• Phase 1: Number of dose-limiting toxicities [ Time Frame: 28 days ]
  Defined as the occurrence of any protocol-defined toxicities occurring after dosing and up to and including Day 28, except those toxicities with a clear alternative explanation.
• Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML) [ Time Frame: 12 months ]
  Defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) as assessed by conventional cytogenetics or fluorescence in situ hybridization (FISH).
• Phase 2: Efficacy of ponatinib assessed by major hematologic response (MaHR) or major molecular response (MMR) in participants with BCR-ABL-positive leukemias [ Time Frame: 3 months ]
  Assessed by polymerase chain reaction (PCR).
• Phase 2: Efficacy of ponatinib assessed by complete response (CR) in participants with leukemias other than BCR-ABL-positive leukemias to determine the efficacy of ponatinib [ Time Frame: 6 months ]
• Phase 2: Efficacy of ponatinib assessed by incomplete complete response (iCR) in participants with leukemias other than BCR-ABL-positive leukemias [ Time Frame: 6 months ]
  Assessed by conventional cytogenetics, FISH, or PCR.
• Phase 2: Efficacy of ponatinib assessed by CR in participants with lymphoma [ Time Frame: 6 months ]
  According to Lugano criteria based on computed tomography (CT) or magnetic resonance imaging (MRI) (or positron emission tomography [PET]).
• Phase 2: Efficacy of ponatinib assessed by overall response rate in participants with solid tumors [ Time Frame: 6 months ]
  Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for central nervous system (CNS) tumors or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for other solid tumors based on CT or MRI (or PET).

• Phase 1: Number of treatment-emergent adverse events [ Time Frame: 6 months ]
• Phase 1: Tmax of ponatinib [ Time Frame: 6 months ]
  Time to maximum concentration.
• Phase 1: AUCss,0-24 of ponatinib [ Time Frame: 6 months ]
  Area under the steady-state plasma or serum concentration-time curve from Hour 0 to 24.
• Phase 1: t½ of ponatinib [ Time Frame: 6 months ]
  Apparent terminal-phase disposition half-life.
• Phase 1: CLss/F of ponatinib [ Time Frame: 6 months ]
  Apparent oral dose clearance at steady state.
• Phase 1: Vz/F of ponatinib [ Time Frame: 6 months ]
  Apparent oral dose volume of distribution.
• Phase 1: MCyR in participants with BCR-ABL-positive leukemias [ Time Frame: 3 months ]
  Defined as CCyR or PCyR as assessed by conventional cytogenetics or FISH.
• Phase 1: MMR in participants with BCR-ABL-positive leukemias [ Time Frame: 3 months ]
  Assessed by quantitative PCR (q-PCR).
• Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML [ Time Frame: 6 months ]
• Phase 1 and Phase 2: CCyR in participants with CP-CML [ Time Frame: 12 months ]
• Phase 1 and Phase 2: MMR in participants with CP-CML [ Time Frame: 12 months ]
• Phase 1 and Phase 2: Time to response (TTR) in participants with CP-CML [ Time Frame: 6 months ]
  Defined as the interval from the date of the first dose of study treatment to first response.
• Phase 1 and Phase 2: Duration of response (DOR) in participants with CP-CML [ Time Frame: 6 months ]
  Defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met.
• Phase 1 and Phase 2: Progression-free survival (PFS) in participants with CP-CML [ Time Frame: 6 months ]
  Defined as the interval from the date of the first dose of study treatment until the date of progression of disease or the date of death from any cause, whichever is earlier.
• Phase 1 and Phase 2: Overall survival (OS) in participants with CP-CML [ Time Frame: 6 months ]
  Defined as the interval from the date of the first dose of study treatment until death from any cause.
• Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML. [ Time Frame: 6 months ]
• Phase 1: CRi in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML [ Time Frame: 6 months ]
  Assessed by conventional cytogenetics, FISH, or q-PCR.
• Phase 1: CR in participants with lymphoma [ Time Frame: 6 months ]
  According to Lugano criteria based on CT or MRI (or PET).
• Phase 1: Overall response rate in participants with solid tumors [ Time Frame: 6 months ]
  Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for CNS tumors or RECIST v1.1 for other solid tumors based on CT or MRI (or PET).
• Phase 2: Anticancer activity of ponatinib assessed by MaHR or MMR in participants with BCR-ABL-positive leukemias (AP-CML, BP-CML or Ph+ALL) [ Time Frame: 3 months ]
• Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias [ Time Frame: 6 months ]
• Phase 2: Anticancer activity of ponatinib assessed by CRi in participants with leukemias other than BCR-ABL-positive leukemias. [ Time Frame: 6 months ]
  Assessed by conventional cytogenetics, FISH, or PCR.
• Phase 2: Anticancer activity of ponatinib assessed by CR in participants with lymphoma [ Time Frame: 6 months ]
  According to Lugano criteria based on CT or MRI (or PET).
• Phase 2: Anticancer activity of ponatinib assessed by overall response rate in participants with solid tumors [ Time Frame: 6 months ]
  Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for CNS tumors or RECIST v1.1 for other solid tumors based on CT or MRI (or PET).
• Phase 2: OS in participants with solid tumors [ Time Frame: 6 months ]
  Defined as the interval from the date of the first dose of study treatment until death from any cause.
• Phase 2: DOR in participants with solid tumors [ Time Frame: 6 months ]
  Defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met.
• Phase 2: PFS in participants with solid tumors [ Time Frame: 6 months ]
  Defined as the interval from the date of the first dose of study treatment until the date of progression of disease or the date of death from any cause, whichever is earlier.
• Phase 2: Number of treatment-emergent adverse events [ Time Frame: 6 months ]
• Phase 2: Clearance of pediatric-friendly formulation of ponatinib [ Time Frame: 6 months ]
• Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib [ Time Frame: 6 months ]
• Phase 2: AUC of pediatric-friendly formulation of ponatinib [ Time Frame: 6 months ]

