An Open-Label Phase I/IIa Study of the Safety and Efficacy of Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for Patients With Relapsed and/or Relapsed-Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 75
- 试验地点
- 7
- 主要终点
- Percentage of Patients Who Achieved Best Overall Disease Response
研究概览
简要总结
The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.
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
- •Male or female, age 18 years or older
- •Patient has a diagnosis of multiple myeloma with documented relapsed and/or relapsed-refractory disease
- •Patient has measurable disease defined as any of the following:
- •Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis
- •≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
- •Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
- •If no monoclonal protein is detected, then ≥ 30% monoclonal bone marrow plasma cells
- •Patient has had at least 2 or more prior lines of therapy including lenalidomide and bortezomib and has demonstrated disease progression on or within 60 days of completion of the last therapy
- •Life expectancy of ≥6 months
- •Patient has an ECOG performance status ≤ 2 (Patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible)
- •Females of childbearing potential must have a negative serum or urine pregnancy test prior to patient registration
- •Female patients of child bearing potential and non-vasectomized male patients agree to practice appropriate methods of birth control
- •Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
- •The patient has, or accepts to have, an acceptable infusion device for infusion of melflufen
- •12 lead ECG with QtcF interval ≤ 470 msec
- •The following laboratory results must be met within 21 days of patient registration:
- •Absolute neutrophil count ≥ 1,000 cells/dL (1.0 x 109/L)
- •Platelet count ≥ 75,000 cells/dL (75 x 109/L)
- •Hemoglobin ≥ 8.0 g/dL
- •Total Bilirubin ≤ 1.5 x upper limit of normal
- •Renal function: Estimated creatinine clearance ≥ 45 ml/min or serum creatinine ≤ 2.5 mg/dL
- •AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
排除标准
- •Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion refractory
- •Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participation in this study
- •Known active infection requiring parenteral or oral anti-infective treatment
- •Other malignancy within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix
- •Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to patient registration.
- •Pregnant or breast-feeding females
- •Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation
- •Known HIV or hepatitis B or C viral infection
- •Patient has concurrent symptomatic amyloidosis or plasma cell leukemia
- •POEMS syndrome
- •Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to start of study treatment. Biologic, novel therapy (including investigational agents in this class) or corticosteroids within 2 weeks prior to patient registration. Patient has side effects of the previous therapy > grade 1 or previous baseline.
- •Prior peripheral stem cell transplant within 12 weeks of patient registration
- •Radiotherapy within 21 days prior to Cycle 1 Day
- •However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
- •Known intolerance to steroid therapy
研究组 & 干预措施
Phase I: Melflufen 15 mg + Dexamethasone
Intravenous (IV) infusion of 15 milligram (mg) melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Melflufen (Drug)
Phase I: Melflufen 15 mg + Dexamethasone
Intravenous (IV) infusion of 15 milligram (mg) melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Dexamethasone (Drug)
Phase I: Melflufen 25 mg + Dexamethasone
IV infusion of 25 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Melflufen (Drug)
Phase I: Melflufen 25 mg + Dexamethasone
IV infusion of 25 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Dexamethasone (Drug)
Phase I: Melflufen 40 mg + Dexamethasone
IV infusion of 40 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Melflufen (Drug)
Phase I: Melflufen 40 mg + Dexamethasone
IV infusion of 40 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Dexamethasone (Drug)
Phase I: Melflufen 55 mg + Dexamethasone
IV infusion of 55 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Melflufen (Drug)
Phase I: Melflufen 55 mg + Dexamethasone
IV infusion of 55 mg melflufen on Day 1 of each 21-day treatment cycle, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycle.
干预措施: Dexamethasone (Drug)
Phase I + II: Melflufen 40 mg + Dexamethasone
IV infusion of 40 mg melflufen on Day 1 of each 21-day or 28-day treatment cycles, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycles. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each treatment cycle.
干预措施: Melflufen (Drug)
Phase I + II: Melflufen 40 mg + Dexamethasone
IV infusion of 40 mg melflufen on Day 1 of each 21-day or 28-day treatment cycles, in combination with 40 mg dexamethasone (oral or IV) on Days 1, 8 and 15 of each 21-day treatment cycles. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each treatment cycle.
干预措施: Dexamethasone (Drug)
Phase II: Melflufen 40 mg (Single Agent)
IV infusion of 40 mg melflufen on Day 1 of each 28-day treatment cycle.
干预措施: Melflufen (Drug)
结局指标
主要结局
Percentage of Patients Who Achieved Best Overall Disease Response
时间窗: Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
The best overall disease response on treatment including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) or progressive disease (PD) were evaluated. Starting on completion of Cycle 2, response was assessed according to International Myeloma Working Group (IMWG) criteria based on Investigator's assessment for all patients at every cycle during treatment period. PD was defined as increase of ≥25% from lowest response value in any 1 of the following: serum M-component (absolute increase must be ≥0.5 gram/deciliter) and/or urine M-component (absolute increase must be ≥200 mg/24 hr); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that could be attributed solely to plasma cell proliferative disorder. SD was defined as not meeting criteria for CR, VGPR, PR or PD.
Overall Response Rate (ORR)
时间窗: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
ORR was defined as percentage of patients with an overall response (OR), defined as first occurrence of confirmed disease response including PR or better (i.e, PR, VGPR, CR or sCR). Starting on completion of Cycle 2, response was assessed according to IMWG criteria based on Investigator's assessment for all patients at every cycle during treatment period. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum plus urine M-protein level \<100 mg/24hr and \>90% decrease in difference between involved and uninvolved free light chain (FLC) levels (only in FLC diseased patients). CR was defined as negative immunofixation on serum and urine, loss of any soft tissue plasmacytomas, \<5% plasma cells in bone marrow and normal FLC ratio of 0.26 to 1.65 (only in FLC diseased patients). sCR was defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or 2 to 4 color flow cytometry.
Clinical Benefit Response Rate (CBRR)
时间窗: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
The CBRR was defined as the percentage of patients with a clinical benefit response (CBR), defined as the first occurrence of confirmed disease response including MR or better (i.e, MR, PR, VGPR, CR, or sCR). Starting on completion of Cycle 2, response was assessed according to the IMWG criteria based on the Investigator's assessment for all patients at every cycle during the treatment period. MR was defined as ≥25% but \<49% reduction of serum M-protein and reduction in 24 hour urine M-protein by 50 to 89%, which still exceeds 200 mg/24 hours. In addition to above; if present at baseline, 25 to 49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response). PR was defined as 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥90% or to \<200 mg/24 hour.
次要结局
- Median Progression-Free Survival (PFS)(Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.)
- Time to First Subsequent Treatment(From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.)
- Duration of Disease Response (DOR)(Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.)
- Median Overall Survival (OS)(From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.)
- Number of Patients With Treatment Emergent Adverse Events (TEAEs)(From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.)
- Time to Disease Response in Patients Who Achieved OR and CBR(Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.)
- Time to Disease Progression(Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.)