Overview
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ponatinib in children aged 1 to < 18 years with advanced leukemias, lymphomas, and solid tumors.
Eligibility
Inclusion Criteria:
Histologically or cytologically confirmed diagnosis of the following malignancies:
- Phase 1: CP-CML, BP-CML, AP-CML ALL. AML. Other leukemias. Lymphoma. Any other tumors, including tumors of the CNS, for which standard therapy is not available or is not indicated.
- Phase 2, Group A with CP-CML: CP-CML at the time of study entry and must be resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy or be in "warning" response status or have the T315I kinase domain mutation.
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.
- 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 as determined by site radiology.
Prior therapies as follows:
- Phase 1: Participants with CML who are resistant to or intolerant of (as defined Appendix
F) to at least 1 prior BCR-ABL-targeted TKI therapy.
Participants with ALL who have progressed on or after 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 (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.
- Phase 2, Group A with CP-CML: Participants who are resistant to or intolerant of at least
1 prior BCR-ABL-targeted TKI therapy.
- 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.
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 (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.
- Karnofsky performance status ≥ 40% for participants ≥ 16 years old or Lansky Play
Scale ≥ 40% for pediatric participants < 16 years old.
- 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.
- Willingness to avoid pregnancy or fathering children.
Prior therapies:
- 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.
- Participants (except the BP-CML, ALL, and AML participants described above) who: Have had
cytotoxic chemotherapy within 21 days (or 42 days for nitrosoureas or mitomycin C) before
the first dose of ponatinib.
Prior radiation therapy 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.
Autologous or allogeneic stem cell transplant < 3 months before the first dose of
ponatinib.
Major surgery within 14 days before the first dose of ponatinib. Inadequate recovery and/or
complications from a major surgery before starting therapy.
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 monoclonal antibody-directed anticancer therapy within 5 half-lives of the first
dose of ponatinib.
- Any chimeric antigen receptor therapy within 28 days before the first dose of
ponatinib
- Ponatinib
- Protocol-defined lab Values
- Significant concurrent, uncontrolled medical condition, including but not limited to
the following:
- Pancreatic: clinical, radiological, or laboratory evidence of pancreatitis.
- 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 P), 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).
- 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 clinically according to
Inclusion Criterion 6.
- Uncontrolled seizure disorder.
- Coagulation:
- Significant bleeding disorder or thrombophilia unrelated to the underlying malignancy
indication for study participation.
- Gastrointestinal:
- Gastrointestinal disorders, such as malabsorption syndrome or any other illness that
could affect oral absorption.
- Genetic:
- Participants with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome.
- Participants with Down syndrome.
- Participants with any active ≥ Grade 2 graft versus host disease.
- Chronic or current active uncontrolled infectious disease requiring systemic
antibiotics, antifungal, or antiviral treatment.
- 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.
- Known HIV infection.
- Current use of prohibited medication (see Section 6.7.2).
- Known hypersensitivity or severe reaction to ponatinib or excipients of ponatinib.
- Receipt of live (including attenuated) vaccines or anticipation of need for such
vaccines during the study.
- Inability or unlikeliness to comply with the dose schedule and study evaluations, in
the opinion of the investigator.
- Females who are pregnant or lactating.
- Other exclusions may apply.