A Two-Part Phase 1/2 Study to Determine Safety, Tolerability, Pharmacokinetics, and Activity of K0706, a Novel Tyrosine Kinase Inhibitor (TKI), in Healthy Subjects and in Subjects With Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 124
- 试验地点
- 35
- 主要终点
- Examination of the Safety and Tolerability of Single Oral Doses of K0706
研究概览
简要总结
Phase 1/2 study to determine safety, tolerability, pharmacokinetics, and anti-leukemic activity of Vodobatinib (K0706) in treatment-refractory/intolerant CML
详细描述
Part A ( for Healthy volunteers) of the study is completed.
Part B dose-escalation study is completed. Recruitment in dose expansion is completed.
Part C study in subjects with treatment-resistant/intolerant CML is also completed.
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
盲法说明
Part B and C: Single arm (Open-label)
Part A: 2 arms: Investigational agent arm and Placebo arm (Double-blind).
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
- •Part A Inclusion Criteria:
- •Healthy males aged 18 to 55 years
- •Part B Key Inclusion Criteria:
- •Subjects diagnosed with Ph+ CML-CP, Ph+ CML-AP, Ph+ CML-BP, or Ph+ ALL who are refractory or intolerant to at least 3 TKIs or are not eligible (e.g.: due to comorbidities, hypersensitivity to excipients, lack of insurance coverage) for their local country's regulatory approved and medically appropriate TKIs (e.g., a TKI that is effective against mutations in the patient's tumor).
- •Part C Key Inclusion Criteria:
- •Subjects diagnosed with Ph+ CML-CP, Ph+ CML-AP, Ph+ CML-BP, who are resistant and/or intolerant to ≥ 3 prior TKIs one of which includes ponatinib (Subjects with Ph+ ALL are not included).
- •Part B and C: Other Inclusion Criteria
- •Willing and able to give written, and dated, informed consent
- •Male or female aged ≥ 18 years
- •Willing and able to comply with the scheduled visits
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
排除标准
- •Any major surgery, as determined by the Investigator, within 4 weeks of IMP administration
- •Inability to undergo venipuncture and/or tolerate venous access
- •Positive exclusion tests: HIV, hepatitis B surface antigen, or hepatitis C virus
- •Known or suspected history of significant drug abuse as judged by the Investigator
- •Part B and C Exclusion Criteria:
- •Presence of T315I
- •Any major surgery, as determined by the Investigator, within 4 weeks of IMP administration
- •Inability to undergo venipuncture and/or tolerate venous access
- •Positive exclusion tests: urine pregnancy tests (if applicable), HIV, hepatitis B surface antigen, or hepatitis C virus
- •Known or suspected history of significant drug abuse as judged by the Investigator
- •Received any other investigational agent within 30 days or a washout of at least 5 half-lives, whichever is longer of IMP administration
- •Subjects who are eligible for potentially curative therapy that is available, including hematopoietic stem cell transplant
- •Another primary malignancy within the past 3 years or earlier (except for adequately treated non-melanoma skin cancer or cervical cancer in situ
研究组 & 干预措施
Vodobatinib (K0706) capsules
干预措施: Vodobatinib (K0706) capsules (Drug)
结局指标
主要结局
Examination of the Safety and Tolerability of Single Oral Doses of K0706
时间窗: Approximately 56 ± 2 days
Number of Participants with Adverse Events in Part A
To Determine the Maximum Tolerated Dose (MTD) as Determined by Frequency of Dose Limiting Toxicities
时间窗: Dose Limiting toxicities observed over a 4 week period
PART B
Incidence and Severity of Treatment Emergent AEs (PART B)
时间窗: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)
Number of Participants with treatment emergent Adverse Events in Part B
For CML Subjects in CP at Study Entry
时间窗: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)
PART C: Proportion of subjects achieving Major Cytogenetic Response \[ defined as complete cytogenetic response (CCyR; 0% Ph+metaphases) or partial cytogenetic response (PCyR; 1-35% Ph+ metaphases)\] as assessed by conventional Karyotyping of Bone marrow aspirate
For CML Subjects in AP at Study Entry
时间窗: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)
PART C: Proportion of subjects achieving Major Hematologic Response \[ defined as complete hematologic response (CHR) or no evidence of leukemia (NEL)\] as assessed by complete blood count of peripheral blood sample
For CML Subjects in BP at Study Entry
时间窗: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)
PART C: Proportion of subjects achieving Major Hematologic Response \[defined as complete hematologic response (CHR) or no evidence of leukemia (NEL)\] as assessed by complete blood count of peripheral blood sample
次要结局
- To Characterize the Pharmacokinetics (Cmax) of K0706 After Single Oral Doses in Healthy Male Subjects(Approximately 28 ± 2 days)
- To Characterize the Pharmacokinetics of K0706 (Cmax) After Single Oral Doses in Fasted and Fed State in Healthy Male Subjects(Approximately 28 ± 2 days)
- Pharmacokinetic Profile of K0706 - Cmax [The Maximum (Peak) Observed Drug Concentration After Dose Administration](All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706))
- Pharmacokinetic Profile of Vodobatinib (K0706) - Tmax [The Time to Reach Maximum (Peak) Drug Concentration After Dose Administration](All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706))
- Pharmacokinetic Profile of Vodobatinib (K0706) - AUC[0-tau] (AUC Over the Dosing Interval of 0-24 Hours).(All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706))
- In Subjects With CML- CP:Proportion of Subjects Achieving Complete Hematological Response as Assessed by Complete Blood Count of Peripheral Blood Sample(All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706))
- In Subjects With CML- CP:Proportion of Subjects Achieving Complete Cytogenetic Response as Assessed by Conventional Karyotyping of Bone Marrow Aspirate(All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706))
- In Subjects With CML- CP:Proportion of Subjects Achieving Major Molecular Response as Assessed by BCR-ABL Transcript Levels (BCR-ABL1 Ratio of ≤ 0.1%) in Peripheral Blood Using PCR (Polymerase Chain Reaction)(All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706))
- In Subjects With CML-AP & BP: Proportion of Subjects Achieving Complete Cytogenetic Response as Assessed by Conventional Karyotyping of Bone Marrow Aspirate(All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706))
- In Subjects With CML-AP & BP: Proportion of Subjects Achieving Partial Cytogenetic Response (PCyR) as Assessed by Conventional Karyotyping of Bone Marrow Aspirate(All subjects will be followed up for 60 months from the first dose of K0706)
- In Subjects With CML-AP & BP: Proportion of Subjects Achieving Major Molecular Response as Assessed by BCR-ABL Transcript Levels (BCR-ABL1 Ratio of ≤ 0.1%) in Peripheral Blood Using PCR (Polymerase Chain Reaction)(All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706))
- Time to Major Cytogenetic Response (MCyR): Time to MCyR is the Time From First Dose to First MCyR (0-35% Ph+ Metaphases); Computed Only for CML-CP Subjects Who Achieved MCyR(All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706))
- Time to Major Molecular Response : Time to MMR is the Time From First Dose to First MMR (BCR-ABL1 Ratio of ≤ 0.1%) Computed Only for CML-CP Subjects Who Achieved MMR(All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706))
- In All Subjects Progression Free Survival (PFS)(All subjects will be followed up at 12, 24, 36 months from the first dose of K0706 and beyond, until intolerance, disease progression or subject withdrawal from the study.)
- In All Subjects Overall Survival (OS)(All subjects will be followed up at 12, 24, 36 months from the first dose of K0706 and beyond, until intolerance, disease progression or subject withdrawal from the study.)
- Incidence and Severity of Treatment Emergent AEs (PART C)(All subjects will be followed up for up to 60 months from the first dose of Vodobatinib (K0706), unless subject discontinues due to intolerance or progression of disease.)
- To Characterize the Pharmacokinetics (AUC(0-inf)) of K0706 After Single Oral Doses in Healthy Male Subjects(Approximately 28 ± 2 days)
- To Characterize the Pharmacokinetics of K0706 (AUC(0-inf)) After Single Oral Doses in Fasted and Fed State in Healthy Male Subjects(Approximately 28 ± 2 days)