An Open-Label, Single-Arm, Phase 1/2 Study Evaluating the Safety and Efficacy of Ponatinib for the Treatment of Recurrent or Refractory Leukemias or Solid Tumors in Pediatric Participants.

1. Histologically or cytologically confirmed diagnosis of the following
malignancies:
a. Phase 1:
* CP-CML, BP-CML, AP-CML (relapse defined in Appendix G).
* ALL.
* AML.
* Other leukemias.
* Lymphoma.
* Any other tumors, including tumors of the CNS, for which standard therapy is
not available or is not indicated.
b. Phase 2, Group A with CP-CML:
* CP-CML (defined in Appendix G) at the time of study entry and must be
resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy or
have the T315I kinase domain mutation or be in "warning" response status.
Warning response status must a) be confirmed by at least 2 assessments
performed at least 1 month apart and b) justify the change of treatment by
comorbidities and tolerability.
* Must have 1 bone marrow aspirate with documentation of BCR-ABL translocation
by conventional cytogenetics, metaphase FISH, or q-PCR performed within 42 days
before the first dose of ponatinib.
c. Phase 2, Group B with other leukemias or solid tumors:
* ALL.
* AML.
* Other leukemias.
* Lymphoma.
* Any other tumors, including tumors of the CNS, with mutations of RET, FLT3,
KIT, FGFR, PDGFR, TIE2 VEGFR, or any other mutations where ponatinib may have
biological activity (eg. EPH receptors and SRC families of kinases) as assessed
on fresh or archived tumor tissue.
* Participants with solid tumors or with lymphoma must have measurable disease
by CT or MRI based on RECIST v1.1 or the Lugano lymphoma guidelines (Cheson et
al 2014) as determined by site radiology.
2. Prior therapies as follows:
a. Phase 1:
* Participants with CML who are resistant to or intolerant of (as defined
Appendix G) to at least 1 prior BCR-ABL-targeted TKI therapy.
* Participants with ALL who have failed all available or indicated therapies,
which may have included 1 prior BCR-ABL-targeted TKI therapy.
* Participants with AML or other leukemias who have progressed on or after at
least 1 prior induction attempt (for France only) or for whom no effective
standard therapy is available or indicated (for other countries).
* Participants with solid tumors (including tumors of the CNS) or lymphomas who
have progressed despite standard therapy or for whom no effective standard
therapy is available or indicated.
b. Phase 2, Group A with CP-CML:
* Participants who are resistant to or intolerant of at least 1 prior BCR-ABL-
targeted TKI therapy.
c. Phase 2, Group B with other leukemias or solid tumors:
* Participants with ALL who have progressed on or after all available or
indicated therapies, which must have included 1 prior BCR-ABL-targeted TKI
therapy (exception for participants with T315I mutation) or are in warning
status.
* Participants with AML or other leukemias who have failed at least 1 prior
induction attempt (for France only) or for whom no effective standard therapy
is available or indicated (for other countries).
* Participants with solid tumors (including tumors of the CNS) or lymphomas who
progressed despite standard therapy or for whom no effective standard therapy
is available or indicated.
3. Must have a parent or legal guardian able to comprehend and willing to sign
a written ICF for the study and assent (when appropriate) according to
institutional standards and to comply with all study visits and procedures.
4. Male and female participants >= 1 to < 18 years old, inclusive, at the time
of signing the informed consent.
5. Karnofsky performance status >= 40% for participants >= 16 years old or Lansky
Play Scale >= 40 for pediatric participants < 16 years old.
6. Participants must have recovered to < Grade 2 per the NCI CTCAE v5.0 or to
baseline from any non-hematologic toxicities (except alopecia) due to previous
therapy.

2. Prior therapies:
a. Participants with BP-CML, ALL, or AML who have received any of the following:
* Corticosteroids or hydroxyurea within 24 hours before the first dose of
ponatinib.
* Vincristine within 7 days before the first dose of ponatinib.
* Other chemotherapy (excluding intrathecal chemotherapy) within 14 days before
the first dose of ponatinib.
b. Participants (except the BP-CML, ALL, and AML participants described above)
who:
* Have had cytotoxic chemotherapy or radiotherapy within 21 days (or 42 days
for nitrosoureas or mitomycin C) before the first dose of ponatinib.
c. Prior radiation therapy or radio-isotope therapy before or radio-isotope
therapy within 6 weeks before the first dose of ponatinib except local
radiotherapy for palliative indication within 14 days before the first dose of
ponatinib. For CNS, at least 90 days must have passed if the participant
received prior total body irradiation or craniospinal or cranial radiotherapy.
d. Autologous or allogeneic stem cell transplant < 3 months before the first
dose of ponatinib.
e. Major surgery within 14 days before the first dose of ponatinib.
Note: Minor surgical procedures, such as central venous catheter placement or
bone marrow aspirate/biopsy, are permitted.
f. Inadequate recovery and/or complications from a major surgery before
starting therapy.
g. Prior treatment with any of the following:
* Immunosuppressive therapy (including post stem cell transplant regimens)
within 14 days before the first dose of ponatinib.
* Any targeted cancer therapy (including TKIs) within 7 days before the first
dose of ponatinib.
* Any other investigational anticancer agents within 30 days or 5 half-lives,
whichever is longer, before randomization.
* Any biotherapeutic (including monoclonal antibody-directed anticancer therapy
within 5 half-lives or 30 days whichever is shorter, before of the first dose
of ponatinib.
Note: Supportive care medications for CNS edema (eg, stable doses of
corticosteroids or bevacizumab) are permitted.
* Any chimeric antigen receptor therapy within 28 days before the first dose of
ponatinib
* Ponatinib.
3. Participants with laboratory values at screening defined as follows:
Solid tumors
a Platelets <= 75 × 109/L
b Hemoglobin <= 8 g/L
c ANC <= 1 × 109/L
Hepatic
d ALT >= 5 × ULN for age (unless related to leukemic involvement)
e AST >= 5 × ULN for age (unless related to leukemic involvement)
f Direct bilirubin >= 1.5 × ULN for age
Pancreatic
g Amylase > 2 × ULN for age
h Lipase > 2 × ULN for age
Renal
i Serum creatinine OR Serum creatinine clearance > ULN for age based on
age/gender chart below:
Age (years) Maximum Serum Creatinine (mg/dL)
Male Female
1 to < 2 0.6 0.6
2 to < 6 0.8 0.8
6 to < 10 1 1
10 to < 13 1.2 1.2
13 to < 16 1.5 1.4
>= 16 1.7 1.4
OR Calculated creatinine clearance of radioisotope glomerular filtration rate <
70 mL/min/1.73 m2
Coagulation
j INR or PT > 1.5 × ULN for age
k aPTT > 1.5 × ULN for age
Lipids
l Triglycerides >= 450 mg/dL
4. Significant concurrent, uncontrolled medical condition, including but not
limited to the following:
a. Pancreatic: clinical, radiological, or laboratory evidence of pancreatitis.
b. Cardiac:
* SF < 27% by ECHO, OR EF < 50% by MUGA.
* Abnormal QTcF on screening ECG, defined as QTcF of >= 450 ms.
* Clinically significant or uncontrolled cardiovascular disease, including
unstable angina, acute MI within 6 months from Day 1 of study drug
administration, New York Heart Association Class III or IV CHF (see Appendix
O), and arrhythmia requiring therapy unless approved by the medical
monitor/sponsor.
* Uncontrolled hypertension.
* Currently taking drug(s) that are known to have a risk of causing prolonged
QTc or TdP unless the drug(s) can be changed to acceptable alternatives (ie, an
alternate class of agents that do not affect the cardiac conduction system), or
the participant can safely discontinue the drug(s).
c. Cerebral:
* Participants with solid tumors with intracranial metastasis OR participants
with active CNS leukemia (ie, CNS-2 status [< 5/µL WBCs and cytospin positive
for blasts, or >= 5 /µL WBCs but negative by Steinherz/Bleyer algorithm
(equation used for traumatic lumbar punctures), disseminated leptomeningeal
disease, or CNS chloroma.
* 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.
* History of cerebrovascular ischemia/hemorrhage with residual deficits.
Note: Participants with a history of cerebrovascular ischemia/hemorrhage
remain eligible provided all neurologic deficits have resolved.
* Uncontrolled seizure disorder.
d. Coagulation:
* Significant bleeding disorder or thrombophilia unrelated to the underlying
malignancy indication for study participation.
e. Gastrointestinal:
* Gastrointestinal disorders, such as malabsorption syndrome or any other
illness that could affect oral absorption.
f. Genetic:
* Participants with DNA fragility syndromes, such as Fanconi anemia and Bloom
syndrome.
* Participants with Down syndrome.
5. Participants with any active >= Grade 2 graft versus host disease.
6. Chronic or current active uncontrolled infectious disease requiring systemic
antibiotics, antifungal, or antiviral treatment.
7. Active HBV or HCV infection that requires treatment or at risk for HBV
reactivation. Hepatitis B virus DNA and HCV RNA must be undetectable upon
testing. At risk for HBV reactivation is defined as hepatitis B surface
antigen positive or
anti-hepatitis B core antibody positive.
8. Known HIV infection.
9. Current use of prohibited medication (see Section 6.7.2).
10. Known hypersensitivity or severe reaction to ponatinib or excipients of
ponatinib.
11. Receipt of live (including attenuated) vaccines or anticipation of need for
such vaccines during the study.
12. Inability or unlikeliness to comply with the dose schedule and study
evaluations, in the opinion of the investigator.
13. Females who are pregnant or lactating.
14. Any condition or illness that would, in the investigator's judgment,
interfere with full participation in the study, including administration of
study drug and attending required study visits; pose a significant risk to the
participant; or interfere with interpretation of study data.
15. Inability of the participant (or parent, guardian, or legally authorized
representative) to comprehend the ICF or unwillingness to sign the ICF.