A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation

Phase 1 cohort 1 (enrollment and treatment completed) eligibility criteria at
the time of enrollment for patients to be administered ponatinib as the tablet
formation:
- Patients must have a body weight >=30 kg.
- Patients must be able to swallow solid oral dosage forms.

Phase 1 cohort 2 eligibility criteria at the time of enrollment:
- Patients must be aged >=1 year and have a body weight of at least 5 kg.
Each patient must meet all the following inclusion criteria to be enrolled
in the study for phase 1 and phase 2.

1. Diagnosis: Patients must have a diagnosis of Ph+ ALL, Ph+ MPAL, or Ph-like
ALL (US only) 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 of the following: flow cytometry lymphoblasts >=5%, or BCR-ABL1 fluorescence
in situ
hybridization, or >=10-2
leukemic clone identified by immunoglobulin heavy chain-T-cell receptor
polymerase chain reaction, OR
ii. M3 BM (>=25% lymphoblasts): by morphology, OR
iii. Patients with combined BM (as defined above) and extramedullary disease.

b. Evidence of Ph+ ALL, MPAL, or Ph-like ALL:
i. Definite evidence of BCR-ABL1 fusion (Ph) for Ph+ ALL and MPAL, OR
ii. Definite evidence of Ph-like ALL with targetable kinase-activating lesions
involving any of the
following kinase genes: ABL1, ABL2, CSF1R, and PDGFRB.
Ph-like ALL diagnosis requires the identification of specified targetable
kinase-activating lesions preferably by RNA sequencing or by alternative
accredited method used by the site. Referring institution*s laboratory results
will be accepted for diagnosis and study enrollment. No confirmation by a
sponsor central laboratory is required.

c. Disease status:
i. For non-US sites: patients who have relapsed (post 0 or 1 HSCT) or are
resistant or intolerant to at
least 1 prior therapy that contained a BCR-ABL1-targeted TKI, OR
For US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or
intolerant to at least
1 prior therapy that contained a second-generation BCR-ABL1-targeted TKI (ie,
dasatinib, nilotinib,
and bosutinib); OR
ii. Have a BCR-ABL1 T315I mutation irrespective of relapse,
resistance/intolerance, or transplant status and irrespective of any prior TKI
use. Referring institution*s laboratory results will be accepted for
enrollment; however, the mutation needs to be confirmed by the central
laboratory. If the mutational status is not concordant, the patient will be
withdrawn from the study and excluded from analyses for RP2D and efficacy, but
included for safety.
A patient will be defined as intolerant if they had a Grade >=3 nonhematologic
toxicity or a Grade 4
hematologic toxicity considered related to the last TKI and lasting for >2
weeks, and led to discontinuation
of therapy.

2. Age: Patients must be >=1 and <=21 years of age at the time of enrollment.
3. Performance Status: Karnofsky performance status >=50% for patients >16 years
of age or Lansky Play Scale >=50% for patients <=16 years of age.
4. Patients must have recovered to less than Grade 2 National Cancer Institute
Common Terminology Criteria for Adverse Events version 5, or to baseline, from
any nonhematologic toxicities (except alopecia) due to previous therapy.
5. Patients must meet the following criteria related to prior therapies:
Cytoreduction with hydroxyurea: Hydroxyurea can be initiated and continued for
up to 24 hours before the start of protocol therapy. Patients who relapsed
while receiving cytotoxic therapy: At least 14 days
must have passed since the completion of the last dose of chemotherapy before
the first dose of
ponatinib can be given except for the following: intrathecal chemotherapy
and/or maintenance therapy such as vincristine, mercaptopurine, methotrexate,
or glucocorticoids. There is no waiting
period for those relapsing on maintenance-like therapy. HSCT: Patients 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 90 days posttransplant at the time
of enrollment. Hematopoietic growth factors: Before the first dose of
ponatinib, at least 7 days must have passed since completion of therapy with
granulocyte colony-stimulating factor or other growth factors, and at least 14
days must have 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
agents that have known AEs occurring beyond 7 days after administration, this
period must be extended beyond the time during which AEs are known to occur.
The duration of this interval must be discussed with the sponsor's medical
monitor/designee.Monoclonal antibodies: After the last dose of monoclonal
antibody, at least 3 half-lives of the administered antibody must have passed
before the first dose of ponatinib. Immunotherapy: Before the first dose of
ponatinib, at least 30 days must have passed 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 days must have passed after the completion of immunosuppressive therapy
(including regimens following stem cell transplant). Radiotherapy: No washout
period is necessary for radiation given to any extramedullary site other than
central nervous system (CNS); >=90 days must have passed if patient received
prior total body irradiation or craniospinal or cranial radiotherapy.
Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of
doxorubicin equivalents of anthracyclines.
6. Patients must have adequate renal and hepatic function.
7. No clinical, radiological or laboratory evidence of pancreatitis, including:
a. Serum lipase must be <2 times the ULN, and
b. Serum amylase must be <2 times the ULN.
8. Adequate cardiac function defined as shortening fraction >=27% by
echocardiogram (ECHO) OR left ventricular ejection fraction of >=50% by
multigated acquisition scan (MUGA).
9. Normal QT interval corrected per Fridericia method (QTcF) on screening
electrocardiogram (ECG), defined as QTcF of <=450 ms.

1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell
leukemia.
2. A history or current diagnosis of CML.
3. Diagnosis of ALL, MPAL, or Ph-like ALL (US only) with targetable
kinase-activating lesions after treatment with cytotoxic therapy for another
cancer.
4. Diagnosis of another concurrent primary malignancy.
5. Clinically significant cardiovascular disease, including but not limited to:
a. Any history of myocardial infarction (MI) or unstable angina.
b. History of or presence of heart block, and/or clinically significant
ventricular or atrial arrhythmias.
c. Uncontrolled hypertension, defined as persistent elevation of systolic
and/or diastolic blood pressures to >=95th percentile based on age, sex, and
height percentiles despite appropriate antihypertensive management.
6. Current systemic use of drug(s) that are known to have a risk of causing
prolonged corrected QT interval (QTc) or torsades de pointes unless drug(s) can
be changed to acceptable alternatives (ie, an alternate class of agents that do
not affect the cardiac conduction system) or the patient can safely discontinue
the drug(s).
7. Uncontrolled hypertriglyceridemia (triglycerides >=450 mg/dL). (Patients with
triglycerides >=450 mg/dL may be enrolled in the absence of any significant
cardiovascular risk after discussion with the sponsor's medical
monitor/designee)
8. Current systemic use of any medications or herbal supplements that are known
to be strong inhibitors or strong inducers of CYP3A within 7 days before the
first dose of study drug.
9. Previous treatment with ponatinib.
10. Planned non-protocol chemotherapy, radiation therapy, another
investigational agent, or immunotherapy while patient is on study treatment.
11. Known allergy or contraindications to any of the drugs (active or
excipient) used in the study.
12. Known gastrointestinal disease or gastrointestinal procedure that could
interfere with the oral absorption of ponatinib.
13. Patients with DNA fragility syndromes, such as Fanconi anemia and Bloom
syndrome.
14. Patients with Down syndrome.
15. Patients with uncontrolled systemic infection, or know laboratory an/or
clinical evidence of active infection with HIV, hepatitis B, or hepatitis C.
16. Patients with pre-existing significant CNS pathology including: history of
severe brain injury, dementia, cerebellar disease, organic brain syndrome,
psychosis, coordination /movement disorder, or autoimmune disease with CNS
involvement are not eligible.
17. Patients with a history of cerebrovascular ischemia/hemorrhage with
residual deficits are not eligible. (Patients with a history of cerebrovascular
ischemia/hemorrhage remain eligible provided all neurologic deficits and
causative factor(s) have resolved.)
18. Uncontrolled seizure disorder. (Patients with seizure disorders that do not
require antiepileptic drugs, or are well controlled with stable doses of
antiepileptic drugs are eligible.)
19. History of severe coagulopathy or cardiovascular or peripheral vascular
events.
20. Any condition or illness that, in the opinion of the investigator or
sponsor, would compromise patient safety or interfere with the evaluation of
the safety or efficacy of ponatinib.
21. Admission or evidence of illicit use, drug abuse, or alcohol abuse.
22. Pregnancy and breastfeeding exclusions:
a. Female patients who are pregnant are excluded since fetal toxicities
and teratogenic effects have been noted for several of the study treatments. A
pregnancy test is required for female patients of childbearing potential.
b. Lactating women who plan to breastfeed their infants.
23. Treatment with live attenuated vaccinations within 30 days prior to
initiation of study treatment regimen.