Recurrent or Refractory Leukemias and Solid Tumors MedDRA version: 21.0 Level: PT Classification code 10000830 Term: Acute leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10000880 Term: Acute myeloid leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10009013 Term: Chronic my
Conditions
Interventions
Trade Name: Iclusig 15 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ponatinib
CAS Number: 1114544-31-8
Current Sponsor code: INCB084344
Other descriptive name: P
Sponsors
Incyte Biosciences International Sàrl
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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. - 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 (Cheson et al 2014) 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. 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 (for 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 BCRABL–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 failed 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. Male and female participants = 1 to < 18 years old, inclusive, at the time of signing the informed consent. 4. Karnofsky performance status = 40% for participants = 16 years old or Lansky Play Scale = 40% for pediatric participants < 16 years old. Are the trial subjects under 18? yes Number of subjects for this age range: 85 F.1.2 Adults (18-64 years) no F.1.2.1 Numbe
Exclusion criteria
Exclusion criteria: Exclusion Criteria: '1. Participants with CP-CML who are in MCyR or better' 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 before or radioisotope 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 Objective: - 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 the PK properties of ponatinib in pediatric participants. . 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 cytogenetic and molecular response. Group B (Other Tumors): To determine anticancer activity of ponatinib in pediatric participants with selected advanced hematologic malignancies or solid tumors. Cohorts A and B: To examine the safety and tolerability of ponatinib in pediatric participants. To obtain PK data on participants dosed with a new pediatric-friendly formulation (when available).;Primary end point(s): - 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. 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, | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - 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. Hematologic malignancies: • BCR-ABL–positive leukemias (CML in AP or BP; Ph+ ALL): - MCyR by cytogenetics or FISH and MMR by q-PCR at 3 months. • 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. - DOR, defined as 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 the date of death from any cause, whichever is earlier. - OS, defined as the interval from the date of the first dose of study treatment until death from any cause. • Other leukemias: - CR. - CRi 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). 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). - 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. • DOR, defined as 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 first dose of study treatment until the date of progression of disease or death from any cause, whichever is earlier. • OS, defined as the interval from the first d | — |
Countries
Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom
Contacts
Public ContactClinical Trial Information
Incyte Corporation
Outcome results
None listed