthat have known AEs occurring beyond 7 days after administration, this periodmust be extended beyond the time during which AEs are known to occur. Theduration of this interval must be discussed with the sponsor's medicalmonitor/designee.

• Monoclonal antibodies: After the last dose of monoclonal antibody, at least 3half-lives of the administered antibody must have passed before the first doseof ponatinib.

• Immunotherapy: Before the first dose of ponatinib, at least 30 days must havepassed after the completion of any type of immunotherapy (eg, tumor vaccines,chimeric antigen receptor T-cell [CAR-T-cell]).

• Immunosuppressive therapy: Before the first dose of ponatinib, at least 14 daysmust have passed after the completion of immunosuppressive therapy (includingregimens following stem cell transplant).

• Radiotherapy: No washout period is necessary for radiation given to anyextramedullary site other than central nervous system (CNS); ≥90 days must havepassed if participant received prior total body irradiation or craniospinal orcranial radiotherapy.

• Anthracyclines: Participants must have had a lifetime exposure of <400milligrams per square meter (mg/m^2) of doxorubicin equivalents ofanthracyclines.

6. a) Adequate renal function defined as: Estimated glomerular filtration rate (eGFR)using the Schwartz formula, OR radioisotope glomerular filtration rate (GFR)≥70mL/min/1.73 m^2, OR a normal serum creatinine based on age and sex. b) Adequate liver function defined as: Direct bilirubin ≤1.5 times the upper limitof normal (ULN) for age AND ALT ≤5 times the ULN for age.

7. No clinical, radiological or laboratory evidence of pancreatitis, including:

8. Serum lipase must be <2 times the ULN, AND

9. Serum amylase must be <2 times the ULN.

10. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) OR left ventricular ejection fraction of ≥50% by ECHO or multigatedacquisition scan (MUGA).

11. Normal QT interval with Fridericia correction method (QTcF) on screeningelectrocardiogram (ECG), defined as QTcF of ≤450 milliseconds (ms).

Exclusion Criteria:

1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cellleukemia.

2. A history or current diagnosis of chronic myeloid leukemia (CML).

3. Diagnosis of ALL, MPAL, or Ph-like ALL with targetable kinase-activating lesionsafter treatment with cytotoxic therapy for another cancer.

4. Diagnosis of another concurrent primary malignancy.

5. Clinically significant cardiovascular disease, including but not limited to:

6. Any history of myocardial infarction (MI) or unstable angina.

7. History of or presence of heart block, and/or clinically significantventricular or atrial arrhythmias.

8. Uncontrolled hypertension, defined as persistent elevation of systolic and/ordiastolic blood pressures to ≥95th percentile based on age, sex, and heightpercentiles despite appropriate antihypertensive management.

9. Current systemic use of drug(s) that are known to have a risk of causing prolongedcorrected QT interval (QTc) or torsades de pointes unless drug(s) can be changed toacceptable alternatives (ie, an alternate class of agents that do not affect thecardiac conduction system) or the participants can safely discontinue the drug(s).

10. Uncontrolled hypertriglyceridemia (triglycerides ≥450 milligrams per deciliter (mg/dL)).

11. Current systemic use of any medications or herbal supplements that are known to bestrong inhibitors or strong inducers of cytochrome P450 3A (CYP3A) within 7 daysbefore the first dose of study drug.

12. Previous treatment with ponatinib.

13. Planned non-protocol chemotherapy, radiation therapy, another investigational agent,or immunotherapy while participant is on study treatment.

14. Known gastrointestinal disease or gastrointestinal procedure that could interferewith the oral absorption of ponatinib.

15. Participants with deoxyribonucleic acid (DNA) fragility syndromes, such as Fanconianemia and Bloom syndrome.

16. Participants with Down syndrome.

17. Participants with uncontrolled systemic infection, or known laboratory and/orclinical evidence of active infection with human immunodeficiency virus (HIV),hepatitis B, or hepatitis C.

18. Participants with pre-existing significant CNS pathology, including history ofsevere brain injury, dementia, cerebellar disease, organic brain syndrome,psychosis, coordination/movement disorder, or autoimmune disease with CNSinvolvement, are not eligible.

19. Participants with a history of cerebrovascular ischemia/hemorrhage with residualdeficits are not eligible. (Participants with a history of cerebrovascularischemia/hemorrhage remain eligible provided all neurologic deficits and causativefactor(s) have resolved).

20. Uncontrolled seizure disorder. (Participants with seizure disorders that do notrequire antiepileptic drugs or are well controlled with stable doses ofantiepileptic drugs are eligible).

21. History of severe coagulopathy or cardiovascular or peripheral vascular events.

22. Treatment with live attenuated vaccinations within 30 days prior to initiation ofstudy treatment regimen.