| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or Refractory Leukemias and Solid Tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent or Refractory Leukemias and Solid Tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000830 |
| E.1.2 | Term | Acute leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009013 |
| E.1.2 | Term | Chronic myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028549 |
| E.1.2 | Term | Myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028553 |
| E.1.2 | Term | Myeloid leukaemia, chronic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028552 |
| E.1.2 | Term | Myeloid leukaemia, acute |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10027655 |
| E.1.2 | Term | Miscellaneous and site unspecified neoplasms malignant and unspecified |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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
|
|
| E.5 End points |
| E.5.1 | 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, 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.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 Dose Escalation:
first 28 days
Phase 2 Expansion:
by 3 months, by 12 months, |
|
| E.5.2 | 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 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 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial 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.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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