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

Sponsor

Incyte Biosciences International Sàrl (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03934372

Collaborator

(none)

Enrollment

Locations

Arm

57.2

Anticipated Duration (Months)

2.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Ponatinib	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 or Solid Tumors in Pediatric Participants

Actual Study Start Date :

Jan 29, 2020

Anticipated Primary Completion Date :

Oct 8, 2024

Anticipated Study Completion Date :

Nov 5, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Phase 1: Number of dose-limiting toxicities [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.
Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML) [12 months]
Defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) as assessed by conventional cytogenetics or fluorescence in situ hybridization (FISH).
Phase 2: Efficacy of ponatinib assessed by major hematologic response (MaHR) or major molecular response (MMR) in participants with BCR-ABL-positive leukemias [3 months]
Assessed by polymerase chain reaction (PCR).
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 [6 months]
Assessed by conventional cytogenetics, FISH, or PCR.
Phase 2: Efficacy of ponatinib assessed by CR in participants with lymphoma [6 months]
According to Lugano criteria based on computed tomography (CT) or magnetic resonance imaging (MRI) (or positron emission tomography [PET]).
Phase 2: Efficacy of ponatinib assessed by overall response rate in participants with solid tumors [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 Measures

Phase 1: Number of treatment-emergent adverse events [6 months]
Phase 1: Tmax of ponatinib [6 months]
Time to maximum concentration.
Phase 1: AUCss,0-24 of ponatinib [6 months]
Area under the steady-state plasma or serum concentration-time curve from Hour 0 to 24.
Phase 1: t½ of ponatinib [6 months]
Apparent terminal-phase disposition half-life.
Phase 1: CLss/F of ponatinib [6 months]
Apparent oral dose clearance at steady state.
Phase 1: Vz/F of ponatinib [6 months]
Apparent oral dose volume of distribution.
Phase 1: MCyR in participants with BCR-ABL-positive leukemias [3 months]
Defined as CCyR or PCyR as assessed by conventional cytogenetics or FISH.
Phase 1: MMR in participants with BCR-ABL-positive leukemias [3 months]
Assessed by quantitative PCR (q-PCR).
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 [6 months]
Defined as the interval from the date of the first dose of study treatment to first response.
Phase 1 and Phase 2: Duration of response (DOR) in participants with CP-CML [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.
Phase 1 and Phase 2: Progression-free survival (PFS) in participants with CP-CML [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.
Phase 1 and Phase 2: Overall survival (OS) in participants with CP-CML [6 months]
Defined as the interval from the date of the first dose of study treatment until death from any cause.
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 [6 months]
Assessed by conventional cytogenetics, FISH, or q-PCR.
Phase 1: CR in participants with lymphoma [6 months]
According to Lugano criteria based on CT or MRI (or PET).
Phase 1: Overall response rate in participants with solid tumors [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).
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. [6 months]
Assessed by conventional cytogenetics, FISH, or PCR.
Phase 2: Anticancer activity of ponatinib assessed by CR in participants with lymphoma [6 months]
According to Lugano criteria based on CT or MRI (or PET).
Phase 2: Anticancer activity of ponatinib assessed by overall response rate in participants with solid tumors [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).
Phase 2: OS in participants with solid tumors [6 months]
Defined as the interval from the date of the first dose of study treatment until death from any cause.
Phase 2: DOR in participants with solid tumors [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.
Phase 2: PFS in participants with solid tumors [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.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of the following malignancies: CP-CML, blast phase chronic myeloid leukemia (BP-CML), accelerated phase chronic myeloid leukemia (AP-CML); acute lymphoblastic leukemia/acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); other leukemias; lymphoma; any other tumors, including tumors of the central nervous system (CNS), for which standard therapy is not available or is not indicated
Phase 1:
Participants with CML who are resistant to or intolerant to at least 1 prior BCR-ABL-targeted TKI therapy.
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 (CP-CML): Participants who are resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy.
Phase 2 (other leukemias or solid tumors):

Participants with ALL who have all available or indicated therapies, which must have included 1 prior BCR-ABL-targeted TKI therapy.

Participants with solid tumors (including tumors of the CNS) with mutations where ponatinib may have biological activity or lymphomas who progressed despite standard therapy or for whom no effective standard therapy is available or indicated.
Karnofsky performance status
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.

Exclusion Criteria:

Prior therapies:
Participants with BP-CML, ALL, or AML who have received corticosteroids or hydroxyurea within 24 hours before the first dose of ponatinib; vincristine within 7 days before the first dose of ponatinib; or 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 or radiotherapy within 21 days (or 42 days for nitrosoureas or mitomycin C) before the first dose of ponatinib.
Autologous or allogeneic stem cell transplant < 3 months before the first dose of ponatinib.
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.
Laboratory values at screening outside the protocol-defined ranges.
Significant concurrent, uncontrolled medical condition, including but not limited to protocol-defined pancreatic, cardiac, cerebral, coagulation, gastrointestinal, and genetic conditions.
Any active ≥ Grade 2 graft-versus-host disease.
Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment or at risk for HBV reactivation.
Known HIV infection.
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.
Females who are pregnant or lactating.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Ghent University Hospital	Ghent	Belgium	09000
2	The Finsen Centre National Hospital	Copenhagen	Denmark	02100
3	Hopital Robert Debre	Paris	France	75019
4	Armand Trousseau Hospital	Paris	France	75571
5	Centre Hospitalier Universitaire de Poitiers	Poitiers	France	86021
6	Chu de Rennes - Hospital Sud	Rennes	France	35700
7	Universitaetsklinikum Erlangen - Medizinische Klinik 5	Erlangen	Germany	91054
8	Universitatsklinikum Essen	Essen	Germany	45147
9	L AZIENDA OSPEDALIERO-UNIVERSITARIA DI BOLOGNA POLICLINICO S. ORSOLA ï¿½ MALPIGHI	Bologna	Italy	40138
10	Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia	Brescia	Italy	25123
11	Ospedale Pediatrico G. Gaslini	Genova	Italy	16147
12	Fondazione Irccs Istituto Nazionale Dei Tumori	Milan	Italy	20133
13	Ospedale San Gerardo - Asst Monza	Monza	Italy	20900
14	University of Milano Bicocca	Monza	Italy	20900
15	Comitato Di Bioetica Della Fondazione Irccs Policlinico San Matteo	Pavia	Italy	27100
16	Ospedale Pediatrico Bambino Gesu Irccs	Rome	Italy	00165
17	Azienda Ospedaliero Universitaria Citta Della Salute E Della Scienza	Torino	Italy	10126
18	Princess Maxima Center For Pediatric Oncology	Utrecht	Netherlands	03584
19	Hospital Sant Joan de Deu de Manresa	Barcelona	Spain	08035
20	Hospital Nino Jesus	Madrid	Spain	28009
21	Hospital Universitario de La Paz	Madrid	Spain	28046
22	Hospital Universitari I Politecnic La Fe	Valencia	Spain	46026
23	Karolinska Universitetssjukhuset Solna	Solna	Sweden	171 76
24	Karolinska University Hospital Solna	Stockholm	Sweden	14141
25	University Hospital Birmingham	Birmingham	United Kingdom	B15 2TH
26	Royal Hospital For Sick Children Yorkhill Glasgow	Glasgow	United Kingdom	G514TF
27	Alder Hey Childrens Nhs Foundation Trust	Liverpool	United Kingdom	L12 2AP
28	The Royal Marsden Nhs Foundation Trust - Sutton	Sutton	United Kingdom	SM2 5PT
29	The Royal Marsden NHS Foundation Trust	Sutton	United Kingdom	SW3 6JJ