PONATINIB for Chronic myeloid leukaemia (CML) | Acute lymphoblastic leukaemia (ALL) | Acute myeloid leukaemia (AML) | Lymphoma | Solid tumours (including CNS tumours)

Inclusion criteria

• {"criterion_text":"- Participants are eligible to be included in the study only if all of the following criteria apply: 1.\tHistologically or cytologically confirmed diagnosis of the following malignancies: a.\tPhase 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.\n- b.\tPhase 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.\n- c.\tPhase 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.\n- d.\tParticipants 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.\n- 2.Prior therapies as follows: a.\tPhase 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.\n- b.\tPhase 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.\n- c.\tPhase 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.\n- 3.\tMust 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.\n- 4.\tMale and female participants ≥ 1 to < 18 years old, inclusive, at the time of signing the informed consent.\n- 5.\tKarnofsky performance status ≥ 40% for participants ≥ 16 years old or Lansky Play Scale ≥ 40% for pediatric participants < 16 years old.\n- 6.\tParticipants 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.\n- 7.\tWillingness to avoid pregnancy or fathering children based on the criteria below. a.\tMale 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.\tFemale 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.\tA female participant not considered to be of childbearing potential as defined in is eligible."}

Exclusion criteria

• {"criterion_text":"- Participants are excluded from the study if any of the following criteria apply: 1.\tRemoved during Protocol Amendment 1.\n- 2.\tPrior therapies: a.\tParticipants 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.\n- Vincristine within 7 days before the first dose of ponatinib.\n- Other chemotherapy (excluding intrathecal chemotherapy) within 14 days before the first dose of ponatinib.\n- b.\tParticipants (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.\n- c.\tPrior 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.\n- d.\tAutologous or allogeneic stem cell transplant < 3 months before the first dose of ponatinib.\n- e.\tMajor surgery within 14 days before the first dose of ponatinib.\n- Note: Minor surgical procedures, such as central venous catheter placement or bone marrow aspirate/biopsy, are permitted.\n- f.\tInadequate recovery and/or complications from a major surgery before starting therapy.\n- g.\tPrior treatment with any of the following: Immunosuppressive therapy (including post stem cell transplant regimens) within 14 days before the first dose of ponatinib.\n- Any targeted cancer therapy (including TKIs) within 7 days before the first dose of ponatinib.\n- Any other investigational anticancer agents within 30 days or 5 half-lives, whichever is longer, before first dose of ponatinib.\n- Any biotherapeutic (including monoclonal antibody–directed) anticancer therapy within 5 half-lives or 30 days whichever is shorter, before the first dose of ponatinib.\n- Note: Supportive care medications for CNS edema (eg, stable doses of corticosteroids or bevacizumab) are permitted.\n- Any chimeric antigen receptor therapy within 28 days before the first dose of ponatinib."}

Primary endpoints

• {"endpoint_text":"- Phase 1 Dose Escalation Determination of DLTs during the DLT evaluation period (first 28 days of treatment).","definition_or_measurement_approach":"DLTs determined during the DLT evaluation period defined as the first 28 days of treatment."}
• {"endpoint_text":"- Phase 2 Expansion Group A (CP-CML): MCyR, defined as CCyR or PCyR by 12 months, assessed by conventional cytogenetics or FISH.","definition_or_measurement_approach":"MCyR = major cytogenetic response, defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) by 12 months; assessment by conventional cytogenetics or FISH."}
• {"endpoint_text":"- Group B (Other Tumors): Hematologic malignancies: •\tBCR-ABL–positive leukemias (CML in AP or BP; Ph+ ALL): MaHR or MMR assessed by q-PCR by 3 months. •\tOther leukemias: CR, CRi, as assessed by conventional cytogenetics, FISH, or q-PCR. •\tLymphoma: CR according to Lugano criteria (Cheson et al 2014) based on CT or MRI (or PET).","definition_or_measurement_approach":"Hematologic malignancies: BCR-ABL–positive leukemias—major haematologic response (MaHR) or major molecular response (MMR) assessed by q-PCR at 3 months; other leukemias—CR/CRi assessed by cytogenetics, FISH or qPCR; lymphoma—CR per Lugano criteria based on CT/MRI/PET."}
• {"endpoint_text":"- Solid tumors: •\tORR, 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).","definition_or_measurement_approach":"ORR = proportion with complete response (CR) or partial response (PR) determined by investigator radiographic assessment per RANO (CNS) or RECIST v1.1 (other solid tumours) using CT/MRI/PET."}

Secondary endpoints

• {"endpoint_text":"- − Phase 1 Dose Escalation: •\tFrequency and severity of AEs and SAEs. •\tChanges in vital signs and clinical evaluations. •\tChanges in clinical laboratory blood samples. • PK parameters: Tmax, AUCss,0-24, t½, CLss/F, Vz/F.","definition_or_measurement_approach":"Safety: frequency/severity of AEs/SAEs, vitals and clinical evaluations, lab changes; PK parameters measured include Tmax, AUCss(0-24), t½, CLss/F, Vz/F."}
• {"endpoint_text":"- Phase 2 Expansion Group A (CP-CML): •\tCHR at 6 months. •\tCCyR at 12 months. •\tMMR at 12 months. •\tTTR, defined as the interval from the date of the first dose of study treatment to first response.","definition_or_measurement_approach":"Efficacy endpoints: CHR at 6 months; CCyR and MMR at 12 months; TTR = time from first dose to first response."}
• {"endpoint_text":"- DOR, defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met. •\tPFS, 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.","definition_or_measurement_approach":"DOR = duration from first response assessment meeting response criteria until progression; PFS = time from first dose until disease progression or death."}
• {"endpoint_text":"- •\tOS, defined as the interval from the date of first dose of study treatment until death from any cause.","definition_or_measurement_approach":"OS = time from first dose until death from any cause."}
• {"endpoint_text":"- Group B (Other Tumors): Hematologic malignancies: BCR-ABL–positive leukemias (CML in AP or BP; Ph+ ALL): MaHR or MMR by 3 months. •\tOther leukemias: CR., CRi, as assessed by conventional cytogenetics, FISH, or q-PCR. •\tLymphoma: CR according to Lugano criteria (Cheson et al 2014) based on CT or MRI (or PET).","definition_or_measurement_approach":"Same as primary group B definitions: MaHR/MMR by 3 months for BCR-ABL–positive; CR/CRi for other leukemias by cytogenetics/FISH/qPCR; lymphoma CR per Lugano."}
• {"endpoint_text":"- Solid tumors: •\tORR, 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). •\tOS, defined as the interval between the date of the first dose of study treatment until the date of death from any cause.","definition_or_measurement_approach":"ORR by RANO/RECIST as above; OS measured from first dose to death."}
• {"endpoint_text":"- DOR, defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met. •\tPFS, 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.","definition_or_measurement_approach":"DOR and PFS definitions as above."}

Sweden

Earliest CTIS Part Ii Submission Date

09-01-2024

Latest Decision Or Authorization Date

25-11-2024

Processing Time Days

321

Number Of Sites

1

Number Of Participants

3

France

Earliest CTIS Part Ii Submission Date

09-01-2024

Latest Decision Or Authorization Date

27-11-2024

Processing Time Days

323

Number Of Sites

4

Number Of Participants

4

Netherlands

Earliest CTIS Part Ii Submission Date

09-01-2024

Latest Decision Or Authorization Date

02-12-2024

Processing Time Days

328

Number Of Sites

1

Number Of Participants

10

Belgium

Earliest CTIS Part Ii Submission Date

09-01-2024

Latest Decision Or Authorization Date

28-11-2024

Processing Time Days

324

Number Of Sites

1

Number Of Participants

10

Spain

Earliest CTIS Part Ii Submission Date

09-01-2024

Latest Decision Or Authorization Date

28-11-2024

Processing Time Days

324

Number Of Sites

4

Number Of Participants

10

Italy

Earliest CTIS Part Ii Submission Date

09-01-2024

Latest Decision Or Authorization Date

11-12-2024

Processing Time Days

337

Number Of Sites

9

Number Of Participants

20

Primary sponsor

Full Name

Incyte Biosciences International S.a.r.l.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Q2 Solutions LLC

Responsibilities

PK Analysis

Name

PPD Development LP

Responsibilities

Shipping biological materials, negotiating site contract agreements and other trial support responsibilities

Third parties

• {"country":"United States","full_name":"Q2 Solutions LLC","duties_or_roles":"PK Analysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Multiple sponsor duties including shipping biological materials and negotiating site contract agreements; other operational support roles listed in sponsor duties.","organisation_type":"Pharmaceutical company"}