An Open-Label, Dose Escalation, Phase 1 Study of IXAZOMIB (MLN9708), a Second-Generation Proteasome Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 116
- 试验地点
- 7
- 主要终点
- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs)
研究概览
简要总结
This is an open-label, multicenter, phase 1, dose escalation study of IXAZOMIB. The primary purpose of this study is to determine the safety profile, establish the maximum tolerated dose, and inform the phase 2 dose of IXAZOMIB administered intravenously in participants with nonhematologic malignancies.
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
- •Each participant must meet all of the following inclusion criteria to be enrolled in the study:
- •Male or female participants 18 years or older.
- •Eastern Cooperative Oncology Group performance status 0-
- •A diagnosis of a nonhematologic malignancy for which standard treatment is no longer effective. In the expanded cohort, enrollment will be limited to participants with a diagnosis of NSCLC, H&N cancer (squamous cell cancer), STS, or PC.
- •Suitable venous access for pharmacokinetic (PK) and pharmacodynamic evaluations.
- •Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
- •Male participants who agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
- •Voluntary written consent must be obtained.
- •Adequate clinical laboratory values during the screening period.
- •In the escalation portion of the study, radiographically or clinically evaluable tumor was required, but measurable disease as defined by response evaluation criteria in solid tumors (RECIST) criteria was not required. In the MTD disease expansion cohorts and the TPEC, clinically measurable disease as defined by RECIST criteria was required for evaluation of NSCLC, H&N cancer, and STS. Prostate specific antigen (PSA) alone was acceptable for evaluation of PC.
- •For participants in the TPEC, tumor tissue that, in the opinion of the investigator, could have been safely biopsied using a core needle.
排除标准
- •Participants meeting any of the following exclusion criteria are not to be enrolled in the study:
- •Peripheral neuropathy greater than or equal to (>=) Grade
- •Female participants who are lactating or have a positive serum pregnancy test during the screening period.
- •Major surgery within 14 days before the first dose of treatment.
- •Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment.
- •Life-threatening illness unrelated to cancer.
- •Diarrhea greater than (>) Grade 1 based on the National Cancer Institute Common Terminology .Criteria for Adverse Events (NCI CTCAE) categorization.
- •Systemic antineoplastic therapy / or radiotherapy within 21 days before the first dose of study treatment.
- •Systemic treatment with prohibited medications.
- •Participant has symptomatic brain metastasis.
- •Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months.
- •QTc >470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period.
- •Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C positive.
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- •Treatment with any investigational products within 28 days before the first dose of study treatment.
- •For participants in the TPEC and participants in the MTD disease expansion cohorts who gave informed consent to undergo tumor biopsy, ongoing anticoagulant therapy (example, aspirin, clopidogrel [Plavix ®], warfarin, or heparin) that cannot be held to permit tumor biopsy .
- •Known allergy to boron or excipients.
研究组 & 干预措施
Part 1: Ixazomib 0.125 milligram per square meter (mg/m^2)
Ixazomib (MLN9708) 0.125 mg/m^2, injection, intravenously (IV), once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
干预措施: IXAZOMIB (Drug)
Part 1: Ixazomib 0.25 mg/m^2
Ixazomib (MLN9708) 0.25 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
干预措施: IXAZOMIB (Drug)
Part 1: Ixazomib 0.5 mg/m^2
Ixazomib (MLN9708) 0.5 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
干预措施: IXAZOMIB (Drug)
Part 1: Ixazomib 1 mg/m^2
Ixazomib (MLN9708) 1 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
干预措施: IXAZOMIB (Drug)
Part 1: Ixazomib 1.33 mg/m^2
Ixazomib (MLN9708) 1.33 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
干预措施: IXAZOMIB (Drug)
Part 1: Ixazomib 1.76 mg/m^2
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
干预措施: IXAZOMIB (Drug)
Part 1: Ixazomib 2.34 mg/m^2
Ixazomib (MLN9708) 2.34 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. Once the MTD will be established, participants with NSCLC, Head and Neck Cancer (H&N), Soft Tissue Sarcoma (STC) or Prostate Cancer (PC) will be included in MTD disease expanded cohort. An additional tumor pharmacodynamics expansion cohort (TPEC) will enroll participants with any type of solid tumor that can be biopsied for tissue analysis before and after treatment with ixazomib.
