Clinical trial NCT03934372: Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias, Lymphomas 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, Lymphomas or Solid Tumors in Pediatric Participants
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
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
Keywords: Leukemia
Solid tumors
Pediatric
Tyrosine kinase inhibitor
lymphomas
Lead sponsor: Incyte Corporation
Sponsor class: INDUSTRY
First posted: 2019-05-01
Enrollment: 60
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Number of dose-limiting toxicities
timeFrame: 28 days
measure: Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML)
timeFrame: 12 months
measure: Phase 2: Efficacy of ponatinib assessed by major hematologic response (MaHR) or major molecular response (MMR) in participants with BCR-ABL-positive leukemias
timeFrame: 3 months
measure: 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
timeFrame: 6 months
measure: Phase 2: Efficacy of ponatinib assessed by incomplete complete response (iCR) in participants with leukemias other than BCR-ABL-positive leukemias
timeFrame: 6 months
measure: Phase 2: Efficacy of ponatinib assessed by CR in participants with lymphoma
timeFrame: 6 months
measure: Phase 2: Efficacy of ponatinib assessed by overall response rate in participants with solid tumors
timeFrame: 6 months
Secondary outcomes:
measure: Phase 1: Number of treatment-emergent adverse events
timeFrame: 6 months
measure: Phase 1: Tmax of ponatinib
timeFrame: 6 months
measure: Phase 1: AUCss,0-24 of ponatinib
timeFrame: 6 months
measure: Phase 1: t½ of ponatinib
timeFrame: 6 months
measure: Phase 1: CLss/F of ponatinib
timeFrame: 6 months
measure: Phase 1: Vz/F of ponatinib
timeFrame: 6 months
measure: Phase 1: MCyR in participants with BCR-ABL-positive leukemias
timeFrame: 3 months
measure: Phase 1: MMR in participants with BCR-ABL-positive leukemias
timeFrame: 3 months
measure: Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML
timeFrame: 6 months
measure: Phase 1 and Phase 2: CCyR in participants with CP-CML
timeFrame: 12 months
measure: Phase 1 and Phase 2: MMR in participants with CP-CML
timeFrame: 12 months
measure: Phase 1 and Phase 2: Time to response (TTR) in participants with CP-CML
timeFrame: 6 months
measure: Phase 1 and Phase 2: Duration of response (DOR) in participants with CP-CML
timeFrame: 6 months
measure: Phase 1 and Phase 2: Progression-free survival (PFS) in participants with CP-CML
timeFrame: 6 months
measure: Phase 1 and Phase 2: Overall survival (OS) in participants with CP-CML
timeFrame: 6 months
measure: Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML.
timeFrame: 6 months
measure: Phase 1: CRi in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML
timeFrame: 6 months
measure: Phase 1: CR in participants with lymphoma
timeFrame: 6 months
measure: Phase 1: Overall response rate in participants with solid tumors
timeFrame: 6 months
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)
timeFrame: 3 months
measure: Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias
timeFrame: 6 months
measure: Phase 2: Anticancer activity of ponatinib assessed by CRi in participants with leukemias other than BCR-ABL-positive leukemias.
timeFrame: 6 months
measure: Phase 2: Anticancer activity of ponatinib assessed by CR in participants with lymphoma
timeFrame: 6 months
measure: Phase 2: Anticancer activity of ponatinib assessed by overall response rate in participants with solid tumors
timeFrame: 6 months
measure: Phase 2: OS in participants with solid tumors
timeFrame: 6 months
measure: Phase 2: DOR in participants with solid tumors
timeFrame: 6 months
measure: Phase 2: PFS in participants with solid tumors
timeFrame: 6 months
measure: Phase 2: Number of treatment-emergent adverse events
timeFrame: 6 months
measure: Phase 2: Clearance of pediatric-friendly formulation of ponatinib
timeFrame: 6 months
measure: Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib
timeFrame: 6 months
measure: Phase 2: AUC of pediatric-friendly formulation of ponatinib
timeFrame: 6 months
Other outcomes:
Locations:
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis (Uz) Leuven
city: Copenhagen
country: Denmark
facility: The Finsen Centre National Hospital
city: Paris
country: France
facility: Hopital Robert Debre
city: Paris
country: France
facility: Armand Trousseau Hospital
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
city: Rennes
country: France
facility: Chu de Rennes - Hospital Sud
city: Erlangen
country: Germany
facility: Universitaetsklinikum Erlangen - Medizinische Klinik 5
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Bologna
country: Italy
facility: Aou Policlinico S. Orsola-Malpighi
city: Brescia
country: Italy
facility: Asst Degli Spedali Civili Di Brescia
city: Genova
country: Italy
facility: Ospedale Pediatrico G. Gaslini
city: Milan
country: Italy
facility: Comitato Etico Fondazione Irccs Istituto Nazionale Dei Tumori Milano
city: Monza
country: Italy
facility: Ospedale San Gerardo - Asst Monza
city: Monza
country: Italy
facility: University of Milano Bicocca
city: Naples
country: Italy
facility: Aorn Santobono Pausilipon
city: Pavia
country: Italy
facility: Comitato Di Bioetica Della Fondazione Irccs Policlinico San Matteo
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesu Irccs
city: Torino
country: Italy
facility: A.O.U Citta Della Salute E Della Scienza Di Torino Presidio Ospedaliero Infantile Regina Margherita
city: Utrecht
country: Netherlands
facility: Princess Maxima Center For Pediatric Oncology
city: Barcelona
country: Spain
facility: Hospital General Universitario Vall D Hebron
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu de Manresa
city: Madrid
country: Spain
facility: Hospital Infantil Unversitario Nino Jesus
city: Madrid
country: Spain
facility: Hospital Universitario de La Paz
city: Valencia
country: Spain
facility: Hospital Universitari I Politecnic La Fe
city: Solna
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Solna
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
city: Glasgow
country: United Kingdom
facility: Royal Hospital For Sick Children Yorkhill Glasgow
city: Liverpool
country: United Kingdom
facility: Alder Hey Childrens Nhs Foundation Trust
city: Sutton
country: United Kingdom
facility: The Royal Marsden Nhs Foundation Trust - Sutton
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Incyte Biosciences International Sàrl
name: Mohammed-El-Amine Bensmaine, MD
role: STUDY_DIRECTOR
References: