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    Summary
    EudraCT Number:2018-004878-99
    Sponsor's Protocol Code Number:INCB84344-102
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2019-07-19
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2018-004878-99
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study evaluating the safety and efficacy of ponatinib for the treatment of recurrent or refractory leukemias or solid tumors in children
    A.4.1Sponsor's protocol code numberINCB84344-102
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/293/2018
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIncyte Biosciences International Sàrl
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIncyte Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIncyte Corporation
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address1801 Augustine Cut-Off
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post codeDE 19803
    B.5.3.4CountryUnited States
    B.5.4Telephone number13024986700
    B.5.5Fax number13024252734
    B.5.6E-mailRA@incyte.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Iclusig 15 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences Distribution B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/716 and EU/3/09/715
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNponatinib
    D.3.9.1CAS number 1114544-31-8
    D.3.9.2Current sponsor codeINCB084344
    D.3.9.3Other descriptive namePONATINIB HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB121686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/716 and EU/3/09/715
    D.3 Description of the IMP
    D.3.1Product nameponatinib 5 mg minitab capsule
    D.3.2Product code INCB084344
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNponatinib
    D.3.9.1CAS number 1114544-31-8
    D.3.9.2Current sponsor codeINCB084344
    D.3.9.3Other descriptive namePONATINIB HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB121686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Iclusig 30 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences Distribution B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/716 and EU/3/09/715
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNponatinib
    D.3.9.1CAS number 1114544-31-8
    D.3.9.2Current sponsor codeINCB084344
    D.3.9.3Other descriptive namePONATINIB HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB121686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Iclusig 45 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences Distribution B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/716 and EU/3/09/715
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNponatinib
    D.3.9.1CAS number 1114544-31-8
    D.3.9.2Current sponsor codeINCB084344
    D.3.9.3Other descriptive namePONATINIB HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB121686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/716 and EU/3/09/715
    D.3 Description of the IMP
    D.3.1Product nameponatinib 5 mg powder-filled capsule
    D.3.2Product code INCB084344
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNponatinib
    D.3.9.1CAS number 1114544-31-8
    D.3.9.2Current sponsor codeINCB084344
    D.3.9.3Other descriptive namePONATINIB HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB121686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/716 and EU/3/09/715
    D.3 Description of the IMP
    D.3.1Product nameponatinib 10 mg film coated Tablet
    D.3.2Product code INCB084344
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNponatinib
    D.3.9.1CAS number 1114544-31-8
    D.3.9.2Current sponsor codeINCB084344
    D.3.9.3Other descriptive namePONATINIB HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB121686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Recurrent or Refractory Leukemias, Lymphomas, and Solid Tumors
    E.1.1.1Medical condition in easily understood language
    Recurrent or Refractory Leukemias, Lymphomas, and Solid Tumors
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10000830
    E.1.2Term Acute leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10000880
    E.1.2Term Acute myeloid leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10009013
    E.1.2Term Chronic myeloid leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10028549
    E.1.2Term Myeloid leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10028553
    E.1.2Term Myeloid leukaemia, chronic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10028552
    E.1.2Term Myeloid leukaemia, acute
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level HLGT
    E.1.2Classification code 10027655
    E.1.2Term Miscellaneous and site unspecified neoplasms malignant and unspecified
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    - 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).
    E.2.3Trial contains a sub-study No
    E.3Principal 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 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.
    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 BCR-ABL–targeted TKI therapy.
    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. 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.
    E.4Principal 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 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.
    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 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
    E.5 End points
    E.5.1Primary 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, 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).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1 Dose Escalation: first 28 days
    Phase 2 Expansion: by 3 months, by 12 months,
    E.5.2Secondary end point(s)
    - Phase 1 Dose Escalation:
    • Frequency, duration, 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 dose of study treatment until death from any cause.

    Group B (Other Tumors):
    Hematologic malignancies:
    • BCR-ABL–positive leukemias (CML in AP or BP; Ph+ ALL):
    − MHR 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).
    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.
    • 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.

    - Cohorts A and B:
    • Frequency, duration, and severity of AEs and SAEs, including growth and development.
    • Changes in vital signs and clinical evaluations.
    • Changes in clinical laboratory blood samples.
    • Population PK model parameters (eg, clearance and volume of distribution) and exposure estimates (eg, AUC).
    E.5.2.1Timepoint(s) of evaluation of this end point
    During all study
    At 3, 6 and 12 months

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase 1/2 study
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the last visit for the last participant on study when participants are still on study at the time of the primary endpoint analysis and are continuing to receive study treatment until treatment withdrawal criteria are met.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days15
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 85
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 9
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 38
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 38
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 85
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Provisions will be made to ensure access to treatment for any remaining participants benefitting from treatment at time of cutoff.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-08-20
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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