An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 149
- 主要终点
- Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs)
研究概览
简要总结
This is a phase 1, multicenter, nonrandomized, open-label, dose escalation study. The study will be conducted in 2 stages, Dose Escalation and Dose Expansion. The Dose Escalation phase will include participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies or for whom no approved therapy is available. The Dose Expansion phase will include participants with metastatic melanoma.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed consent.
- •Male or female participants 18 years or older.
- •Dose Escalation phase: Participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies of for whom no approved therapy is available.
- •Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma).
- •Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable.
- •For participants undergoing biopsy procedures: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be within the normal range.
- •Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=)
- •Adequate tissue sample from either archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or new biopsy of tumor.
- •Previous chemotherapy, immunotherapy, and hormone therapy must be completed at least 4 weeks prior to the administration of MLN2480 and radiation must be completed at least 3 weeks prior to the administration of MLN2480; all associated toxicity must be resolved to <=Grade
- •Expected survival time of at least 3 months in the opinion of the investigator.
- •Participants who do not have hypo- or hyperthyroidism.
- •Ability to swallow and retain oral medication.
- •Female participants who are postmenopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 3 months after the last dose of study drug or agree to practice true abstinence.
- •Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 3 months after the last dose of alisertib or agree to practice true abstinence.
- •Exclusion Criteria
- •History of any major disease that might interfere with safe protocol participation.
- •Dose Expansion phase: Previous treatment with RAF or MEK inhibitors.
- •Laboratory values as specified in study protocol.
- •Current enrollment in any other investigational treatment study.
- •Evidence of current uncontrolled cardiovascular conditions within the past 6 months.
- •Prior investigational agents for malignant or non-malignant disease within 4 weeks prior to Day
- •Active hepatitis or human immunodeficiency virus (HIV) infection.
- •Active bacterial or viral infection.
- •Female participants who are pregnant or currently breastfeeding.
- •Major surgery within 28 days of Day
- •Refractory nausea and vomiting, malabsorption, or significant bowel or stomach resection.
- •Inability to comply with study requirements.
- •Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.
排除标准
- 未提供
研究组 & 干预措施
MLN2480
干预措施: MLN2480 (Drug)
结局指标
主要结局
Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs)
时间窗: Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW])
Dose limiting AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose limiting AEs were defined as any of the following events: Grade 4 neutropenia for more than 7 days under maximum supportive therapy; febrile neutropenia; platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; if Course 2 was not initiated within 14 days due to AE related to the protocol treatment; Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (example, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.
Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings
时间窗: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Number of Participants With TEAEs Categorized Into Investigations Related to Laboratory Test of Chemistry, Hematology or Urinalysis
时间窗: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Eastern Cooperative Oncology Group (ECOG) Performance Score
时间窗: at EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
ECOG performance score was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1 (restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); 2 (ambulatory greater than(\>) 50 percent (%) of waking hours), capable of all self-care, unable to carry out any work activities); 3 (capable of only limited self-care, confined to bed or chair \>50% of waking hours); 4(completely disabled, cannot carry on any self-care, totally confined to bed or chair); 5 (dead). A higher score indicated greater functional impairment.
Number of Participants With TEAEs Related to Physical Examination Findings
时间窗: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV)
时间窗: Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths
时间窗: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
次要结局
- Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Tmax: Time to Reach the Cmax for TAK-580(Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days))
- Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, t1/2z: Terminal Phase Disposition Half-life for TAK-580(Escalation (Esc.) and Expansion (Exp.) Q2D: C1D21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D22 at multiple time-points (up to168 h) post-dose (C=28 days))
- Overall Response Rate (ORR)(Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase))
- Progression-free Survival (PFS)(Baseline up to the date of first document PD, or death due to any cause, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase))
- Q2D Dose Escalation Phase and Q2D Dose Expansion Pharmacokinetic Cohort, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for TAK-580(Cycle 1 Days 1 and 21 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 22 days))
- Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in RAF Inhibition Biomarkers at Specified Time Points(Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW]))
- Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Ctrough: Trough Concentration for TAK-580(Escalation and Expansion Q2D Cohorts: C1D21 pre-dose (C=22 days [Escalation Q2D] and 28 days [Expansion Q2D]); Escalation QW Cohorts: C1D22 pre-dose (C= 28 days))
- Duration of Response (DOR)(From the first documented response (CR or PR) up to the date of first documented PD (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase))
- Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-580(Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 hours [h]) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days))
- Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, CLr: Renal Clearance for TAK-580(Q2D Cohorts: Cycle1 Days 1 and 21 up to 24 hours post-dose (Cycle1 length= 22 days); QW Cohorts: Cycle2 Days 1 and 22 up to 7 hours post-dose (Cycle 2 length= 28 days))
- QW Dose Escalation Phase, AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for TAK-580(Cycle 1 Days 1 and 22 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days))
- Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in Apoptotic Biomarkers at Specified Time Points(Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW]))