A Phase I Study of the Safety and Pharmacokinetics of Escalating Intravenous Doses of the Proteasome Inhibitor PR-171 in Patients With Hematological Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 48
- 试验地点
- 5
- 主要终点
- Maximum Observed Plasma Concentration of Carfilzomib (Cmax)
研究概览
简要总结
The purpose of this study is to test the safety and tolerability of carfilzomib at different dose levels on hematological cancers such as multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's disease, or Waldenstrom's macroglobulinemia. Carfilzomib is a proteasome inhibitor, an enzyme responsible for degrading a wide variety of cellular proteins.
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
- •Written informed consent in accordance with federal, local, and institutional guidelines
- •Males and females ≥18 years of age
- •Histologically confirmed diagnosis of one of the hematologic malignancies below:
- •Multiple myeloma (MM)
- •Non-Hodgkin's lymphoma (NHL)
- •Waldenström's Macroglobulinemia (WM)
- •Hodgkin's disease (HD)
- •Subjects who are refractory or relapsed following at least two prior therapies
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
- •Adequate cardiovascular function without symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months
- •Adequate hepatic function, with bilirubin < 2.0 times the upper limit of normal, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of < 3.0 times the upper limit of normal
- •Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count (ANC) ≥ 1000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50,000/mm³
- •Screening ANC should be independent of granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks)
- •Subjects receiving supportive care including erythropoietin, darbepoetin and/or bisphosphonates can continue to do so, but must be transfusion independent; subjects receiving erythropoietic support must remain on the same dose for the first 28 days of study participation
- •An estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault
- •Serum creatinine ≤ 2.0 mg/dL
- •Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing
- •Female subjects of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test. Male subjects must use an effective barrier method of contraception throughout the study and for three months following the last dose if sexually active with a female of child-bearing potential.
排除标准
- •Female subjects who are pregnant or lactating
- •Subjects who are transfusion dependent
- •Subjects with NHL or HL who have received steroid therapy in the previous seven days
- •Subjects with MM or Waldenström's Macroglobulinemia who have received steroid therapy in the previous three weeks, except for MM subjects in the Carfilzomib + DEX Expansion Cohort, where previous treatment with dexamethasone will be allowed. The dose and schedule of administration of dexamethasone will be adjusted to that used in the protocol
- •Radiation, chemotherapy, or immunotherapy in the previous four weeks, or subjects who, in the judgment of the Investigator, have not recovered from the effects of previous therapy
- •For the Dose Escalation period, subjects who have received prior radioimmunotherapy with anti-cluster of differentiation (CD)20 monoclonal antibodies such as Bexxar® or Zevalin®; subjects treated with these products will be allowed in the Dose Expansion period
- •Subjects who have received allogeneic stem cell transplant therapy
- •Subjects with NHL or HL who have received autologous stem cell transplant therapy and have relapsed within 100 days of therapy
- •Rituxan therapy within three months before Day 1 unless there is evidence of disease progression
- •Major surgery within three weeks before Day 1
- •Congestive heart failure (CHF) (New York Heart Association class III to IV)
- •Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
- •Subjects who are known or suspected of having human immunodeficiency virus (HIV) infection or who are HIV seropositive
- •Active hepatitis A, B, or C infection; or positive for Hepatitis C ribonucleic acid (RNA) or hepatitis B antigen
- •Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer with stable prostate specific antigen (PSA) levels for three years
- •Subjects with treatment-related myelodysplastic disorder
- •Subjects with known brain metastasis (active central nervous system [CNS] disease only)
- •Serious psychiatric or medical conditions that could interfere with treatment
- •Participation in an investigational therapeutic study within one month prior to Day 1
- •Significant neurotoxicity (Grade 2 or higher with pain) at the time of study initiation
- •Concurrent therapy with approved or investigative anticancer therapeutics
- •Subjects with previous hypersensitivity to bortezomib injection
- •Subjects with contraindications to receiving allopurinol
- •Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment
- •Subjects with known or suspected amyloidosis
- •Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis
研究组 & 干预措施
CFZ 1.2 mg/m²
Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 2.4 mg/m²
Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 4.0 mg/m²
Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 6.0 mg/m²
Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 8.4 mg/m²
Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 11.0 mg/m²
Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 15.0 mg/m²
Participants received carfilzomib 115.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 20.0 mg/m²
Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 27.0 mg/m²
Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 20/27 mg/m²
Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles.
干预措施: Carfilzomib (Drug)
CFZ 20/27 mg/m² + DEX
Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
干预措施: Carfilzomib (Drug)
CFZ 20/27 mg/m² + DEX
Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Maximum Observed Plasma Concentration of Carfilzomib (Cmax)
时间窗: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
Number of Participants With Dose-limiting Toxicities (DLTs)
时间窗: 28 days
A DLT was defined as any of the following occurring in the first 28 days of study participation: Nonhematologic: * \> Grade 2 neuropathy with pain * ≥ Grade 3 nonhematologic toxicity (excluding nausea, vomiting, or diarrhea) * ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: * Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 10ˆ9/L) lasting ≥ 14 days without hematopoietic growth factor support * Febrile neutropenia (ANC \< 1.0 × 10ˆ9/L with a fever ≥ 38.3°C) * Grade 4 thrombocytopenia (platelets \< 25.0 × 10ˆ9/L) or thrombocytopenia associated with bleeding. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0.
Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax)
时间窗: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib
时间窗: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib
时间窗: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
次要结局
- Best Clinical Response to Treatment(From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.)
- Duration of Response(From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.)
- Time to Progression(From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.)
- Progression-free Survival(From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.)