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临床试验/NCT03934372
NCT03934372招募中1 期

An Open-Label, Single-Arm, Phase 1/2 Study Evaluating the Safety and Efficacy of Ponatinib for the Treatment of Recurrent or Refractory Leukemias, Lymphomas or Solid Tumors in Pediatric Participants

Incyte Biosciences International Sàrl45 个研究点 分布在 7 个国家目标入组 70 人开始时间: 2020年1月29日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
1 期
状态
招募中
入组人数
70
试验地点
45
主要终点
Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML)
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ponatinib in children aged 1 to < 18 years with advanced leukemias, lymphomas, and solid tumors.

研究设计

研究类型
Interventional
分配方式
Na
干预模型
Single Group
主要目的
Treatment
盲法
None

入排标准

年龄范围
1 Year 至 17 Years（Child）
性别
All
接受健康志愿者
否

入选标准

  • •Histologically or cytologically confirmed diagnosis of the following malignancies:
  • •- 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.
  • •- 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.
  • •- 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 as determined by site radiology.
  • •Prior therapies as follows:
  • •- Phase 1: Participants with CML who are resistant to or intolerant of (as defined Appendix F) 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.
  • •- Phase 2, Group A with CP-CML: Participants who are resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy.
  • •- 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.
  • •Karnofsky performance status ≥ 40% for participants ≥ 16 years old or Lansky Play Scale ≥ 40% for pediatric participants < 16 years old.
  • •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.
  • •Willingness to avoid pregnancy or fathering children.

排除标准

  • •Prior therapies:
  • •- 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.
  • •- 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.
  • •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.
  • •Autologous or allogeneic stem cell transplant < 3 months before the first dose of ponatinib.
  • •Major surgery within 14 days before the first dose of ponatinib. Inadequate recovery and/or complications from a major surgery before starting therapy.
  • •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
  • •Ponatinib
  • •Protocol-defined lab Values
  • •Significant concurrent, uncontrolled medical condition, including but not limited to the following:
  • •Pancreatic: clinical, radiological, or laboratory evidence of pancreatitis.
  • •SF < 27% by ECHO, OR EF < 50% by MUGA.
  • •Abnormal QTcF on screening ECG, defined as QTcF of ≥ 450 ms.
  • •Clinically significant or uncontrolled cardiovascular disease, including unstable angina, acute MI within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV CHF (see Appendix P), and arrhythmia requiring therapy unless approved by the medical monitor/sponsor.
  • •Uncontrolled hypertension.
  • •Currently taking drug(s) that are known to have a risk of causing prolonged QTc or TdP unless the drug(s) can be changed to acceptable alternatives (ie, an alternate class of agents that do not affect the cardiac conduction system), or the participant can safely discontinue the drug(s).
  • •Cerebral:
  • •Participants with solid tumors with intracranial metastasis OR participants with active CNS leukemia (ie, CNS-2 status [< 5/μL WBCs and cytospin positive for blasts, or ≥ 5 /μL WBCs but negative by Steinherz/Bleyer algorithm (equation used for traumatic lumbar punctures), disseminated leptomeningeal disease, or CNS chloroma.
  • •Pre-existing significant CNS pathology including history of severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder, or autoimmune disease with CNS involvement.
  • •History of cerebrovascular ischemia/hemorrhage with residual deficits.
  • •Note: Participants with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved clinically according to Inclusion Criterion
  • •Uncontrolled seizure disorder.
  • •Coagulation:
  • •Significant bleeding disorder or thrombophilia unrelated to the underlying malignancy indication for study participation.
  • •Gastrointestinal:
  • •Gastrointestinal disorders, such as malabsorption syndrome or any other illness that could affect oral absorption.
  • •Participants with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome.
  • •Participants with Down syndrome.
  • •Participants with any active ≥ Grade 2 graft versus host disease.
  • •Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
  • •Active HBV or HCV infection that requires treatment or at risk for HBV reactivation. Hepatitis B virus DNA and HCV RNA must be undetectable upon testing. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive.
  • •Known HIV infection.
  • •Current use of prohibited medication (see Section 6.7.2).
  • •Known hypersensitivity or severe reaction to ponatinib or excipients of ponatinib.
  • •Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study.
  • •Inability or unlikeliness to comply with the dose schedule and study evaluations, in the opinion of the investigator.
  • •Females who are pregnant or lactating.
  • •Other exclusions may apply.

研究组 & 干预措施

Ponatinib

Experimental

Phase 1: Ponatinib administered according to age-based cohort doses and formulations to determine the maximum tolerated dose and recommended Phase 2 dose. Phase 2: Ponatinib administered at the recommended Phase 2 dose.

干预措施: Ponatinib (Drug)

结局指标

主要结局

Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML)

时间窗: 12 months

Defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) as assessed by conventional cytogenetics or fluorescence in situ hybridization (FISH).

Phase 2: Efficacy of ponatinib assessed by CR in participants with lymphoma

时间窗: 6 months

According to Lugano criteria based on computed tomography (CT) or magnetic resonance imaging (MRI) (or positron emission tomography \[PET\]).

Phase 1: Number of dose-limiting toxicities

时间窗: 28 days

Defined as the occurrence of any protocol-defined toxicities occurring after dosing and up to and including Day 28, except those toxicities with a clear alternative explanation.

Phase 2: Efficacy of ponatinib assessed by major hematologic response (MaHR) or major molecular response (MMR) in participants with BCR-ABL-positive leukemias

时间窗: 3 months

Assessed by polymerase chain reaction (PCR).

Phase 2: Efficacy of ponatinib assessed by complete response (CR) in participants with leukemias other than BCR-ABL-positive leukemias to determine the efficacy of ponatinib

时间窗: 6 months

Phase 2: Efficacy of ponatinib assessed by incomplete complete response (iCR) in participants with leukemias other than BCR-ABL-positive leukemias

时间窗: 6 months

Assessed by conventional cytogenetics, FISH, or PCR.

Phase 2: Efficacy of ponatinib assessed by overall response rate in participants with solid tumors

时间窗: 6 months

Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for central nervous system (CNS) tumors or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for other solid tumors based on CT or MRI (or PET).

次要结局

  • Phase 2: Anticancer activity of ponatinib assessed by MaHR or MMR in participants with BCR-ABL-positive leukemias (AP-CML, BP-CML or Ph+ALL)(3 months)
  • Phase 2: Anticancer activity of ponatinib assessed by CRi in participants with leukemias other than BCR-ABL-positive leukemias.(6 months)
  • Phase 1: t½ of ponatinib(6 months)
  • Phase 1: Vz/F of ponatinib(6 months)
  • Phase 1 and Phase 2: Duration of response (DOR) in participants with CP-CML(6 months)
  • Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML.(6 months)
  • Phase 1: CR in participants with lymphoma(6 months)
  • Phase 1: Overall response rate in participants with solid tumors(6 months)
  • Phase 1: Tmax of ponatinib(6 months)
  • Phase 1: MCyR in participants with BCR-ABL-positive leukemias(3 months)
  • Phase 1 and Phase 2: CCyR in participants with CP-CML(12 months)
  • Phase 2: Anticancer activity of ponatinib assessed by overall response rate in participants with solid tumors(6 months)
  • Phase 2: PFS in participants with solid tumors(6 months)
  • Phase 1: CLss/F of ponatinib(6 months)
  • Phase 1: MMR in participants with BCR-ABL-positive leukemias(3 months)
  • Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML(6 months)
  • Phase 1 and Phase 2: MMR in participants with CP-CML(12 months)
  • Phase 1 and Phase 2: Time to response (TTR) in participants with CP-CML(6 months)
  • Phase 1 and Phase 2: Overall survival (OS) in participants with CP-CML(6 months)
  • Phase 1: CRi in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML(6 months)
  • Phase 2: OS in participants with solid tumors(6 months)
  • Phase 1: Number of treatment-emergent adverse events(6 months)
  • Phase 1: AUCss,0-24 of ponatinib(6 months)
  • Phase 1 and Phase 2: Progression-free survival (PFS) in participants with CP-CML(6 months)
  • Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias(6 months)
  • Phase 2: Anticancer activity of ponatinib assessed by CR in participants with lymphoma(6 months)
  • Phase 2: DOR in participants with solid tumors(6 months)
  • Phase 2: Number of treatment-emergent adverse events(6 months)
  • Phase 2: Clearance of pediatric-friendly formulation of ponatinib(6 months)
  • Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib(6 months)
  • Phase 2: AUC of pediatric-friendly formulation of ponatinib(6 months)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (45)

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