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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03934372
• Other study ID #: INCB 84344-102
• Status: Recruiting
• Phase: Phase 1/Phase 2
• 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
• 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.

Related Conditions & MeSH terms

• Accelerated Phase Chronic Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Acute Lymphocytic Leukemia
• Acute Myeloid Leukemia
• Blast Crisis
• Blast Phase Chronic Myeloid Leukemia
• Chronic Phase Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Chronic-Phase
• Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Solid Tumors

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