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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT03934372

Studienbeginn:
Januar 2020

Letztes Update:
16.02.2024

Wirkstoff:
Ponatinib

Indikation (Clinical Trials):
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

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
-

Sponsor:
Incyte Biosciences International Sàrl

Collaborator:
-

Studienleiter

Mohammed-El-Amine Bensmaine, MD
Study Director
Incyte Biosciences International Sàrl

Kontakt

Incyte Corporation Call Center (ex-US)
Kontakt:
Phone: +800 00027423
E-Mail: globalmedinfo@incyte.com» Kontaktdaten anzeigen

Studienlocations
(3 von 32)

Universitaetsklinikum Erlangen - Medizinische Klinik 5
91054 Erlangen
(Bayern)
GermanyNoch nicht rekrutierend» Google-Maps
Universitatsklinikum Essen
45147 Essen
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
Universitair Ziekenhuis (Uz) Leuven
03000 Leuven
BelgiumNoch nicht rekrutierend» Google-Maps
The Finsen Centre National Hospital
02100 Copenhagen
DenmarkNoch nicht rekrutierend» Google-Maps
Centre Hospitalier Universitaire de Poitiers
86021 Poitiers
FranceRekrutierend» Google-Maps
Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi
40138 Bologna
ItalyRekrutierend» Google-Maps
Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
25123 Brescia
ItalyRekrutierend» Google-Maps
Comitato Etico Fondazione Irccs Istituto Nazionale Dei Tumori Milano
20133 Milan
ItalyRekrutierend» Google-Maps
Ospedale San Gerardo - Asst Monza
20900 Monza
ItalyNoch nicht rekrutierend» Google-Maps
Aorn Santobono Pausilipon
80122 Naples
ItalyNoch nicht rekrutierend» Google-Maps
Comitato Di Bioetica Della Fondazione Irccs Policlinico San Matteo
27100 Pavia
ItalyRekrutierend» Google-Maps
Ospedale Pediatrico Bambino Gesu Irccs
00165 Rome
ItalyRekrutierend» Google-Maps
Azienda Ospedaliero Universitaria Citta Della Salute E Della Scienza
10126 Torino
ItalyRekrutierend» Google-Maps
Princess Maxima Center For Pediatric Oncology
03584 Utrecht
NetherlandsRekrutierend» Google-Maps
Hospital General Universitario Vall D Hebron
08035 Barcelona
SpainRekrutierend» Google-Maps
Hospital Sant Joan de Deu de Manresa
08035 Barcelona
SpainRekrutierend» Google-Maps
Hospital Infantil Unversitario Nino Jesus
28009 Madrid
SpainRekrutierend» Google-Maps
Hospital Universitario de La Paz
28046 Madrid
SpainAbgeschlossen» Google-Maps
Hospital Universitari I Politecnic La Fe
46026 Valencia
SpainRekrutierend» Google-Maps
Karolinska Universitetssjukhuset Solna
171 76 Solna
SwedenNoch nicht rekrutierend» Google-Maps
Karolinska University Hospital Solna
14141 Stockholm
SwedenRekrutierend» Google-Maps
University Hospital Birmingham
B15 2TH Birmingham
United KingdomNoch nicht rekrutierend» Google-Maps
Royal Hospital For Sick Children Yorkhill Glasgow
G514TF Glasgow
United KingdomNoch nicht rekrutierend» Google-Maps
Alder Hey Childrens Nhs Foundation Trust
L12 2AP Liverpool
United KingdomNoch nicht rekrutierend» Google-Maps
The Royal Marsden Nhs Foundation Trust - Sutton
SM2 5PT Sutton
United KingdomRekrutierend» Google-Maps
The Royal Marsden NHS Foundation Trust
SW3 6JJ Sutton
United KingdomNoch nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. 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.

2. 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).

3. 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).

4. 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)

5. 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.

6. 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]).

7. 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).

Secondary outcome:

1. Phase 1: Number of treatment-emergent adverse events (Time Frame - 6 months)

2. Phase 1: Tmax of ponatinib (Time Frame - 6 months):
Time to maximum concentration.

3. 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.

4. Phase 1: t½ of ponatinib (Time Frame - 6 months):
Apparent terminal-phase disposition half-life.

5. Phase 1: CLss/F of ponatinib (Time Frame - 6 months):
Apparent oral dose clearance at steady state.

6. Phase 1: Vz/F of ponatinib (Time Frame - 6 months):
Apparent oral dose volume of distribution.

7. 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.

8. Phase 1: MMR in participants with BCR-ABL-positive leukemias (Time Frame - 3 months):
Assessed by quantitative PCR (q-PCR).

9. Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML (Time Frame - 6 months)

10. Phase 1 and Phase 2: CCyR in participants with CP-CML (Time Frame - 12 months)

11. Phase 1 and Phase 2: MMR in participants with CP-CML (Time Frame - 12 months)

12. 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.

13. 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.

14. 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.

15. 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.

16. Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML. (Time Frame - 6 months)

17. 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.

18. Phase 1: CR in participants with lymphoma (Time Frame - 6 months):
According to Lugano criteria based on CT or MRI (or PET).

19. 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).

20. 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)

21. Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias (Time Frame - 6 months)

22. 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.

23. 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).

24. 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).

25. 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.

26. 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.

27. 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.

28. Phase 2: Number of treatment-emergent adverse events (Time Frame - 6 months)

29. Phase 2: Clearance of pediatric-friendly formulation of ponatinib (Time Frame - 6 months)

30. Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib (Time Frame - 6 months)

31. Phase 2: AUC of pediatric-friendly formulation of ponatinib (Time Frame - 6 months)

Geprüfte Regime

  • Ponatinib (Iclusig, INCB84344):
    Ponatinib administered as a tablet or age-appropriate formulation for pediatric participants according to age-based cohort assignment.

Quelle: ClinicalTrials.gov


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