A Phase 2B Study of Selinexor (KPT-330), in Combination With Carfilzomib, Daratumumab or Pomalidomide in Patients With Multiple Myeloma Relapsing on Current Therapy
试验速览
- 阶段
- 2 期
- 状态
- 暂停
- 入组人数
- 96
- 试验地点
- 2
- 主要终点
- Overall Response Rate (ORR) of patients receiving selinexor with carfilzomib and dexamethasone (Arm 1)
研究概览
简要总结
This is a prospective, 2-arm (with an additional exploratory arm), open-label, multicenter study looking at the response rate of patients receiving selinexor (KPT-330), in combination with carfilzomib, daratumumab or pomalidomide.
Multiple Myeloma patients with documented disease progression or refractory disease while on current treatment with any carfilzomib-containing regimen (arm 1), any pomalidomide-containing regimen (arm 2) or any daratumumab-containing regimen (exploratory arm) will be included in the study. Patients will be assigned to the respective groups according to their current treatment. If a subject has received more than one of the above therapies, then assignment will be made at their physician's discretion (e.g treatment decision can be made based upon patient and physician preferred tolerance.).
Patients will receive treatment until progressive disease (PD), death, toxicity that cannot be managed by standard of care, or withdrawal, whichever occurs first.
详细描述
This is a Phase 2b, two-arm, open-label, multicenter study of Sd (selinexor 100, 80 or 60 mg) in combination with carfilzomib, or pomalidomide in patients with MM previously treated with carfilzomib or pomalidomide respectively, and refractory to prior treatment. An additional exploratory arm will focus on patients treated with SD in combination with daratumumab.
This study will enroll approximately 96 patients overall (43 in each of the arms and 10 additional patients in the exploratory arm. Patients will be assigned to the respective arms based on their previous treatment.
Patients who are relapsed or refractory to their current carfilzomib-based regimen will be enrolled on Arm 1 and will receive the following treatment regimen on a 28-day cycle:
Carfilzomib 56 mg/m2 on days 1, 8 and 15. They will also receive dexamethasone 40 mg (or 20 mg if patient is ≥ 75 years old) once weekly and Selinexor 80 mg on days 1, 8 and 15.
Patients who are relapsed or refractory to their current pomalidomide-based regimen will be enrolled on Arm 2 and will receive the following treatment regimen on a 28-day cycle:
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
- •Age ≥18 years at time of informed consent.
- •Histologically confirmed MM and evidence of disease progression while on one of the below MM regimens:
- •Arm 1: Refractory to or disease progression while on a carfilzomib-containing regimen
- •Arm 2: Refractory to or disease progression while on a pomalidomide-containing regimen
- •Exploratory Arm: Refractory to or disease progression while on a daratumumab-containing regimen
- •Measurable disease as defined: Serum M-protein ≥ 0.5 g/dL; urine M-protein excretion at least 200 mg/24h; serum FLC ≥ 100 mg/L, provided that FLC is abnormal; if serum protein electrophoresis is felt to be unreliable for routine M-protein measurement (i.e. IgA MM) then quantitative Ig levels by nephelometry or turbidometry are acceptable; for non-secretory disease, bone marrow plasma cells ≥ 20% or a biopsy-proven target lesion by PET/CT or MRI is acceptable
- •Documented evidence of disease progression (by IMWG criteria) or refractory disease on the current treatment as defined as:
- •Achieving SD or less for ≥ 1 cycle during treatment with regimens stated in #2 (i.e. relapsed) OR
- •<25% response (i.e. never achieved MR) or PD during or within 60 days from the end-of most recent MM regimen as listed in #2 (i.e. refractory).
- •Any non-hematological toxicities (except for peripheral neuropathy) that patients experienced from treatments in previous regimens have resolved to Grade 2 or less by Cycle 1 Day
- •ECOG 2 or less
- •Adequate hepatic function within 28 days prior to C1D1:
- •Total bilirubin < 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 × ULN), and
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to <2 × ULN.
- •Adequate renal function within 28 days prior to C1D1 as determined by estimated creatinine clearance of ≥ 30 mL/min, calculated using the Cockcroft and Gault formula (140 - Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female (Cockcroft 1976).
- •Adequate hematopoietic function within 7 days prior to C1D1: total white blood cell (WBC) count ≥1500/mm3, absolute neutrophil count ≥1000/mm3, hemoglobin ≥8.5 g/dL and platelet count ≥75,000/mm3 (patients for whom <50% of bone marrow nucleated cells are plasma cells) or ≥50,000/mm3 (patients for whom ≥50% of bone marrow nucleated cells are plasma cells).
- •Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study.
- •Patients must have:
- •At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the Screening hemoglobin assessment, and
- •At least a 1-week interval from the last platelet transfusion prior to the Screening platelet assessment.
- •However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study.
- •Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.
排除标准
- •Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:
- •Smoldering MM
- •Radiation therapy, chemotherapy or immunotherapy other than above stated regimens in #2 ≤2 weeks prior to C1D
- •Patients on long-term glucocorticosteroids during screening do not require a washout period. Prior RT is permitted for treatment of fractures or to prevent fractures as well as for pain management.
- •Active graft versus host disease after allogeneic stem cell transplant.
- •Life expectancy <3 months.
- •Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus ribonucleic acid (RNA) or hepatitis B virus surface antigen.
- •Has any concurrent medical condition or disease (eg, uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with study procedures.
- •Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.
- •Known intolerance, hypersensitivity, or contraindication to glucocorticoids.
- •Pregnant or breastfeeding females.
- •Body surface area (BSA) <1.4 m2 at baseline, calculated by the Dubois (Dubois 1916) or Mosteller (Mosteller 1987) method.
- •Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment.
- •Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (CPGO) (NCCN CPGO) for antiemesis and anorexia/cachexia (palliative care).
- •Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent.
- •Contraindication to any of the required concomitant drugs or supportive treatments.
- •Patients unwilling or unable to comply with the protocol
研究组 & 干预措施
Carfilzomib-containing Regimen
Carfilzomib 56 mg/m2 on days 1, 8 and 15. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 80 mg on days 1, 8 and 15.
干预措施: Selinexor 80 MG (Drug)
Carfilzomib-containing Regimen
Carfilzomib 56 mg/m2 on days 1, 8 and 15. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 80 mg on days 1, 8 and 15.
干预措施: Carfilzomib (Drug)
Carfilzomib-containing Regimen
Carfilzomib 56 mg/m2 on days 1, 8 and 15. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 80 mg on days 1, 8 and 15.
干预措施: Dexamethasone (Drug)
Pomalidomide-containing Regimen
Pomalidomide 4 mg po daily for 21 days. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 60 mg on days 1, 8 and 15.
干预措施: Selinexor 60 MG (Drug)
Pomalidomide-containing Regimen
Pomalidomide 4 mg po daily for 21 days. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 60 mg on days 1, 8 and 15.
干预措施: Pomalidomide (Drug)
Pomalidomide-containing Regimen
Pomalidomide 4 mg po daily for 21 days. Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 60 mg on days 1, 8 and 15.
干预措施: Dexamethasone (Drug)
Exploratory/Daratumumab-containing Regimen
Daratumumab on current schedule (16 mg/kg IV days 1, 8, 15 and 22 for cycles 1-2; days 1 and 15 for cycles 3-6; day 1 for cycle 7 and on).
Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 100 mg on days 1, 8, 15 and 22.
干预措施: Selinexor 100 MG (Drug)
Exploratory/Daratumumab-containing Regimen
Daratumumab on current schedule (16 mg/kg IV days 1, 8, 15 and 22 for cycles 1-2; days 1 and 15 for cycles 3-6; day 1 for cycle 7 and on).
Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 100 mg on days 1, 8, 15 and 22.
干预措施: Daratumumab (Drug)
Exploratory/Daratumumab-containing Regimen
Daratumumab on current schedule (16 mg/kg IV days 1, 8, 15 and 22 for cycles 1-2; days 1 and 15 for cycles 3-6; day 1 for cycle 7 and on).
Dexamethasone 20 mg if ≥ 75 years old and 40 mg if < 75 years old on days 1, 8, 15 and 22.
Selinexor 100 mg on days 1, 8, 15 and 22.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Overall Response Rate (ORR) of patients receiving selinexor with carfilzomib and dexamethasone (Arm 1)
时间窗: 30 Months
ORR will include patients who experience partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR), based on International Myeloma Working Group (IMWG) response criteria (Kumar 2016)
Overall Response Rate (ORR) of patients receiving selinexor with pomalidomide and dexamethasone (Arm 2)
时间窗: 30 Months
ORR will include patients who experience partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR), based on International Myeloma Working Group (IMWG) response criteria (Kumar 2016)
次要结局
- Progression Free Survival (PFS)(30 Months)
- Overall Survival (OS)(30 Months)
- MRD Negativity(30 Months)
- Incidence of Adverse Events [Safety and Tolerability] using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v 4.03.(30 Months)
- Time To Next Treatment (TTNT)(30 Months)