A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 449
- 试验地点
- 42
- 主要终点
- Percentage of BP-CML/Ph+ ALL Participants With MaHR
研究概览
简要总结
The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation.
详细描述
The preliminary analysis of the phase 1 clinical trial revealed evidence of clinical antitumor activity in patients with resistance to approved second-generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, including patients with the T315I mutation of the BCR-ABL gene (BCR-ABL). This Phase 1 study, taken together with the strong preclinical data that characterize ponatinib, provides the rationale for moving to a pivotal phase 2 trial of this agent in a population of patients with chronic myeloid leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL) who are resistant or intolerant to prior TKI therapy and in those patients with the T315I mutation.
PACE is a multi-center, international, phase 2, uncontrolled, open-label trial of oral ponatinib in patients with Philadelphia chromosome-positive (Ph+) disease. The study enrolled 449 patients. Participants assigned to 1 of 6 cohorts in accordance with disease group and received:
- Ponatinib 45 mg
This multi-center trial is conducted worldwide. The overall time to participate in this study is 96 months after last dose of study drug treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL
- •Previously treated with and developed resistance or intolerance to dasatinib or nilotinib OR developed the T3151 mutation after any tyrosine kinase inhibitor (TKI) therapy
- •≥18 years old
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- •Minimum life expectancy of ≥3 months
- •Adequate kidney function
- •Adequate liver function
- •Normal pancreatic function
- •Normal QT Fridericia-corrected interval (QTcF) ≤450 ms for males and ≤470 ms for females
- •Negative pregnancy test (if woman of childbearing potential)
- •Agree to use effective form of contraception (as applicable)
- •Ability to comply with study procedures, in the Investigator's opinion
排除标准
- •Received prior TKI treatment within 7 days prior to receiving the first dose of ponatinib, or have not recovered from adverse events (except alopecia) due to agents previously administered.
- •Received other therapies as follows:
- •For CML chronic phase (CP) and accelerated phase (AP) participants, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib; interferon, cytarabine, or immunotherapy within 14 days prior to first dose of ponatinib; or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.
- •For CML blast phase (BP) participants, received chemotherapy within 14 days prior to the first dose of ponatinib.
- •For Ph+ ALL participants, received corticosteroids within 24 hours before the first dose of ponatinib; or vincristine within 7 days prior to the first dose of ponatinib; or received other chemotherapy within 14 days prior to the first dose of ponatinib.
- •Underwent stem cell transplant <60 days prior to receiving first dose of ponatinib
- •Evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy
- •Taking medications that are known to be associated with Torsades de Pointes
- •Require concurrent treatment with immunosuppressive agents (other than corticosteroids prescribed for a short course of therapy)
- •Previously treated with ponatinib
- •CML CP participants are excluded if they are in Complete cytogenetic response (CCyR)
- •Participants with CML AP, CML BP, or Ph+ ALL are excluded if they are in Major Hematologic Response (MaHR).
- •Have active Central Nervous System (CNS) disease
- •Have significant or active cardiovascular disease
- •Have a significant bleeding disorder unrelated to CML or Ph+ALL
- •Have a history of pancreatitis or alcohol abuse
- •Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
- •Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of ponatinib
- •Diagnosed with another primary malignancy in the past 3 years
- •Pregnant or lactating
- •Underwent major surgery within 14 days prior to first dose of ponatinib
- •Have ongoing or active infection
- •Suffer from any other condition or illness that would compromise safety or interfere with evaluation of the drug
研究组 & 干预措施
Cohort A: CP-CML R-I
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
干预措施: Ponatinib (Drug)
Cohort B: CP-CML with T315I Mutation
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
干预措施: Ponatinib (Drug)
Cohort C: Accelerated Phase (AP)-CML R-I
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
干预措施: Ponatinib (Drug)
Cohort D: AP-CML with T315I Mutation
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
干预措施: Ponatinib (Drug)
Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
干预措施: Ponatinib (Drug)
Cohort F: BP-CML or Ph+ ALL with T315I Mutation
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
干预措施: Ponatinib (Drug)
Unassigned to Cohorts A-F
Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
干预措施: Ponatinib (Drug)
结局指标
主要结局
Percentage of BP-CML/Ph+ ALL Participants With MaHR
时间窗: Up to 6 months after initiation of study treatment
MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, ANC≥1000/mm\^3, platelets ≥100,000/mm\^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤ institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm\^3 ≤platelets\<100,000/mm\^3; (ii) 500/mm\^3≤ANC\<1000/mm\^3.
Percentage of AP-CML Participants With Major Hematologic Response (MaHR)
时间窗: Up to 6 months after initiation of study treatment
MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). Response criteria for CHR is reported as white blood cells (WBC)≤institutional upper limit of normal, absolute neutrophil count (ANC)≥1000/mm\^3, platelets≥100,000/mm\^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm\^3≤platelets\<100,000/mm\^3; (ii) 500/mm\^3≤ANC\<1000/mm\^3.
Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR)
时间窗: Up to 12 months after initiation of study treatment
MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.
次要结局
- Percentage of CP-CML Participants With CHR(Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose))
- Percentage of CP-CML Participants With Major Molecular Response (MMR)(Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose))
- Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR(Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose))
- Percentage of CP-CML Participants With Confirmed MCyR(Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose))
- Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR(Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose))
- Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)(From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months))
- Time to Response(Up to approximately 48 months after first dose)
- Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR(Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose))
- Duration of Response(Up to approximately 48 months after first dose)
- Progression-free Survival (PFS)(Every 12 weeks ± 2 weeks from last dose of study drug or the investigator/participant decision to discontinue treatment, whichever occurred later (Up to approximately 96 months after last dose))
- Overall Survival (OS)(From the first dose of study treatment until death (Up to 96 months post last dose))