A Phase 1 Study of Oprozomib to Assess Food Effect, Drug-Drug Interaction With Midazolam, and Safety and Tolerability in Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Amgen
- 入组人数
- 43
- 试验地点
- 7
- 主要终点
- Food Effect/QTc - Cmax
研究概览
简要总结
The purpose of this Phase 1 of the study is to evaluate the effect of food on the pharmacokinetics (PK) of oprozomib, the drug-drug interaction of oprozomib with midazolam, and the safety and tolerability of oprozomib in patients with advanced 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
- •Histologically confirmed diagnosis of an advanced malignancy.
- •Relapsed after standard therapy for their malignancy, or if no standard therapy is defined, relapsed after investigational therapy and considered by the treating physician to be an appropriate candidate for a Phase 1 clinical study
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
- •Adequate hepatic function, with bilirubin ≤ 1.5 times the upper limit of normal (ULN) in the absence of Gilbert's disease or hemolysis, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times ULN.
- •Absolute neutrophil count (ANC) ≥ 1000/mm
- •Screening ANC must be independent of myeloid growth factor support for at least 1 week, or pegylated growth factors for 2 weeks.
- •Hemoglobin > 7g/dL. Patients may receive red blood cell (RBC) transfusions or erythropoietin or darbepoetin in accordance with institutional guidelines up to 1 week before screening.
- •Platelet count > 30,000 mm
- •Patients will not have received platelet transfusions for at least 1 week before screening.
- •Uric acid, if elevated, must be lowered to less than the ULN.
- •Calculated or measured creatinine clearance (CrCl) ≥ 30 mL/min calculated using the formula of Cockcroft and Gault [(140 - age) × mass (kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female.
排除标准
- •Recovered (i.e., ≤ Grade 1 toxicity or patient's baseline status) from the reversible nonhematologic effects of prior anticancer therapy, excluding alopecia.
- •Systemic chemotherapy with approved or investigational anticancer therapeutics, including steroid therapy intended to treat underlying malignancy, within 3 weeks before the first oprozomib dose; for antibody therapy, a minimum of 3 half-lives must elapse before the first oprozomib dose.
- •Radiation therapy within 3 weeks before first oprozomib dose. Radioimmunotherapy within 8 weeks before first oprozomib dose.
- •Autologous stem cell transplant (ASCT) within 8 weeks and allogeneic SCT within 16 weeks prior to initiation of study treatment. Patients with prior allogeneic SCT must not have evidence of moderate-to-severe graft-versus-host disease (as defined in Filipovich 2005).
- •Unresolved toxicity (NCI-CTCAE version 4.03) ≥ Grade 2 from previous anticancer therapy, except alopecia.
- •Major surgery within 3 weeks before first oprozomib dose.
- •Congestive heart failure (New York Heart Association Class III to IV)
- •Symptomatic cardiac ischemia.
- •Conduction abnormalities uncontrolled by conventional intervention, including but not limited to persistent or permanent atrial fibrillation.
- •History of ventricular fibrillation or ventricular tachycardia.
- •History of torsade de pointe.
- •Myocardial infarction within 6 months before first dose.
- •Abnormal measurements on 12-lead ECG.
- •Uncontrolled diabetes mellitus or hypertension
- •Dysphagia or inability to swallow tablets.
- •Insufficiency of the exocrine pancreas, steatorrhea, or other disorders of the digestive system that impair absorption.
- •Resection of any portion of the stomach or intestines, with the exception of appendectomy.
- •History of bariatric surgery, except in cases where no bowel was resected and all devices have been removed.
- •Active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks before first dose, unless cultures or polymerase chain reaction (PCR) have been negative for 14 days.
- •Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive, or suspected hepatitis C infection.
- •Primary malignancy of the central nervous system.
- •Patient has symptomatic brain metastasis. Patients with brain metastases must have stable neurologic status following surgery or radiation for at least 2 weeks after completion of the definitive therapy, AND be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
- •Significant peripheral neuropathy (Grade 2 with pain or ≥ Grade 3).
- •Systemic treatment with strong inhibitors of P-glycoprotein ([P-gp]; i.e., itraconazole, ketoconazole) within 14 days before the first dose of oprozomib.
- •Patients must not have used any potent CYP3A4 inhibitors (i.e., ketoconazole) within 7 days prior to enrollment, or any potent CYP3A4 inducers (i.e., rifampin) within 14 days prior to enrollment.
研究组 & 干预措施
Part I: Food Effect/QTc
Subjects will receive a single dose of oprozomib 270 mg in 1 of 3 fasting/fed conditions:
- Diet A: Fasted conditions
- Diet B: A low-fat breakfast. A low-fat breakfast is defined as having a total caloric value of less than 400 calories, with less than 20% from fat
- Diet C: A high-fat breakfast. A high-fat breakfast is defined as having a total caloric value of 800 to 1000 calories, with approximately 50% from fat
干预措施: Oprozomib (Drug)
Part II: Drug-Drug Interaction (DDI)
- Period 1: Midazolam 2 mg single oral dose on one day between Day -7 and -4
- Period 2: Midazolam 2 mg single oral dose 1 hour following oprozomib dose on Day 1 of Cycle 1 and Day 2 of Cycle 2. Oprozomib 300 mg dose on Days 1, 2, 8 and 9 of Cycles 1 and Cycle 2
干预措施: Oprozomib (Drug)
Part II: Drug-Drug Interaction (DDI)
- Period 1: Midazolam 2 mg single oral dose on one day between Day -7 and -4
- Period 2: Midazolam 2 mg single oral dose 1 hour following oprozomib dose on Day 1 of Cycle 1 and Day 2 of Cycle 2. Oprozomib 300 mg dose on Days 1, 2, 8 and 9 of Cycles 1 and Cycle 2
干预措施: Midazolam (Drug)
Extension
After subjects complete the Food Effect/QTc or DDI part, subjects may participate in the extension part of the study, where oprozomib treatment will be continued on Days 1, 2, 8, and 9 of each 14-day cycle. During this part of the study, it is recommended that oprozomib be taken with food.
干预措施: Oprozomib (Drug)
结局指标
主要结局
Food Effect/QTc - Cmax
时间窗: Approximately 5 days or up to 2 weeks
Pharmacokinetics (PK) parameter Cmax (maximum plasma concentration of oprozomib) between each diet (oprozomib under fasting versus low-fat, and fasting versus high-fat conditions).
Food Effect/QTc - AUC
时间窗: Approximately 5 days or up to 2 weeks
Pharmacokinetics (PK) parameter AUC (area under the concentration-time curve from time zero to the last measurable time point \[AUC0-t\], area under the concentration-time curve from time zero to infinity \[AUC0-inf\]) of oprozomib between each diet (oprozomib under fasting versus low-fat, and fasting versus high-fat conditions).
Food Effect - tmax and t1/2
时间窗: Approximately 5 days or up to 2 weeks
Pharmacokinetics (PK) parameters tmax (time to reach maximum plasma concentration) and t1/2 (terminal half-life) between each diet (oprozomib under fasting versus low-fat, and fasting versus high-fat conditions).
Food Effect - QT/QTc interval
时间窗: Approximately 5 days or up to 2 weeks
QT/QTc interval will be extracted from continuous ECGs performed during each period in the Food Effect/QTc part of the study: * Twelve (12)-lead ECGs will be serially recorded digitally and read centrally * The RR, PR and QT intervals and QRS duration will be analyzed * QTc will be calculated using Bazett's and Fridericia's formulas
Drug-Drug Interaction (DDI) - Cmax
时间窗: Approximately 1 month
Pharmacokinetics (PK) parameter Cmax (maximum plasma concentration) of midazolam, in the presence and absence of oprozomib.
Drug-Drug Interaction (DDI) - AUC
时间窗: Approximately 1 month
Pharmacokinetics (PK) parameter AUC (area under the concentration-time curve from time zero to the last measurable time point \[AUC0-t\], area under the concentration-time curve from time zero to infinity \[AUC0-inf\]) of midazolam, in the presence and absence of oprozomib.
次要结局
- Adverse Events (AEs) and Serious Adverse Events (SAEs)(Approximately 18 months)