A Phase I/II Multicenter, Randomized, Open Label, Dose-Escalation Study To Determine The Maximum Tolerated Dose, Safety, And Efficacy Of CC-4047 Alone Or In Combination With Low-Dose Dexamethasone In Patients Wth Relapsed And Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide And Bortezomib
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 259
- 试验地点
- 19
- 主要终点
- Phase 2: Kaplan-Meier Estimates of Progression-free Survival (PFS) as of the 01 April 2011 Cut-off
研究概览
简要总结
The purpose of this study is to determine the maximum tolerated dose and effectiveness of the study drug (CC-4047) Alone Or in Combination With Low-dose Dexamethasone as treatment for patients with relapsed and refractory multiple myeloma
详细描述
The Phase 1 segment of the study was designed to determine the maximum tolerated dose (MTD) of single-agent pomalidomide, which was to be determined in the first cycle of treatment. Following completion of the first cycle, participants were allowed to continue the study at their assigned dose of pomalidomide.
Participants who developed progressive disease (PD) at any time, or who had not achieved at least a 25% reduction of serum myeloma (M)-protein levels (if measurable) and a 50% reduction of urine M-protein (if measurable) compared with baseline after completion of 4 cycles of pomalidomide, had the option to receive oral dexamethasone 40 mg on days 1, 8, 15, and 22 of each 28-day treatment cycle in addition to their current dose of pomalidomide. Participants with PD who chose not to add dexamethasone to pomalidomide therapy were to be discontinued from the study. Participants who chose to add dexamethasone were allowed to continue study treatment until PD developed again, unacceptable toxicity or participant withdrew consent, at which time they were to be discontinued.
Based on results from the phase 1 portion, the Data Monitoring Committee confirmed 4 mg/day as MTD of pomalidomide. Therefore, the recommended starting dose of pomalidomide for Phase 2 was 4 mg/day on Days 1-21 of each 28-day cycle. In the combination treatment arm, the starting dose of dexamethasone was 40 mg once per day. For subjects who were > 75 years of age, the starting dose of dexamethasone was 20 mg once per day. To prevent blood clots, all participants were to be given aspirin 81-100 mg daily (commercial supply) unless contraindicated. If contraindicated, another form of anti-thrombotic therapy was provided.
Participants in the Phase II combination treatment arm could continue study treatment until PD developed, at which time they were to be discontinued. Participants in the single agent pomalidomide treatment arm who developed PD, confirmed by the IRAC, at any time had the option to receive oral dexamethasone in addition to their current dose of pomalidomide at the starting dose described above. Participants with PD who chose not to add dexamethasone to pomalidomide therapy were discontinued from study treatment. Participants who chose to add dexamethasone to pomalidomide therapy could continue study treatment until PD developed again, unacceptable toxicity or participant withdrew consent, at which point they were discontinued.
Upon discontinuation from study treatment for PD or any other reason, participants were to be assessed two times per year, up to five years, for survival, second primary malignancy and subsequent anti-myeloma therapies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Must be greater than or equal to 18 years at the time of signing the informed consent form
- •Must be able to adhere to the study visit schedule and other protocol requirements
- •Have a documented diagnosis of multiple myeloma and have relapsed and refractory disease. Patients must have received at least 2 prior therapies. Patients must have relapsed after having achieved at least stable disease for at least one cycle of treatment to at least one prior regimen and then developed PD. Patients must also have documented evidence of PD during or within 60 days (measured from the end of the last cycle) of completing treatment with the last anti-myeloma drug regimen used just prior to study entry (refractory disease)
- •Patients must have also undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of bortezomib (either in separate regimens or within the same regimen)
- •Measurable levels of myeloma paraprotein in serum (greater than or equal to 0.5 g/dL) or urine (greater than or equal 0.2 g/dL excreted in a 24 hour collection sample)
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
- •Females of childbearing potential (FCBP) [An FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months)] must agree to refrain from becoming pregnant for 28 days prior to initiation of study drug, while on study drug and for 28 days after discontinuation of study drug and must agree to regular pregnancy testing during this timeframe.
- •All patients must also agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study
- •Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 28 days following discontinuation from this study even if he has undergone a successful vasectomy. Males must also agree to refrain from donating blood, semen or sperm during the above referenced timeframe.
