Clinical Trials /

Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias or Solid Tumors

NCT03934372

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Leukemia
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias or Solid Tumors
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: INCB 84344-102
  • NCT ID: NCT03934372

Conditions

  • 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

Interventions

DrugSynonymsArms
PonatinibIclusig, INCB84344Ponatinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
PonatinibExperimentalPhase 1: Ponatinib administered according to age-based cohort doses and formulations to determine the maximum tolerated dose and recommended Phase 2 dose. Phase 2: Ponatinib administered at the recommended Phase 2 dose.
  • Ponatinib

Eligibility Criteria

        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.
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Number of dose-limiting toxicities
Time Frame:28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Incyte Biosciences International Sàrl

Trial Keywords

  • Leukemia
  • Solid tumors
  • Pediatric
  • Tyrosine kinase inhibitor

Last Updated

May 5, 2020