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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03934372
Other study ID # INCB 84344-102
Secondary ID
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date January 29, 2020
Est. completion date January 4, 2025

Study information

Verified date February 2024
Source Incyte Corporation
Contact Incyte Corporation Call Center (ex-US)
Phone +800 00027423
Email globalmedinfo@incyte.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Recruitment information / eligibility

Status Recruiting
Enrollment 60
Est. completion date January 4, 2025
Est. primary completion date December 7, 2024
Accepts healthy volunteers No
Gender All
Age group 1 Year to 17 Years
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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Ponatinib
Ponatinib administered as a tablet or age-appropriate formulation for pediatric participants according to age-based cohort assignment.

Locations

Country Name City State
Belgium Ghent University Hospital Ghent
Belgium Universitair Ziekenhuis (Uz) Leuven Leuven
Denmark The Finsen Centre National Hospital Copenhagen
France Armand Trousseau Hospital Paris
France Hopital Robert Debre Paris
France Centre Hospitalier Universitaire de Poitiers Poitiers
France Chu de Rennes - Hospital Sud Rennes
Germany Universitaetsklinikum Erlangen - Medizinische Klinik 5 Erlangen
Germany Universitatsklinikum Essen Essen
Italy Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi Bologna
Italy Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia Brescia
Italy Ospedale Pediatrico G. Gaslini Genova
Italy Comitato Etico Fondazione Irccs Istituto Nazionale Dei Tumori Milano Milan
Italy Ospedale San Gerardo - Asst Monza Monza
Italy University of Milano Bicocca Monza
Italy Aorn Santobono Pausilipon Naples
Italy Comitato Di Bioetica Della Fondazione Irccs Policlinico San Matteo Pavia
Italy Ospedale Pediatrico Bambino Gesu Irccs Rome
Italy Azienda Ospedaliero Universitaria Citta Della Salute E Della Scienza Torino
Netherlands Princess Maxima Center For Pediatric Oncology Utrecht
Spain Hospital General Universitario Vall D Hebron Barcelona
Spain Hospital Sant Joan de Deu de Manresa Barcelona
Spain Hospital Infantil Unversitario Nino Jesus Madrid
Spain Hospital Universitario de La Paz Madrid
Spain Hospital Universitari I Politecnic La Fe Valencia
Sweden Karolinska Universitetssjukhuset Solna Solna
Sweden Karolinska University Hospital Solna Stockholm
United Kingdom University Hospital Birmingham Birmingham
United Kingdom Royal Hospital For Sick Children Yorkhill Glasgow Glasgow
United Kingdom Alder Hey Childrens Nhs Foundation Trust Liverpool
United Kingdom The Royal Marsden NHS Foundation Trust Sutton
United Kingdom The Royal Marsden Nhs Foundation Trust - Sutton Sutton

Sponsors (1)

Lead Sponsor Collaborator
Incyte Biosciences International Sàrl

Countries where clinical trial is conducted

Belgium,  Denmark,  France,  Germany,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Phase 1: Number of dose-limiting toxicities 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. 28 days
Primary Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML) Defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) as assessed by conventional cytogenetics or fluorescence in situ hybridization (FISH). 12 months
Primary Phase 2: Efficacy of ponatinib assessed by major hematologic response (MaHR) or major molecular response (MMR) in participants with BCR-ABL-positive leukemias Assessed by polymerase chain reaction (PCR). 3 months
Primary 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 6 months
Primary Phase 2: Efficacy of ponatinib assessed by incomplete complete response (iCR) in participants with leukemias other than BCR-ABL-positive leukemias Assessed by conventional cytogenetics, FISH, or PCR. 6 months
Primary Phase 2: Efficacy of ponatinib assessed by CR in participants with lymphoma According to Lugano criteria based on computed tomography (CT) or magnetic resonance imaging (MRI) (or positron emission tomography [PET]). 6 months
Primary Phase 2: Efficacy of ponatinib assessed by overall response rate in participants with solid tumors 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). 6 months
Secondary Phase 1: Number of treatment-emergent adverse events 6 months
Secondary Phase 1: Tmax of ponatinib Time to maximum concentration. 6 months
Secondary Phase 1: AUCss,0-24 of ponatinib Area under the steady-state plasma or serum concentration-time curve from Hour 0 to 24. 6 months
Secondary Phase 1: t½ of ponatinib Apparent terminal-phase disposition half-life. 6 months
Secondary Phase 1: CLss/F of ponatinib Apparent oral dose clearance at steady state. 6 months
Secondary Phase 1: Vz/F of ponatinib Apparent oral dose volume of distribution. 6 months
Secondary Phase 1: MCyR in participants with BCR-ABL-positive leukemias Defined as CCyR or PCyR as assessed by conventional cytogenetics or FISH. 3 months
Secondary Phase 1: MMR in participants with BCR-ABL-positive leukemias Assessed by quantitative PCR (q-PCR). 3 months
Secondary Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML 6 months
Secondary Phase 1 and Phase 2: CCyR in participants with CP-CML 12 months
Secondary Phase 1 and Phase 2: MMR in participants with CP-CML 12 months
Secondary Phase 1 and Phase 2: Time to response (TTR) in participants with CP-CML Defined as the interval from the date of the first dose of study treatment to first response. 6 months
Secondary Phase 1 and Phase 2: Duration of response (DOR) in participants with CP-CML Defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met. 6 months
Secondary Phase 1 and Phase 2: Progression-free survival (PFS) in participants with CP-CML 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. 6 months
Secondary Phase 1 and Phase 2: Overall survival (OS) in participants with CP-CML Defined as the interval from the date of the first dose of study treatment until death from any cause. 6 months
Secondary Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML. 6 months
Secondary Phase 1: CRi in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML Assessed by conventional cytogenetics, FISH, or q-PCR. 6 months
Secondary Phase 1: CR in participants with lymphoma According to Lugano criteria based on CT or MRI (or PET). 6 months
Secondary Phase 1: Overall response rate in participants with solid tumors 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). 6 months
Secondary 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) 3 months
Secondary Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias 6 months
Secondary Phase 2: Anticancer activity of ponatinib assessed by CRi in participants with leukemias other than BCR-ABL-positive leukemias. Assessed by conventional cytogenetics, FISH, or PCR. 6 months
Secondary Phase 2: Anticancer activity of ponatinib assessed by CR in participants with lymphoma According to Lugano criteria based on CT or MRI (or PET). 6 months
Secondary Phase 2: Anticancer activity of ponatinib assessed by overall response rate in participants with solid tumors 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). 6 months
Secondary Phase 2: OS in participants with solid tumors Defined as the interval from the date of the first dose of study treatment until death from any cause. 6 months
Secondary Phase 2: DOR in participants with solid tumors Defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met. 6 months
Secondary Phase 2: PFS in participants with solid tumors 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. 6 months
Secondary Phase 2: Number of treatment-emergent adverse events 6 months
Secondary Phase 2: Clearance of pediatric-friendly formulation of ponatinib 6 months
Secondary Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib 6 months
Secondary Phase 2: AUC of pediatric-friendly formulation of ponatinib 6 months
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