An Open-Label Study to Determine the Maximum Tolerated Dose and Evaluate the Safety and Efficacy of CEP-18770 in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 8
- 主要终点
- Maximum Tolerated Dose of CEP-18770
研究概览
简要总结
The primary objective of the study is to determine the maximum tolerated dose (MTD) of CEP-18770 in combination with lenalidomide and dexamethasone in participants with relapsed or refractory multiple myeloma.
详细描述
After cycle 1, the start of treatment in each cycle may occur within a 3-day window. In addition, after cycle 2, the start of treatment in cycle 3 may be delayed by 1 week if, in the opinion of the investigator, the delay is warranted. If a participant cannot receive 75% of the planned dose for any of the 3 agents (missing more than 1 dose of CEP-18770, or more than 5 doses of lenalidomide [either consecutively or separately], or more than 1 dose of dexamethasone [either consecutively or separately]), due to a drug-related adverse event, the event will be considered a dose limiting toxicity (DLT), even if the grade of toxicity is lower than specified DLT determination. Participants will receive intravenous (IV) CEP-18770 on Days 1, 8, and 15, oral lenalidomide on days 1 through 21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment with all 3 drugs will continue for up to 12 cycles (approximately 11 months), or until disease progression or intolerable toxicities. Participants experiencing clinical benefit may continue to receive additional treatment at the investigator's discretion and following sponsor notification. In part 2 of the study, participants will receive CEP-18770 as a slow IV bolus (approximately 1 milliliter per minute) at the maximum tolerated dose on days 1, 8, and 15 of every 28-day cycle. Participants who complete or discontinue study drug treatment and whose disease has not progressed will have study visits every 7-9 weeks during follow-up until disease progression, death, or until they have been monitored for 1 year after the first administration of study drug, whichever occurs first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •The participant is a man or woman at least 18 years of age with documented multiple myeloma.
- •The participant has relapsed or progressive disease after receiving at least 1 previous chemotherapy treatment but no more than 5 previous therapies.
- •The participant has measurable disease defined as 1 of the following:
- •serum M-protein 0.5 grams (g)/deciliter (dL) or greater
- •urine M-protein 200 mg/24 hours or greater
- •The participant has a life expectancy of more than 3 months.
- •Written informed consent is obtained.
- •The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
- •The participant has adequate hepatic and renal function and hematologic assessments as specified by the study protocol
- •The participant has been independent of support with granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) for more than 1 week at the time of screening.
- •The participant has been independent of platelet transfusions for 1 week at the time of screening.
- •The participant may have received an allogeneic and/or autologous transplant.
- •The participant must agree to register into the mandatory risk evaluation and mitigation program for receiving lenalidomide if required by local regulations.
- •Agreement by women of childbearing potential (not surgically sterile or 24 months postmenopausal) to use 2 medically accepted methods of contraception and must agree to continue use of these methods from 4 weeks prior to treatment to 4 weeks after treatment. Acceptable methods of contraception include at least one highly effective method (for example, intrauterine device [IUD], non-combination hormonal contraception, tubal ligation, or partner's vasectomy) and one additional method (for example, latex condom, diaphragm, or cervical cap).
- •Agreement by men who are sexually active with a woman of childbearing potential (as defined in the criterion above), to use a condom during any sexual contact for the duration of the study and for 4 weeks after the last administration of study drug. This requirement applies even if the man has had a vasectomy.
- •The participant may not donate blood, semen or sperm while taking lenalidomide or for 4 weeks after the last administration of lenalidomide.
- •The participant may not breastfeed while taking lenalidomide or for 4 weeks after the last administration of lenalidomide.
排除标准
- •The participant has nonmeasurable multiple myeloma, defined as less than 0.5 g/dL M-protein in the serum, and less than 200 mg/24 hours M-protein in the urine.
- •The participant could not tolerate previous lenalidomide or low-dose dexamethasone treatment.
- •The participant had previous treatment with CEP-
- •The participant has POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy or monoclonal proliferative disorder, and skin changes [increased skin pigment, increased body hair, thickening of the skin, whitening of the nails, etc]).
- •The participant has plasma cell leukemia or primary amyloidosis.
- •The participant received chemotherapy with approved or investigative anticancer therapeutics within 3 weeks before the first dose of study drug.
- •The participant received radiation therapy or immunotherapy within 4 weeks or localized radiation therapy within 1 week prior to the first dose of study drug.
- •The participant had major surgery within 3 weeks before the first dose of study drug.
- •The participant has congestive heart failure (New York Heart Association Class III to IV) or had symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within the last 6 months.
- •The participant had an acute infection requiring systemic antibiotics, antiviral agents, or antifungal agents within 2 weeks before the first dose of study drug.
- •The participant has a known or suspected human immunodeficiency virus (HIV) infection, acute or chronic hepatitis B virus or hepatitis C virus on the basis of their medical history.
- •The participant has myelodysplastic or myeloproliferative syndrome.
- •The participant has significant neuropathy (at least grade 2, or grade 1 with pain).
- •The participant is a pregnant or lactating woman.
- •The participant has known hypersensitivity to CEP-18770, lenalidomide, thalidomide, dexamethasone, mannitol, or hydroxypropyl betadex.
- •The participant received glucocorticoid therapy (prednisone >10 mg/day orally or equivalent) within the last 2 weeks prior to the first dose of study drug.
- •The participant has a history of malignancy, other than multiple myeloma, within the last 5 years excluding adequately treated curable disease or indolent disease that is not likely to require therapy during the conduct of the study.
- •The participant has known central nervous system (CNS) involvement.
研究组 & 干预措施
CEP-18770 Dose A
Participants will receive CEP-18770 Dose A intravenously (IV) on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: CEP-18770 (Drug)
CEP-18770 Dose A
Participants will receive CEP-18770 Dose A intravenously (IV) on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: Lenalidomide (Drug)
CEP-18770 Dose A
Participants will receive CEP-18770 Dose A intravenously (IV) on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: Dexamethasone (Drug)
CEP-18770 Dose B
Participants will receive CEP-18770 Dose B IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: CEP-18770 (Drug)
CEP-18770 Dose B
Participants will receive CEP-18770 Dose B IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: Lenalidomide (Drug)
CEP-18770 Dose B
Participants will receive CEP-18770 Dose B IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: Dexamethasone (Drug)
CEP-18770 Dose C
Participants will receive CEP-18770 Dose C IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: CEP-18770 (Drug)
CEP-18770 Dose C
Participants will receive CEP-18770 Dose C IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: Lenalidomide (Drug)
CEP-18770 Dose C
Participants will receive CEP-18770 Dose C IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Maximum Tolerated Dose of CEP-18770
时间窗: Cycle 1 (28 days)
MTD was based on the assessment of dose-limiting toxicity (DLT) during cycle 1 only and was defined as the highest dose at which fewer than one-third of participants in a cohort experience DLT. A DLT was defined as any of the following drug-related toxicities occurring during Cycle 1: Hematologic adverse events (AEs) (Grade 4 hematologic AEs, Grade 3 hematologic AEs with sequelae); Grade 3 nonhematologic AEs; Neuropathy (Grade 2 neuropathy, Grade 1 neuropathy with pain, worsening grade of neuropathy or new symptoms of pain associated with neuropathy); Any other toxicity that, in the judgment of the principal investigator, was a DLT; If a participant cannot receive 75% of the planned dose for any of the 3 agents (missing \>1 dose of CEP-18770, or \>5 doses of lenalidomide, or \>1 dose of dexamethasone \[either consecutively or separately\]), due to a drug-related AE, the event was considered a DLT, even if the grade of toxicity was lower than specified DLT determination as described above.
Overall Response Rate (ORR) in Participants Treated at the (Maximum Tolerated Dose) MTD, as Assessed Using International Myeloma Working Group (IMWG) Criteria
时间窗: From the first administration of CEP-18770 up to approximately 1.5 years
The ORR is defined as percentage of participants who achieve a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) during the study. sCR: negative immunofixation in serum and urine; disappearance of any soft tissue plasmacytomas; \< 5% plasma cells in bone marrow; normal free light chain (FLC) ratio; and absence of clonal cells in bone marrow. CR: negative immunofixation in serum and urine; disappearance of any soft tissue plasmacytomas; and \<5% plasma cells in bone marrow. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis; 90% or greater reduction in serum M-protein level and urine M-protein level less than 100 milligrams (mg)/24 hours. PR: ≥50% reduction in serum M-protein level; ≥90% reduction in 24-hour urinary M-protein level or reduction to less than 200 mg per 24 hours; and ≥50% reduction in the size of any soft tissue plasmacytomas present at baseline.
次要结局
- Duration of Response (DOR) for Participants Treated With CEP-18770 at the MTD, as Assessed Using IMWG Criteria(From the date of first response to the date of disease progression (up to approximately 1.5 years))
- Time to Progression (TTP) for Participants Treated With CEP-18770 at the MTD, as Assessed Using IMWG Criteria(From the date of first dose of study drug to the date of disease progression (up to approximately 1.5 years))
- Maximum Observed Plasma Concentration (Cmax) of CEP-18770(Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1)
- Number of Participants With Adverse Events (AEs)(From the first administration of CEP-18770 up to approximately 1.5 years)
- Time to Reach Cmax (Tmax) of CEP-18770(Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1)
- Area Under the Plasma Concentration-Time Curve From Time 0 to t (AUC0-t) of CEP-18770(Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1)