An Open-Label, Dose-Escalation, Phase 1 Study of IXAZOMIB (MLN9708), A Second-Generation Proteasome Inhibitor, in Adult Patients With Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 7
- 主要终点
- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
This study is an open-label, multicenter, phase 1, dose-escalation study of IXAZOMIB in adult patients with lymphoma. This study will be the first to administer IXAZOMIB to patients with lymphoma.
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
- •Male or female patients 18 years or older.
- •Eastern Cooperative Oncology Group performance status 0-
- •Patients must have a confirmed diagnosis of lymphoma that is relapsed and/or refractory after at least 2 prior chemotherapeutic regimens and for which no curative option exists. Patients with Waldenstrom's macroglobulinemia are not eligible for enrollment in this study. Patients with Hodgkin lymphoma are considered eligible for this study.
- •Suitable venous access for PK and pharmacodynamic evaluations.
- •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 to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
- •Voluntary written consent must be obtained.
- •Adequate blood and chemistry values during the screening period:
- •Absolute neutrophil count (ANC) ≥ 1,500/mm3; platelet count ≥ 100,000/mm
- •Total bilirubin must be ≤ 1.5 × the upper limit of the normal range upper limit of normal (ULN).
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be ≤ 2.5 × the upper limit of normal (ULN). AST and ALT may be elevated up to 5 times the upper limit of normal if their elevation can be reasonably ascribed to the presence of metastatic disease.
- •Calculated creatinine clearance ≥ 30 mL/minute.
排除标准
- •Peripheral neuropathy ≥ Grade
- •Female patients 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 > Grade 1 based on the NCI CTCAE categorization.
- •Systemic antineoplastic therapy/or radiotherapy within 21 days before the first dose of study treatment.
- •Systemic treatment with prohibited medications.
- •Patient has symptomatic brain metastases.
- •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.
研究组 & 干预措施
IXAZOMIB
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 Events (SAEs)
时间窗: Baseline up to 30 days after last dose of study drug
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
Number of Participants Reporting at Least 1 TEAE Related to Laboratory Assessments
时间窗: Baseline and Days 1, 8, and 15 of each treatment cycle (up to Cycle 45)
The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. Hematology, clinical chemistry and urinalysis were performed. TEAEs related to laboratory assessment observed at any time-points were reported under 3 system organ classes: blood and lymphatic system disorders, metabolism and nutrition disorders, and investigations.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
时间窗: Baseline and Days 1, 8, 15 of each treatment cycle up to 45 treatment cycles
Vital signs included body temperature, weight, systolic and diastolic blood pressure and heart rate.
Maximum Tolerated Dose (MTD)
时间窗: Treatment Cycle 1
The MTD was defined as the highest dose of ixazomib that generated dose limiting toxicity (DLT) during Cycle 1 in 0 of 3 or 1 of 6 participants. DLT defined as any of the following considered possibly related to therapy by investigator: Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cell per cubic millimeter \[cells/mm\^3\]) for \>7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for \>7 days; platelet count \<25,000 cells/mm\^3; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count \<10,000/mm\^3; Grade 2 peripheral neuropathy with pain or Grade 3 peripheral neuropathy; \>=Grade 3 nausea/emesis, diarrhea controlled by maximal supportive therapy; Grade 3 QTc prolongation\>500 millisecond (msec);any \>=Grade 3 nonhematologic toxicity except arthralgia/myalgia; \<1 week fatigue; delay in the initiation of the subsequent therapy cycle by \>=7 days ; other Grade 2 ixazomib-related nonhematologic toxicities requiring therapy discontinuation.
Recommended Phase 2 Dose (RP2D)
时间窗: Baseline up to Treatment Cycle 45
The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK), pharmacodynamic and preliminary efficacy data observed in Cycles 1 and 2 and beyond.
次要结局
- C0: Initial Plasma Concentration After Bolus Intravenous Administration(Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 336 hours postdose))
- AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib(Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose))
- Terminal Phase Elimination Half-life (T1/2) for Ixazomib(Cycle 1 Day 15: Predose and at multiple time points (up to 336 hours postdose))
- Rac: Accumulation Ratio for Ixazomib(Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose))
- Ae (0-4): Amount of Drug Excreted in Urine From 0 to 4 Hours Postdose(Cycle 1, Days 1 and 15: 0 to 4 hours postdose)
- Fe (0-4): Fraction of Dose Excreted Unchanged in Urine From 0 to 4 Hours Postdose(Cycle 1, Days 1 and 15: 0 to 4 hours postdose)
- CLr: Renal Clearance(Cycle 1, Days 1 and 15: 0 to 4 hours postdose)
- Emax: Maximum Observed Effect for Ixazomib(Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose))
- TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib(Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose))
- Overall Best Response(Baseline up to Cycle 45)