- •All patients must agree not to share medication with another person.
排除标准
- •Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form.
- •Any serious concurrent medical conditions that may make the patient non-evaluable or put the patient's safety at risk.
- •Pregnant or lactating females
- •Any of the following laboratory abnormalities:
- •Absolute neutrophil count (ANC) < 1,000 cells/mm3
- •Platelet count < 75,000/mm3 for patients in whom < 50% of bone marrow nucleated cells are plasma cells; or a platelet count < 30,000/mm3 for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells
- •Serum creatinine > 3.0 mg/dL
- •Serum glutamic oxaloacetic transaminase/Aspartate transaminase (SGOT/AST) or Serum Glutamic Pyruvate Transaminase/Alanine transaminase (SGPT/ALT) > 3.0 X upper limit of normal (ULN)
- •Serum total bilirubin > 2.0 mg/dL
- •Prior history of malignancies, other than multiple myeloma, unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following:
- •Basal or squamous cell carcinoma of the skin
- •Carcinoma in situ of the cervix or breast
- •Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
- •Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection
- •Hypersensitivity to thalidomide, lenalidomide, or dexamethasone
- •Peripheral neuropathy ≥ Grade 2
- •Use of any anti-myeloma drug therapy within 14 days of the initiation of study drug treatment or use of any experimental non-drug therapy within 28 days of the initiation of study drug treatment
- •Radiation therapy within 14 days of initiation of study drug treatment Inability or unwillingness to comply with birth control requirements
研究组 & 干预措施
Phase 1: 2 mg pomalidomide
Pomalidomide 2 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Pomalidomide (Drug)
Phase 1: 2 mg pomalidomide
Pomalidomide 2 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Dexamethasone (Drug)
Phase 1: 2 mg pomalidomide
Pomalidomide 2 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Aspirin (Drug)
Phase 1: 3 mg pomalidomide
Pomalidomide 3 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Pomalidomide (Drug)
Phase 1: 3 mg pomalidomide
Pomalidomide 3 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Dexamethasone (Drug)
Phase 1: 3 mg pomalidomide
Pomalidomide 3 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Aspirin (Drug)
Phase 1: 4 mg pomalidomide
Pomalidomide 4 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Pomalidomide (Drug)
Phase 1: 4 mg pomalidomide
Pomalidomide 4 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Dexamethasone (Drug)
Phase 1: 4 mg pomalidomide
Pomalidomide 4 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Aspirin (Drug)
Phase 1: 5 mg pomalidomide
Pomalidomide 5 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Pomalidomide (Drug)
Phase 1: 5 mg pomalidomide
Pomalidomide 5 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Dexamethasone (Drug)
Phase 1: 5 mg pomalidomide
Pomalidomide 5 mg daily on days 1-21 of each 28-day cycle. Participants with progressive disease (PD) had the option of adding dexamethasone 40 mg on Days 1, 8, 15, 22 of each 28-day cycle to the pomalidomide treatment, or discontinuing study treatment.
干预措施: Aspirin (Drug)
Phase 2: pomalidomide + dexamethasone
Combination therapy of 4 mg pomalidomide given once per day on Days 1-21 of each 28-day cycle and the starting dose of dexamethasone (determined by age) on days 1, 8, 15, and 22 of each 28-day cycle. The starting dose of dexamethasone was 40 mg for participants who were ≤ 75 years of age and 20 mg for participants who were > 75 years of age. Dose reduction steps for dexamethasone were provided for drug-related toxicities.
干预措施: Pomalidomide (Drug)
Phase 2: pomalidomide + dexamethasone
Combination therapy of 4 mg pomalidomide given once per day on Days 1-21 of each 28-day cycle and the starting dose of dexamethasone (determined by age) on days 1, 8, 15, and 22 of each 28-day cycle. The starting dose of dexamethasone was 40 mg for participants who were ≤ 75 years of age and 20 mg for participants who were > 75 years of age. Dose reduction steps for dexamethasone were provided for drug-related toxicities.
干预措施: Dexamethasone (Drug)
Phase 2: pomalidomide + dexamethasone
Combination therapy of 4 mg pomalidomide given once per day on Days 1-21 of each 28-day cycle and the starting dose of dexamethasone (determined by age) on days 1, 8, 15, and 22 of each 28-day cycle. The starting dose of dexamethasone was 40 mg for participants who were ≤ 75 years of age and 20 mg for participants who were > 75 years of age. Dose reduction steps for dexamethasone were provided for drug-related toxicities.
干预措施: Aspirin (Drug)
Phase 2: pomalidomide
4 mg pomalidomide was given once per day on Days 1-21 of each 28-day cycle until PD. Participants in the single agent pomalidomide treatment arm who developed confirmed PD at any time had the option to receive oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle at the starting dose of 20 or 40 mg depending on age in addition to their current dose of pomalidomide, or to discontinue treatment.
干预措施: Pomalidomide (Drug)
Phase 2: pomalidomide
4 mg pomalidomide was given once per day on Days 1-21 of each 28-day cycle until PD. Participants in the single agent pomalidomide treatment arm who developed confirmed PD at any time had the option to receive oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle at the starting dose of 20 or 40 mg depending on age in addition to their current dose of pomalidomide, or to discontinue treatment.
干预措施: Dexamethasone (Drug)
Phase 2: pomalidomide
4 mg pomalidomide was given once per day on Days 1-21 of each 28-day cycle until PD. Participants in the single agent pomalidomide treatment arm who developed confirmed PD at any time had the option to receive oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle at the starting dose of 20 or 40 mg depending on age in addition to their current dose of pomalidomide, or to discontinue treatment.
干预措施: Aspirin (Drug)
结局指标
主要结局
Phase 2: Kaplan-Meier Estimates of Progression-free Survival (PFS) as of the 01 April 2011 Cut-off
时间窗: up to 67 weeks
Progression free survival (PFS) is the time from randomization to the first documentation of disease progression or death from any cause during study, whichever occurs earlier. Disease progression was assessed by the Independent Response Adjudication Committee (IRAC). For the primary PFS analysis, participants who withdrew for any reason or received another antimyeloma therapy (except adding dexamethasone to the Phase 2: Pomalidomide arm) without documented PD (as determined by the IRAC review) were censored on the date of their last adequate response assessment, prior to receiving any other anti-myeloma therapy. Subjects who were still active at the time of the data cut-off date without PD (as determined by the IRAC) were censored on the date of their last adequate response assessment. Data collection is ongoing and future data results will be included as available.
Phase 1: Participants With Dose-Limiting Toxicities (DLT) in Cycle 1
时间窗: Up to Day 28 (Cycle 1)
The maximum tolerated dose was defined as the highest dose level at which no more than 1 of 6 participants experiences a DLT within the first 28-day cycle. DLTs were defined as: * Grade 4 neutropenia or thrombocytopenia * Febrile neutropenia * Grade 3 or 4 nausea, vomiting or diarrhea despite optimal symptomatic treatment * Serum transaminase \> 20 \* upper limit of normal (ULN) * Serum transaminase \> 5 \* ULN for \>= 7 days * Delay of the start of cycle 2 by \>7 days due to pomalidomide-related adverse event
Phase 2: Percentage of Participants With Progression-Free Survival (PFS) Events as of the 01 April 2011 Cut-off
时间窗: up to 67 weeks
Percentage of participants with the progression-free survival events: disease progression and death. Disease progression was assessed by the Independent Response Adjudication Committee (IRAC). Data collection is ongoing and future data results will be included as available.
次要结局
- Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) as of the 01 April 2011 Cut-off(Up to week 70)
- Phase 2: Kaplan-Meier Estimates of Duration of Response as of the 01 April 2011 Cut-off(up to 70 weeks)
- Phase 2: Time to Response as of the 01 April 2011 Cut-off(up to 70 weeks)
- Phase 2: Kaplan-Meier Estimates of Overall Survival as of the 01 April 2011 Cut-off(up to 70 weeks)
- Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) While on Both Pomalidomide and Dexamethasone as of the 01 April 2011 Cut-off(Up to week 126)
- Phase 2: Summary of Best Myeloma Response As Assessed by Independent Response Adjudication Committee (IRAC) Using European Group for Blood and Bone Marrow Transplant (EBMT) Criteria as of the 01 April 2011 Cut-off(up to 70 weeks)
- Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) While on Single-Agent Pomalidomide as of the 01 April 2011 Cut-off(Up to week 104)