A Phase 1 Dose Escalation Study of MLN8237, an Aurora A Kinase Inhibitor, in Adult Patients With Nonhematological Malignancies, Followed by a Phase 2 of MLN8237 in Lung, Breast, Head and Neck, or Gastroesophageal Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 273
- 主要终点
- Phase 2: Percentage of Participants With Objective Response
研究概览
简要总结
This is an open-label, multicenter study with a phase 1 dose escalation portion and a 2-stage, phase 2 portion, investigating MLN8237 (alisertib) in patients with advanced nonhematological malignancies.
详细描述
Following the determination of the Recommended Phase 2 Dose (RP2D) and schedule (Phase 1), 20 response-evaluable patients in each of the 5 tumor indications will be enrolled (Phase 2-Stage 1). An interim analysis will determine which tumor indications will proceed to enroll an additional 25 patients (Phase 2-Stage 2) to further evaluate Overall Response Rate (ORR) and other secondary endpoints.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Each patient must meet all of the following inclusion criteria to be enrolled in the study:
- •18 years or older
- •Histologically or cytologically confirmed metastatic and/or advanced solid tumor (Phase 1 only)
- •Phase 2 requires Non-small cell lung cancer (NSCLC); Small-cell lung cancer; Breast adenocarcinoma (female patients only); Squamous cell cancer of the head and neck (HNSCC); or Gastroesophageal adenocarcinoma
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
- •Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
- •Voluntary written consent
- •Wiling to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
- •Measurable disease (Phase 2 only)
排除标准
- •Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
- •Female patients who are pregnant or lactating
- •Serious medical or psychiatric illness that could interfere with protocol completion
- •Receipt of more than 2 previous cytotoxic chemotherapeutic regimens (4 previous regimens for breast cancer). There is no limit on the number of prior noncytotoxic therapies
- •Prior treatment with Aurora A-targeted agents, including MLN8237
- •Prior treatment with high-dose chemotherapy
- •Prior allogeneic bone marrow or other organ transplant
- •Antineoplastic therapy, radiation therapy or any experimental therapy 21 days prior to first dose of MLN8237
- •Symptomatic brain metastasis
- •Radiotherapy to greater than 25% of bone marrow
- •Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected
- •Myocardial infarction within 6 months of enrollment
- •Uncontrolled cardiovascular condition
- •Major surgery within 14 days of first dose of MLN8237
- •Active infection requiring systemic therapy, or other serious infection
- •Inability to swallow oral medication
- •Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
- •Patients requiring full systemic anticoagulation
- •History of uncontrolled sleep apnea syndrome
- •Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 and during the study
研究组 & 干预措施
MLN8237 (Alisertib)
MLN8237 administered as an enteric-coated tablet (ECT)
干预措施: MLN8237 (Alisertib) (Drug)
结局指标
主要结局
Phase 2: Percentage of Participants With Objective Response
时间窗: Baseline until complete response or partial response, assessed every 2 cycles up to end of study (up to 50 cycles)
Percentage of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than \[\<\] 10 millimeter \[mm\]). No new lesions. PR was defined as greater than or equal to (\>=) 30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: Phase 1: Cycle 1 Day 1 to Cycle 2 Day 21
Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. DLT defined as any of the following considered related to alisertib by investigator: Grade 4 neutropenia (absolute neutrophil count \<500 cells/cubic meter \[cells/mm\^3\]) for \>7 days; Grade 4 neutropenia with coincident fever; Grade 4 thrombocytopenia (platelets \<25,000 cells/mm3) for \>7 days; Platelet count \<10,000 cells/mm3; Grade 3 thrombocytopenia with clinically significant bleeding; Delay in initiation of the subsequent therapy cycle by \>7 days due to treatment-related toxicity; \>=Grade 3 nonhematological toxicity except \>=Grade 3 nausea/emesis occurred in the absence of optimal antiemetic therapy; \>=Grade 3 diarrhea occurred in the absence of optimal supportive therapy with loperamide/comparable antidiarrheal; Grade 3 fatigue for \<1 week; Other Grade 3 nonhematological toxicity that could be safely, reliably controlled to \<=Grade 2 with appropriate treatment.
次要结局
- Phase 1: Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib(Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose)
- Phase 1: Terminal Phase Elimination Half-life (T1/2) for Alisertib(Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose)
- Phase 1: Steady State Oral Clearance (CLss/F) for Alisertib(Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose)
- Phase 2: Progression-free Survival (PFS)(Baseline until progressive disease, assessed every 2 cycles up to end of study (up to 50 cycles))
- Phase 1: Peak to Trough Ratio for Alisertib(Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose)
- Phase 2: Time to Disease Progression (TTP)(Baseline until disease progression, assessed every 2 cycles up to end of study (up to 50 cycles))
- Phase 2: Relationship Between Clinical Response and Molecular Markers of Response(12 months)
- Phase 2: Number of Participants Reporting One or More Treatment-emergent Adverse Events and Serious Adverse Events(Baseline up to 30 days after the last dose of study drug)
- Phase 1: Rac- Accumulation Ratio for Alisertib(Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose)
- Phase 2: Duration of Response (DOR)(Baseline up to Week 50)
- Phase 1: Cmax- Maximum Observed Plasma Concentration for Alisertib(Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours post-dose)
- Phase 1: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib(Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose)