Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias, Lymphomas or Solid Tumors
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT03934372 |
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Recruitment Status :
Recruiting
First Posted : May 1, 2019
Last Update Posted : May 15, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| 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 | Drug: Ponatinib | Phase 1 Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 60 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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, Lymphomas or Solid Tumors in Pediatric Participants |
| Actual Study Start Date : | January 29, 2020 |
| Estimated Primary Completion Date : | December 7, 2024 |
| Estimated Study Completion Date : | January 4, 2025 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Ponatinib
Phase 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.
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Drug: Ponatinib
Ponatinib administered as a tablet or age-appropriate formulation for pediatric participants according to age-based cohort assignment.
Other Name: Iclusig, INCB84344 |
- 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 ]
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| Ages Eligible for Study: | 1 Year to 17 Years (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03934372
| Contact: Incyte Corporation Call Center (ex-US) | +800 00027423 | globalmedinfo@incyte.com |
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| Study Director: | Mohammed-El-Amine Bensmaine, MD | Incyte Biosciences International Sàrl |
| Responsible Party: | Incyte Biosciences International Sàrl |
| ClinicalTrials.gov Identifier: | NCT03934372 |
| Other Study ID Numbers: |
INCB 84344-102 |
| First Posted: | May 1, 2019 Key Record Dates |
| Last Update Posted: | May 15, 2023 |
| Last Verified: | May 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Leukemia Solid tumors Pediatric Tyrosine kinase inhibitor lymphomas |
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Ponatinib Lymphoma Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Chronic-Phase Leukemia, Myeloid, Accelerated Phase Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases |
Leukemia, Lymphoid Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Chronic Disease Disease Attributes Pathologic Processes Cell Transformation, Neoplastic Carcinogenesis Neoplastic Processes Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |