An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and Dexamethasone in Combination With Either Bortezomib or Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 56
- 试验地点
- 16
- 主要终点
- Phase 1: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
研究概览
简要总结
This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma to combination regimens of melflufen with currently approved agents. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Male or female, age 18 years or older
- •A prior diagnosis of multiple myeloma with documented disease progression in need of treatment at time of screening
- •One to four prior lines of therapy
- •Measurable disease defined as any of the following:
- •Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
- •≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP)
- •Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
- •Life expectancy of ≥ 6 months
- •ECOG performance status ≤
- •(Patients with lower performance status based solely on bone pain secondary to multiple myeloma may be eligible following consultation and approval of the medical monitor)
- •Patient is a female of childbearing potential (FCBP)* with a negative serum or urine pregnancy test prior to initiation of therapy and agrees to practice appropriate methods of birth control, or the patient is male and agrees to practice appropriate methods of birth control
- •Ability to understand the purpose and risks of the study and provide signed and dated informed consent
- •12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec
- •Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study drug administration on Cycle 1 Day 1:
- •Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy)
- •Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required transfusions during the 10 days prior to initiation of therapy)
- •Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted)
- •Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilbert's syndrome, that have been reviewed and approved by the medical monitor
- •AST/SGOT and ALT/SGPT ≤ 3.0 x ULN
- •Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min and serum creatinine ≤ 2 mg/dL
- •Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter)
- •Must be intolerant or refractory to a prior IMiD; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose.
- •Must have had a prior IMiD and a proteasome inhibitor (PI); alone or in combination and must be refractory or intolerant to an IMiD, PI or both.
- •(FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to cancer therapy does not rule out childbearing potential) for at least 24 consecutive months.
排除标准
- •Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy)
- •Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. platelet count fails to increase by > 10,000 cells/mm3 after transfusion of an appropriate dose of platelets)
- •Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months)
- •Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy
- •Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance
- •Pregnant or breast-feeding females
- •Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
- •Known human immunodeficiency virus or active hepatitis B or C viral infection
- •Concurrent symptomatic amyloidosis or plasma cell leukemia
- •POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
- •Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy. The use of live vaccines within 30 days before initiation of therapy. IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy. Other investigational therapies and monoclonal antibodies (mAb) within 4 weeks of initiation of therapy Prednisone up to but no more than 10 mg orally once daily (q.d.) or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to initiation of therapy
- •Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted)
- •Prior peripheral stem cell transplant within 12 weeks of initiation of therapy
- •Prior allogeneic stem cell transplantation with active graft-versus-host- disease
- •Prior major surgical procedure or radiation therapy within 4 weeks of initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy)
- •Known intolerance to the required dose and schedule of steroid therapy as determined by the investigator
- •Prior treatment with melflufen
- •Refractory to a PI in the last line of therapy prior to enrollment in this trial; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose
- •History of allergic reaction/hypersensitivity attributed to compounds containing boron, mannitol, polysorbate 80 or sodium citrate dihydrate
- •Prior exposure to an antiCD-38 mAb
- •Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal
- •Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
- •≥ Grade 3 conduction system abnormalities unless patient has a pacemaker
- •Active hepatitis B (defined as HBsAg+) or those at risk for reactivation (HBsAg-, Anti- HBs+, Anti-HBc+)
- •Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-)
- •Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may only be enrolled after approval of the sponsor and consideration of risk of reactivation (additional screening and monitoring for reactivation of Hepatitis B and consultation with a liver disease specialist may be required)
研究组 & 干预措施
A (melflufen+bortezomib+dex)
Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with bortezomib at 1.3mg/m² S.Q. on Days 1, 4, 8, 11 and dexamethasone 20 mg (12 mg ≥ 75 years) Days 1, 4, 8, 11 and 40 mg (20 mg ≥ 75 years) on Day 15 and 22 of each 28-day cycle.
干预措施: Melphalan flufenamide (Melflufen) (Drug)
A (melflufen+bortezomib+dex)
Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with bortezomib at 1.3mg/m² S.Q. on Days 1, 4, 8, 11 and dexamethasone 20 mg (12 mg ≥ 75 years) Days 1, 4, 8, 11 and 40 mg (20 mg ≥ 75 years) on Day 15 and 22 of each 28-day cycle.
干预措施: Dexamethasone (Drug)
A (melflufen+bortezomib+dex)
Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with bortezomib at 1.3mg/m² S.Q. on Days 1, 4, 8, 11 and dexamethasone 20 mg (12 mg ≥ 75 years) Days 1, 4, 8, 11 and 40 mg (20 mg ≥ 75 years) on Day 15 and 22 of each 28-day cycle.
干预措施: Bortezomib (Drug)
B (melflufen+daratumumab+dex)
Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with daratumumab 16 mg/kg weekly for 8 doses, every other week for 8 doses and then once every 4 weeks. Dexamethasone p.o. 40 mg weekly (20 mg weekly for patients age ≥ 75 years).
干预措施: Melphalan flufenamide (Melflufen) (Drug)
B (melflufen+daratumumab+dex)
Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with daratumumab 16 mg/kg weekly for 8 doses, every other week for 8 doses and then once every 4 weeks. Dexamethasone p.o. 40 mg weekly (20 mg weekly for patients age ≥ 75 years).
干预措施: Dexamethasone (Drug)
B (melflufen+daratumumab+dex)
Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with daratumumab 16 mg/kg weekly for 8 doses, every other week for 8 doses and then once every 4 weeks. Dexamethasone p.o. 40 mg weekly (20 mg weekly for patients age ≥ 75 years).
干预措施: Daratumumab (Drug)
结局指标
主要结局
Phase 1: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
时间窗: Cycle 1: Day 1 to Day 28
Toxicity was graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 4.03. DLT criteria that apply to Regimens A and B: * Grade 3 non-hematologic toxicity preventing the administration of \> 1 dose of bortezomib or daratumumab during the 1st cycle. * Grade 4 or greater non-hematologic toxicity. * Grade 4 thrombocytopenia (platelet count \< 25,000 cells/ mm\^3) preventing the administration of \> 1 dose of bortezomib or daratumumab during the 1st cycle or with clinically significant bleeding during the 1st cycle. * Grade 4 neutropenia (ANC \< 500 cells/mm\^3), lasting more than 7 days during the 1st cycle. * Greater than 14 days' delay to meet the criteria for the start of a new cycle (Cycle 2) due to toxicity.
Phase 2: Overall Response Rate (ORR)
时间窗: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
ORR was defined as the percentage of participants who achieved a best confirmed response of Partial Response (PR) or better.
次要结局
- Duration of Response (DOR)(Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks))
- Best Response (BR)(Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks))
- Progression-Free Survival (PFS)(Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks))
- Overall Survival (OS)(Up to 24 months following confirmed disease progression, or initiation of subsequent therapy (a maximum of 198.9 weeks))
- Time to Progression (TTP)(Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks))
- Clinical Benefit Rate (≥ Minimal Response)(Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks))
- Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)(Cycle 1 Day 1 up to a maximum of 198.9 weeks)
- Time to Response (TTR)(Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks))
- Duration of Clinical Benefit (DOCB)(Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks))
- Time to Next Treatment (TTNT)(Until death or initiation of subsequent therapy (a maximum of 194.3 weeks))