A Phase 1 Study of Oral IXAZOMIB (MLN9708) to Assess Relative Bioavailability, Food Effect, Drug-Drug Interaction With Ketoconazole, Clarithromycin or Rifampin; and Safety and Tolerability in Patients With Advanced Nonhematologic Malignancies or Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 112
- 主要终点
- Cmax: Maximum Observed Plasma Concentration for Ixazomib
研究概览
简要总结
This is an open-label, multicenter, sequential, 5-arm, phase 1 study of oral IXAZOMIB designed to assess drug-drug interaction with ketoconazole (Arm 1), the relative bioavailability of 2 capsule formulations of IXAZOMIB (Arm 2), food effect (Arm 3), drug-drug interaction with rifampin (Arm 4), and drug-drug interaction with clarithromycin (Arm 5) in participants with advanced nonhematologic malignancies or lymphoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 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 participants 18 years or older.
- •Participants must have a diagnosis of histologically or cytologically confirmed metastatic and/or advanced solid tumor malignancy or lymphoma for which no effective standard treatment is available.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or
- •Female participants who are postmenopausal at least 1 year, or surgically sterile, or if of childbearing potential, agree to practice 2 effective methods of contraception, at the same time from the time of signing the consent form through 90 days after the last dose of study drug, or agree to practice true abstinence.
- •Male participants, even if surgically sterilized, agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug or agree to practice true abstinence.
- •Voluntary written informed consent.
- •Clinical laboratory values as specified in protocol.
- •Suitable venous access.
- •Recovered (that is, less than [< ] Grade 1 toxicity or participant's baseline status) from the reversible effects of prior anticancer therapy.
排除标准
- •Peripheral neuropathy greater than (>) Grade 2 on clinical examination.
- •Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2, strong inhibitors of CYP3A, or strong CYP3A inducers or use of ginkgo biloba or St. John's wort within 14 days before the first dose of IXAZOMIB.
- •Participant has symptomatic brain metastasis. Participants 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.
- •Female participants who are pregnant or lactating.
- •Serious illness that could interfere with protocol completion.
- •Autologous stem cell transplant within 6 months before Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time.
- •Prior treatment with rituximab or other unconjugated any antibody treatment within 42 days (21 days if there is clear evidence of progressive disease or immediate treatment is mandated).
- •Ongoing treatment with corticosteroids.
- •Radiotherapy within 21 days before the first dose of study drug.
- •Major surgery within 14 days before the first dose of study drug.
- •Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to first dose of study drug.
- •Life-threatening illness unrelated to cancer.
- •Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive, or suspected hepatitis C infection.
- •Diagnosis or treatment of another malignancy within 2 years preceding first dose, or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
- •Evidence of uncontrolled cardiovascular conditions.
- •QTc > 500 milliseconds on a 12-lead electrocardiogram (ECG).
- •Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance of IXAZOMIB including difficulty swallowing capsules; diarrhea > Grade 1 despite supportive therapy.
- •Participants with gastric achlorhydria (Arm 1 only).
- •Participants who have used any nicotine containing products within 14 days before the first dose of study drug (Arm 1, Arm 4, and Arm 5).
- •Treatment with any investigational products or systemic antineoplastic therapies within 21 days before the first dose of IXAZOMIB.
- •Participants with known hypersensitivity to macrolide antibiotics (example, clarithromycin, erythromycin, azithromycin) or a history of jaundice/liver injury during prior exposure to clarithromycin (Arm 5 only).
研究组 & 干预措施
Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg
Ixazomib 2.5 milligram (mg), capsule B, orally, once on Day 1 and 15 along with ketoconazole 400 mg, tablets, orally, once daily from Day 12 to 25 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 2.5 mg (Drug)
Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg
Ixazomib 2.5 milligram (mg), capsule B, orally, once on Day 1 and 15 along with ketoconazole 400 mg, tablets, orally, once daily from Day 12 to 25 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 4 mg Capsule B (Drug)
Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg
Ixazomib 2.5 milligram (mg), capsule B, orally, once on Day 1 and 15 along with ketoconazole 400 mg, tablets, orally, once daily from Day 12 to 25 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ketoconazole (Drug)
Arm 2: Ixazomib 4 mg Capsule A or B
Ixazomib 4 mg, capsule A, orally, once on Day 1 followed by ixazomib 4 mg, capsule B once on Day 15 of Cycle 1 (28-day treatment cycle) or ixazomib 4 mg, capsule B, orally, once on Day 1 followed by ixazomib 4 mg, capsule A once on Day 15 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 4 mg Capsule A (Drug)
Arm 2: Ixazomib 4 mg Capsule A or B
Ixazomib 4 mg, capsule A, orally, once on Day 1 followed by ixazomib 4 mg, capsule B once on Day 15 of Cycle 1 (28-day treatment cycle) or ixazomib 4 mg, capsule B, orally, once on Day 1 followed by ixazomib 4 mg, capsule A once on Day 15 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 4 mg Capsule B (Drug)
Arm 3: Ixazomib 4 mg Fasted or Fed
Ixazomib 4 mg, capsule B, orally, under fasted state, once on Day 1 followed by ixazomib 4 mg, capsule B, orally, under fed state, once on Day 15 of Cycle 1 (28-day treatment cycle) or ixazomib 4 mg, capsule B, orally, under fed state, once on Day 1 followed by ixazomib 4 mg, capsule B, orally, under fasted state, once on Day 15 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 4 mg Capsule B (Drug)
Arm 4: Ixazomib 4 mg + Rifampin 600 mg
Ixazomib, 4 mg, capsule B, orally, once on Day 8 along with rifampin 600 mg, capsule, orally, once daily from Day 1 to 14 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Rifampin (Drug)
Arm 4: Ixazomib 4 mg + Rifampin 600 mg
Ixazomib, 4 mg, capsule B, orally, once on Day 8 along with rifampin 600 mg, capsule, orally, once daily from Day 1 to 14 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 4 mg Capsule B (Drug)
Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg
Ixazomib, 2.5 mg, capsule B, orally, once on Day 6 along with clarithromycin, 500 mg, tablet, orally, twice daily from Day 1 to 16 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 2.5 mg (Drug)
Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg
Ixazomib, 2.5 mg, capsule B, orally, once on Day 6 along with clarithromycin, 500 mg, tablet, orally, twice daily from Day 1 to 16 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Ixazomib 4 mg Capsule B (Drug)
Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg
Ixazomib, 2.5 mg, capsule B, orally, once on Day 6 along with clarithromycin, 500 mg, tablet, orally, twice daily from Day 1 to 16 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.
干预措施: Clarithromycin (Drug)
结局指标
主要结局
Cmax: Maximum Observed Plasma Concentration for Ixazomib
时间窗: Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hours[hrs])post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
时间窗: Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
时间窗: Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
次要结局
- Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities(Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45)
- Number of Participants With Clinically Significant Vital Sign Abnormalities(Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45)
- Percentage of Participants With Best Overall Response(Baseline up to end of treatment (approximately 1.9 years))
- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45))