A Phase 1B/2 Multi-Center, Open Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of ACY-1215 (RICOLINOSTAT) in Combination With Pomalidomide and Low-Dose Dexamethasone in Patients With Relapsed and Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Celgene
- 入组人数
- 103
- 试验地点
- 2
- 主要终点
- Maximum Tolerated Dose (MTD) of ACY-1215- Phase 1b
研究概览
简要总结
Phase 1b: To evaluate the side effects and determine the best dose of ACY-1215 in combination with Pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory multiple myeloma.
Phase 2: To determine the overall response rate of ACY-1215 in combination with Pomolidomide and low-dose dexamethasone in patients with relapsed-and-refractory multiple myeloma
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must have a documented diagnosis of multiple myeloma and have relapsed-and-refractory disease. Patients must have received at least 2 lines of prior therapies. Patients must have relapsed after having achieved at least stable disease (SD) for at least one cycle of treatment to at least one prior regimen and then developed progressive disease (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)
- •Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen)
- •Must not be a candidate for autologous stem cell transplant (ASCT), has declined the option of ASCT, or has relapsed after prior ASCT
- •Must have measurable levels of myeloma paraprotein in serum (≥ 0.5 g/dL) or urine (≥ 0.2 g/24 hours)
- •Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
- •Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to, and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods,and Education and Counseling Guidance must be followed per protocol
- •Must be able to take acetylsalicylic acid (ASA) (81 or 325 mg) daily as prophylactic anticoagulation. Patients intolerant to ASA may use low molecular weight heparin. Lovenox is recommended. Coumadin will be allowed provided the patient is fully anticoagulated, with an international normalized ratio (INR) of 2 to 3
排除标准
- •Pregnant or lactating females
- •Prior therapy with HDAC inhibitor
- •Any of the following laboratory abnormalities:
- •ANC < 1,000/µL
- •Platelet count < 75,000/ µL for patients in whom < 50% of bone marrow nucleated cells are plasma cells; and < 50,000/ µL for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells
- •Hemoglobin < 8g/dL (<4.9 mmol/L; prior red blood cell [RBC] transfusion is permitted)
- •Creatine clearance < 45mL/min according to Cockcroft-Gault formula. If creatine clearance calculated from the 24-hour urine sample is ≥ 45 mL/min, patient will qualify for the study
- •Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST), or serum glutamic pyruvic transaminase (SGPT)/ alanine aminotransferase (ALT) > 3.0 × ULN
- •Serum total bilirubin > 2.0 mg/dL
- •Prior history of malignancies, other than MM, 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)
- •Corrected QT interval using Fridericia's formula (QTcF) value > 480 msec at screening; family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy; previous history of drug-induced QTc prolongation or the need for treatment with medications known or suspected of producing prolonged QTc intervals on electrocardiogram (ECG)
- •Positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection
- •Hypersensitivity to thalidomide, lenalidomide, or dexamethasone (such as Steven Johnson Syndrome). Hypersensitivity, such as rash, that can be medically managed is allowable
- •Peripheral neuropathy ≥ Grade 2 despite supportive therapy
- •Radiotherapy or systemic therapy (standard or an investigational or biologic anticancer agent) within 14 days of initiation of study drug treatment
- •Current enrollment in another clinical trial involving treatment and/or is receiving an investigational agent for any reason
- •Inability or unwillingness to comply with birth control requirements or regional REMS/RevAid programs
研究组 & 干预措施
ACY-1215 in combination with pomalidomide and dexamethasone
ACY-1215 (Ricolinostat) in combination with pomalidomide and dexamethasone
干预措施: ACY-1215 (Ricolinostat) in combination with pomalidomide and dexamethasone (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of ACY-1215- Phase 1b
时间窗: From first dose until the end of Phase 1b (up to a maximum of approximately 50 weeks).
The maximum tolerated dose (MTD) was defined as the highest dose level at which no more than 1 of 6 patients experienced a dose-limiting toxicity (DLT) within the first 28-day cycle. If no more than 1 of these 6 patients experienced a DLT within the first 28-day cycle, then the last dose level enrolled to meet these criteria was identified as the recommended dose for the Phase 2 segment of the study.
Overall Response Rate (ORR) Per Investigator - Phase 2
时间窗: From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).
Overall response rate (ORR) is defined as the percentage of participants with a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: * No detectable myeloma cells in the bone marrow. * Normal free light chain ratio. * Absence of clonal cells in the bone marrow. CR: * Negative immunofixation on the serum and urine. * Disappearance of any soft tissue plasmacytomas. * Less than 5% plasma cells in the bone marrow. VGPR: * Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or * At least a 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 hours. PR: * At least a 50% reduction in serum M-protein. * Reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours. * For patients with non-secretory myeloma, a reduction of at least 50% in the size of soft tissue plasmacytomas is required.
次要结局
- Time to Response (TTR)(From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).)
- Duration of Response (DoR)(From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).)
- Time to Progression (TTP)(From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).)
- Progression-free Survival (PFS)(From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).)
- Overall Response Rate (ORR) Per Central Adjudication Committee(From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).)
- Number of Participants With Adverse Events (AEs)(From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks))
- Number of Participants With Serious Adverse Events (SAEs)(From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks))
- Number of Participants With Adverse Events (AEs) Leading to Discontinuation(From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks))
- Number of Participants With Adverse Events (AEs) Related to Study Drug(From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks))
- Plasma Levels of ACY-1215 and Pomalidomide - Phase 1b(Cycle 1 day 1, Cycle 1 Day 2, Cycle 1 Day 8)
- Number of Participants With Anti-Drug Antibodies (ADA) - Phase 1b(Cycle 1 day 1, Cycle 1 Day 2, Cycle 1 Day 8)