干预措施: IXAZOMIB (Drug)
Part 2:Ixazomib 1.76 mg/m^2-NSCLC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with NSCLC during Part 2 of the study.
干预措施: IXAZOMIB (Drug)
Part 2: Ixazomib 1.76 mg/m^2-H&N
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with H&N during Part 2 of the study.
干预措施: IXAZOMIB (Drug)
Part 2: Ixazomib 1.76 mg/m^2-STC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with STC during Part 2 of the study.
干预措施: IXAZOMIB (Drug)
Part 2: Ixazomib 1.76 mg/m^2-PC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with PC during Part 2 of the study.
干预措施: IXAZOMIB (Drug)
Part 2: Ixazomib 1.76 mg/m^2-TPEC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with various types of solid tumors suitable for biopsy in tumor pharmacodynamic expansion cohort (TPEC) during Part 2 of the study.
干预措施: IXAZOMIB (Drug)
结局指标
主要结局
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs)
时间窗: Part 1: Cycle 1 Day 1 up to Cycle 10 Day 41; Part 2: Cycle 1 Day 1 up to Cycle 12 Day 41
Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities
时间窗: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41)
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
时间窗: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41)
Vital sign measurements included diastolic and systolic blood pressure, heart rate, weight and oral temperature.
Part 1: Number of Participants With Dose Limiting Toxicity (DLT)
时间窗: Part 1: Cycle 1 Day 1 up to Cycle 1 Day 21
Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. DLT is any of following related to ixazomib:Grade (GR) 4 neutropenia (absolute neutrophil count\<500 cells/cubic meter\[cells/mm\^3\])for\>7 days; GR 3 neutropenia with coincident fever and/or infection; GR 4 thrombocytopenia (platelets \<25,000 cells/mm3)for\>7 days; GR 3 thrombocytopenia with clinically significant bleeding; Platelet count\<10,000 cells/mm3; GR 3 peripheral neuropathy;\>=GR 3 nausea/emesis in absence of optimal antiemetic therapy; \>=GR 3 diarrhoea in absence of optimal supportive therapy;GR 3 QTc prolongation noted on average of 3 electrocardiograms (ECGs);\>=GR 3 nonhematological toxicity except GR 3 arthralgia/myalgia or GR 3 fatigue for\<1 week; Delay in initiation of subsequent therapy cycle by\>7 days due to treatment-related toxicity Other\>=GR 2 nonhematological toxicity that opinion of investigator, requires discontinuation of therapy with Ixazomib.
次要结局
- Part 1: AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post-dose for Ixazomib(Part 1: Cycle 1 Days 1 and 11: pre-dose and at multiple time points (up to 72 hours) post-dose)
- 20S Proteasome Activity of Ixazomib in the Tumor Tissue(Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose)
- Expression of Biomarker (ATF-3) in Tumor Tissue(Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose)
- Part 1: C0: Initial Plasma Concentration After Bolus Intravenous Administration(Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose)
- Part 1: Rac: Accumulation Ratio for Ixazomib(Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose)
- Part 1: Terminal Phase Elimination Half-life (T1/2) for Ixazomib(Part 1: Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose)
- Part 1: E Max: Maximum Observed Effect for Ixazomib(Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose)
- Part 1: TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib(Part 1: Cycle 1 Days 1 and 11 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose)
- Number of Participants With Best Overall Response(Day 18 up to Day 21 of each cycle (Part 1: up to Cycle 10; Part 2: up to Cycle 12))
- Part 2: Ixazomib Concentration in Postdose Clinical Tumor Samples in Ixazomib 1.76 mg/m^2-TPEC(Cycle 1 Days 1 and 4: Predose and (from 4-20 hours) post-dose)