• Acute Myeloid Leukemia
• Accelerated Phase Chronic Myeloid Leukemia
• Blast Phase Chronic Myeloid Leukemia
• Chronic Phase Chronic Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Acute Lymphocytic Leukemia
• Leukemia
• Lymphoma
• Solid Tumors

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of the following malignancies: CP-CML, blast phase chronic myeloid leukemia (BP-CML), accelerated phase chronic myeloid leukemia (AP-CML); acute lymphoblastic leukemia/acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); other leukemias; lymphoma; any other tumors, including tumors of the central nervous system (CNS), for which standard therapy is not available or is not indicated

• Phase 1:

  • Participants with CML who are resistant to or intolerant 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 failed at least 1 prior induction attempt or for whom no effective standard therapy is available or indicated.
  • 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 (CP-CML): Participants who are resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy or have the T315I kinase domain mutation.

• Phase 2 (other leukemias or solid tumors):

  • Participants with ALL who have failed all available or indicated therapies, which must have included 1 prior BCR-ABL-targeted TKI therapy.
  • Participants with AML or other leukemias who have failed at least 1 prior induction attempt or for whom no effective standard therapy is available or indicated.
  • Participants with solid tumors (including tumors of the CNS) with mutation of RET, KIT, FGFR, PDGFR, VEGFR or any other mutations where ponatinib may have biological activity 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.
• 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.

Exclusion Criteria:

• Participants with CP-CML who are in MCyR or better.

• Prior therapies:

  • Participants with BP-CML, ALL, or AML who have received corticosteroids or hydroxyurea within 24 hours before the first dose of ponatinib; vincristine within 7 days before the first dose of ponatinib; or 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 or radiotherapy within 21 days (or 42 days for nitrosoureas or mitomycin C) before the first dose of ponatinib.
  • Prior radiation therapy within 6 weeks or radio-isotope therapy within 6 weeks before the first dose of ponatinib.
  • Autologous or allogeneic stem cell transplant < 3 months before the first dose of ponatinib.
  • 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.
• Laboratory values at screening outside the protocol-defined ranges.
• Significant concurrent, uncontrolled medical condition, including but not limited to protocol-defined pancreatic, cardiac, cerebral, coagulation, gastrointestinal, and genetic conditions.
• Any active ≥ Grade 2 graft-versus-host disease.
• Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment or at risk for HBV reactivation.
• Known HIV infection.
• 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.
• Females who are pregnant or lactating.