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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Lymphoma; Acute Myeloid Leukemia; Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphocytic Leukemia; Solid Tumors; Chronic Phase Chronic Myeloid Leukemia; Accelerated Phase Chronic Myeloid Leukemia; Blast Phase Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Ponatinib

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Incyte Corporation Call Center (ex-US); Phone Number: +800 00027423; Email: globalmedinfo@incyte.com

Study Locations

• Belgium
  • Ghent, Belgium, 09000
    • Recruiting
    • Ghent University Hospital
• France
  • Paris, France, 75019
    • Recruiting
    • Hôpital Robert Debré
  • Paris, France, 75571
    • Recruiting
    • Armand Trousseau Hospital
  • Poitiers, France, 86021
    • Recruiting
    • Centre Hospitalier Universitaire De Poitiers
  • Rennes, France, 35700
    • Recruiting
    • Chu de Rennes - Hospital Sud
• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • Aou Policlinico S. Orsola-Malpighi
  • Brescia, Italy, 25123
    • Recruiting
    • Asst Degli Spedali Civili Di Brescia
  • Genova, Italy, 16147
    • Recruiting
    • Ospedale Pediatrico G. Gaslini
  • Milan, Italy, 20133
    • Recruiting
    • Comitato Etico Fondazione Irccs Istituto Nazionale Dei Tumori Milano
  • Monza, Italy, 20900
    • Recruiting
    • University of Milano Bicocca
  • Naples, Italy, 80122
    • Not yet recruiting
    • Aorn Santobono Pausilipon
  • Pavia, Italy, 27100
    • Recruiting
    • Comitato Di Bioetica Della Fondazione Irccs Policlinico San Matteo
  • Rome, Italy, 00165
    • Recruiting
    • Ospedale Pediatrico Bambino Gesù IRCCS
  • Torino, Italy, 10126
    • Recruiting
    • A.O.U Citta Della Salute E Della Scienza Di Torino Presidio Ospedaliero Infantile Regina Margherita
• Netherlands
  • Utrecht, Netherlands, 03584
    • Recruiting
    • Princess Máxima Center for Pediatric Oncology
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital General Universitario Vall D Hebron
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Sant Joan de Déu de Manresa
  • Madrid, Spain, 28009
    • Recruiting
    • Hospital Infantil Unversitario Nino Jesus
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitari i Politecnic La Fe
• Sweden
  • Stockholm, Sweden, 14141
    • Recruiting
    • Karolinska University Hospital Solna
• United Kingdom
  • Glasgow, United Kingdom, G514TF
    • Recruiting
    • Royal Hospital For Sick Children Yorkhill Glasgow
  • Liverpool, United Kingdom, L12 2AP
    • Recruiting
    • Alder Hey Childrens Nhs Foundation Trust
  • Sutton, United Kingdom, SM2 5PT
    • Recruiting
    • The Royal Marsden Nhs Foundation Trust - Sutton

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Ponatinib; Ponatinib administered as a tablet or age-appropriate formulation for pediatric participants according to age-based cohort assignment.; Other Names: Iclusig, INCB84344

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of treatment-emergent adverse events		6 months
Phase 1: Tmax of ponatinib	Time to maximum concentration.	6 months
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
Phase 1: t½ of ponatinib	Apparent terminal-phase disposition half-life.	6 months
Phase 1: CLss/F of ponatinib	Apparent oral dose clearance at steady state.	6 months
Phase 1: Vz/F of ponatinib	Apparent oral dose volume of distribution.	6 months
Phase 1: MCyR in participants with BCR-ABL-positive leukemias	Defined as CCyR or PCyR as assessed by conventional cytogenetics or FISH.	3 months
Phase 1: MMR in participants with BCR-ABL-positive leukemias	Assessed by quantitative PCR (q-PCR).	3 months
Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML		6 months
Phase 1 and Phase 2: CCyR in participants with CP-CML		12 months
Phase 1 and Phase 2: MMR in participants with CP-CML		12 months
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
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
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
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
Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML.		6 months
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
Phase 1: CR in participants with lymphoma	According to Lugano criteria based on CT or MRI (or PET).	6 months
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
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
Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias		6 months
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
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
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
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
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
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
Phase 2: Number of treatment-emergent adverse events		6 months
Phase 2: Clearance of pediatric-friendly formulation of ponatinib		6 months
Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib		6 months
Phase 2: AUC of pediatric-friendly formulation of ponatinib		6 months

Collaborators and Investigators

• Sponsor: Incyte Biosciences International Sàrl
• Investigators: Study Director: Mohammed-El-Amine Bensmaine, MD, Incyte Biosciences International Sàrl

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2020
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): February 1, 2028

Study Registration Dates

• First Submitted: April 29, 2019
• First Submitted That Met QC Criteria: April 29, 2019
• First Posted (Actual): May 1, 2019

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Solid tumors; Pediatric; Leukemia; Tyrosine kinase inhibitor; lymphomas
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Neoplastic Processes; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia, Lymphoid; Myeloproliferative Disorders; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Cell Transformation, Neoplastic; Carcinogenesis; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia; Leukemia, Myeloid, Acute; Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Blast Crisis; Leukemia, Myeloid, Chronic-Phase; Leukemia, Myeloid, Accelerated Phase; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; ponatinib
• Other Study ID Numbers: INCB 84344-102; 2018-004878-99 (EudraCT Number); 2023-509699-41-00 (Registry Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No