A study evaluating the safety and efficacy of ponatinib for the treatment of recurrent or refractory leukemias or solid tumors in children

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Incyte Biosciences International S.a.r.l.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

22 Nov 2019 → ongoing

Decision date (initial)

2024-02-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Incyte Biosciences International Sàrl

External identifiers

EU CT number

2023-509699-41-00

EudraCT number

2018-004878-99

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Pharmacokinetic, Efficacy, Dose response, Pharmacogenetic, Therapy

Phase 1 Dose Escalation:
To determine the MTD and/or RP2D of oral ponatinib administered QD in pediatric participants with selected advanced hematologic malignancies or solid tumors.
Phase 2 Expansion:
Group A (CP-CML):
To determine the efficacy of oral ponatinib administered QD in pediatric participants with CP CML who are resistant or intolerant to at least 1 prior BCR-ABL–targeted TKI therapy or who have the T315I mutation.
Group B (Other Tumors):
To determine the efficacy of oral ponatinib administered QD in pediatric participants with other selected advanced hematologic malignancies or solid tumors.

Secondary objectives 2

1. Phase 1 Dose Escalation: To examine the safety and tolerability of ponatinib in pediatric participants with selected advanced hematologic malignancies or solid tumors. To evaluate preliminary anticancer activity of ponatinib in pediatric participants. Phase 2 Expansion Group A (CP-CML): To determine the antileukemia activity of ponatinib participants with CP-CML. To determine the cytogenetics and molecular response. Group B (Other Tumors): To determine anticancer activity of ponatinib in pediatric participants with selected advanced hematologic malignancies or solid tumors.
2. 2.Prior therapies as follows: a. Phase 1: Participants with CML who are resistant to or intolerant of 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. b. Phase 2, Group A with CP-CML: Participants who are resistant to or intolerant of at least 1 prior BCR ABL–targeted TKI therapy (exception for participants with T315I mutation) or are in warning status. c. 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. 3. Must have a parent or legal guardian able to comprehend and willing to sign a written ICF for the study and assent (when appropriate) according to local law, regulations, and institutional standards and to comply with all study visits and procedures. 4. Male and female participants ≥ 1 to < 18 years old, inclusive, at the time of signing the informed consent. 5. Karnofsky performance status ≥ 40% for participants ≥ 16 years old or Lansky Play Scale ≥ 40% for pediatric participants < 16 years old. 6. 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. 7. Willingness to avoid pregnancy or fathering children based on the criteria below. a. Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days (a spermatogenesis cycle) after the last dose of study treatment Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed. b. Female participants of childbearing potential must have a negative serum pregnancy test at screening and before the first dose of study treatment on Day 1 and must agree to take appropriate precautions to avoid pregnancy from screening through 6 months after the last dose of study treatment (permanent discontinuation) Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed. c. A female participant not considered to be of childbearing potential as defined in is eligible.

Conditions and MedDRA coding

Recurrent or Refractory Leukemias, Lymphomas, and Solid Tumors

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001186-PIP01-11

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Participants are eligible to be included in the study only if all of the following criteria apply: 1. Histologically or cytologically confirmed diagnosis of the following malignancies: a. 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. b. 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 have the T315I kinase domain mutation or be in ""warning"" response status. Warning response status must a) be confirmed by at least 2 assessments performed at least 1 month apart and b) justify the change of treatment by comorbidities and tolerability. 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. c. 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. d. 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. Note: Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. "
2. 2.Prior therapies as follows: a. Phase 1: Participants with CML who are resistant to or intolerant of 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. b. Phase 2, Group A with CP-CML: Participants who are resistant to or intolerant of at least 1 prior BCR ABL–targeted TKI therapy (exception for participants with T315I mutation) or are in warning status. c. 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. 3. Must have a parent or legal guardian able to comprehend and willing to sign a written ICF for the study and assent (when appropriate) according to local law, regulations, and institutional standards and to comply with all study visits and procedures. 4. Male and female participants ≥ 1 to < 18 years old, inclusive, at the time of signing the informed consent. 5. Karnofsky performance status ≥ 40% for participants ≥ 16 years old or Lansky Play Scale ≥ 40% for pediatric participants < 16 years old. 6. 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. 7. Willingness to avoid pregnancy or fathering children based on the criteria below. a. Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days (a spermatogenesis cycle) after the last dose of study treatment Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed. b. Female participants of childbearing potential must have a negative serum pregnancy test at screening and before the first dose of study treatment on Day 1 and must agree to take appropriate precautions to avoid pregnancy from screening through 6 months after the last dose of study treatment (permanent discontinuation) Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed. c. A female participant not considered to be of childbearing potential as defined in is eligible.

Exclusion criteria 1

1. Participants are excluded from the study if any of the following criteria apply: 1. Removed during Protocol Amendment 1. 2. Prior therapies: a. 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. b. 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. c. 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. For CNS, at least 90 days must have passed if the participant received prior total body irradiation or craniospinal or cranial radiotherapy. d. Autologous or allogeneic stem cell transplant < 3 months before the first dose of ponatinib. e. Major surgery within 14 days before the first dose of ponatinib. Note: Minor surgical procedures, such as central venous catheter placement or bone marrow aspirate/biopsy, are permitted. f. Inadequate recovery and/or complications from a major surgery before starting therapy. g. 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 first dose of ponatinib. Any biotherapeutic (including monoclonal antibody–directed) anticancer therapy within 5 half-lives or 30 days whichever is shorter, before the first dose of ponatinib. Note: Supportive care medications for CNS edema (eg, stable doses of corticosteroids or bevacizumab) are permitted. Any chimeric antigen receptor therapy within 28 days before the first dose of ponatinib.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Phase 1 Dose Escalation Determination of DLTs during the DLT evaluation period (first 28 days of treatment). Phase 2 Expansion Group A (CP-CML): MCyR, defined as CCyR or PCyR by 12 months, assessed by conventional cytogenetics or FISH.
2. Group B (Other Tumors): Hematologic malignancies: • BCR-ABL–positive leukemias (CML in AP or BP; Ph+ ALL): MaHR or MMR assessed by q-PCR by 3 months. • Other leukemias: CR, CRi, as assessed by conventional cytogenetics, FISH, or q-PCR. • Lymphoma: CR according to Lugano criteria (Cheson et al 2014) based on CT or MRI (or PET).
3. Solid tumors: • ORR, 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).

Secondary endpoints 7

1. − Phase 1 Dose Escalation: • Frequency and severity of AEs and SAEs. • Changes in vital signs and clinical evaluations. • Changes in clinical laboratory blood samples. • PK parameters: Tmax, AUCss,0-24, t½, CLss/F, Vz/F.
2. Phase 2 Expansion Group A (CP-CML): • CHR at 6 months. • CCyR at 12 months. • MMR at 12 months. • TTR, defined as the interval from the date of the first dose of study treatment to first response.
3. DOR, defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met. • PFS, defined as defined as the interval from the date of the first dose of study treatment until the date of progression of disease or death from any cause, whichever is earlier.
4. • OS, defined as the interval from the date of first dose of study treatment until death from any cause.
5. Group B (Other Tumors): Hematologic malignancies: BCR-ABL–positive leukemias (CML in AP or BP; Ph+ ALL): MaHR or MMR by 3 months. • Other leukemias: CR., CRi, as assessed by conventional cytogenetics, FISH, or q-PCR. • Lymphoma: CR according to Lugano criteria (Cheson et al 2014) based on CT or MRI (or PET).
6. Solid tumors: • ORR, 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). • OS, defined as the interval between the date of the first dose of study treatment until the date of death from any cause.
7. DOR, defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met. • PFS, defined as the interval from the date of the first dose of study treatment until the date of progression of disease or death from any cause, whichever is earlier.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Incyte Biosciences International S.a.r.l.

Sponsor organisation

Incyte Biosciences International S.a.r.l.

Address

Rue Docteur-Yersin 10

City

Morges

Postcode

1110

Country

Switzerland

Scientific contact point

Organisation

Incyte Biosciences International S.a.r.l.

Contact name

For Clinical Trials Information: [email protected]

Public contact point

Organisation

Incyte Biosciences International S.a.r.l.

Contact name

For Clinical Trials Information: [email protected]

Third parties 2

Locations

6 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 52 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications