A Multicenter, Open Label Phase I/II Study of Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Dose Limiting Toxicity (DLT)
研究概览
简要总结
This protocol is a phase I/II multicenter study designed to assess the safety and the efficacy of the proposed combinations as up-front treatment in elderly Multiple Myeloma (MM) patients.
详细描述
Treatment schedule for 9 cycles of induction:
Phase I:
In the phase I portion of the study, the following dose levels of carfilzomib will be studied with fixed doses of dexamethasone and cyclophosphamide to define the maximum tolerated dose (MTD):
Level-1:
- Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 36 mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 36 mg/m2 IV once daily on days 1-2, 8-9, 15-16.
- Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15
- Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9, 15-16, 22-23
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
- 65 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient is of a legally consenting age as defined by local regulations.
- •Patient is age ≥ 65 year of age or who are ineligible for autologous stem cell transplantation.
- •Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
- •Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
- •Women of childbearing potential must have a negative serum pregnancy test within the 7 days prior to study drug administration and a negative urine pregnancy test within the 3 days prior to the first study drug administration.
- •Women of childbearing potential and male subjects who are sexullay active with WOCBP must agree to use 2 highly effective methods of contraception during the study and for 30 days following the last dose of study treatment including a male condom.
- •Patient is a newly diagnosed MM patient.
- •Patient has measurable disease, defined as follows: any quantifiable serum monoclonal protein value (generally, but not necessarily, ≥ 0.5 g/dL of M-protein) and, where applicable, urine light-chain excretion of >200 mg/24 hours. For patients with oligo or non-secretory MM, it is required that they have measurable plasmacytoma > 2 cm as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan) or an abnormal free light chain ratio (n.v.: 0.26-1.65). We anticipate that less than 10% of patients admitted to this study will be oligo- or non-secretory MM with free light chains only in order to maximize interpretation of benefit results.
- •Patient has a Karnofsky performance status ≥60%.
- •Patient has a life-expectancy >3 months.
- •Patient has the following laboratory values within 14 days before Baseline (day 1 of the Cycle 1, before study drug administration):
- •Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to drug administration.
- •Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors.
- •Corrected serum calcium ≤14 mg/dL (3.5 mmol/L)
- •Alanine transaminase (ALT): ≤ 3 x the ULN.
- •Total bilirubin: ≤ 2 x the ULN.
- •Calculated or measured creatinine clearance: ≥ 15 mL/minute
- •LVEF ≥40%. 2D transthoracic ECHO is the preferred method of evaluation. Multigated Acquisition Scan is acceptable if ECHO is not available
排除标准
- •Patients with non-secretory MM, unless serum free light chains are present and the ratio is abnormal.
- •Women who are pregnant and/or breast feeding.
- •Patient has active infectious hepatitis type B or C or HIV.
- •Pulmonary Hypertension.
- •QTc Interval ≥ 450 msec.
- •Uncontrolled Atrial Fibrillation/Flutter.
- •History of Torsade de pointe, Ventricular Tachycardia, Ventricular Fibrillation.
- •Uncontrolled Infection.
- •Patients with myocardial infarction or unstable angina ≤ 4 months or other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
- •Patient with peripheral neuropathy > CTCAE grade
- •Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
- •Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
- •Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to baseline.
- •Patient has any other clinically significant illness that would, in the investigator's opinion, increase the patient's risk for toxicity.
- •Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix or breast, or localized prostate cancer of Gleason score <7 with a stable PSA).
研究组 & 干预措施
CCyd
Treatment schedule for 9 cycles of induction:
Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.
Carfilzomib given 20 mg/m2 IV once daily on Day 1-2 of Cycle 1 only followed by 36/45/56/70 mg/m2 on days 8-9, 15-16 of Cycle 1, then for all subsequent doses 36/45/56/70 mg/m2 IV once daily on days 1-2, 8-9, 15-16, followed by 12-day rest period (day 17 through 28).
Treatment schedule for maintenance until progression or intolerance:
Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.
干预措施: Carfilzomib (Drug)
CCyd
Treatment schedule for 9 cycles of induction:
Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.
Carfilzomib given 20 mg/m2 IV once daily on Day 1-2 of Cycle 1 only followed by 36/45/56/70 mg/m2 on days 8-9, 15-16 of Cycle 1, then for all subsequent doses 36/45/56/70 mg/m2 IV once daily on days 1-2, 8-9, 15-16, followed by 12-day rest period (day 17 through 28).
Treatment schedule for maintenance until progression or intolerance:
Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.
干预措施: Cyclophosphamide (Drug)
CCyd
Treatment schedule for 9 cycles of induction:
Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.
Carfilzomib given 20 mg/m2 IV once daily on Day 1-2 of Cycle 1 only followed by 36/45/56/70 mg/m2 on days 8-9, 15-16 of Cycle 1, then for all subsequent doses 36/45/56/70 mg/m2 IV once daily on days 1-2, 8-9, 15-16, followed by 12-day rest period (day 17 through 28).
Treatment schedule for maintenance until progression or intolerance:
Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Dose Limiting Toxicity (DLT)
时间窗: 1 year
Non-hematologic: * Grade 2 neuropathy with pain * any Grade 3 tox. (excluding nausea, vomiting, diarrhea) * Grade 3 nausea, vomiting, or diarrhea despite maximal antiemetic/antidiarrheal therapy * Grade 4 fatigue lasting for ≥ 7 days * Any non-hematologic tox. requiring a dose reduction within Cycle 1 * Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2. Hematologic: * Grade 4 neutropenia (ANC \< 0.5 x 109/L) lasting for ≥ 7 days * Febrile neutropenia (ANC \< 1.0 x 109/L with a fever ≥ 38.3ºC) * Grade 4 thrombocytopenia (platelets \< 25.0 x 109/L) lasting ≥ 7 days despite dose delay * Grade 3-4 thrombocytopenia associated with bleeding * Any hematologic tox. requiring a dose reduction within Cycle 1 * Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2.
次要结局
- Progression-free survival (PFS)(3 years)
- Duration of response (DOR)(3 years)
- Time to next therapy (TTNT)(3 years)
- Response and survival(3 years)
- Adverse event(1 years)
- Time to progression (TTP)(3 years)
- Overall survival (OS)(3 years)
- Responses(3 years)
- Maintenance(3 years)
- Response rate (RR)(3 years)