A Phase 3 Randomized, Controlled, Open-label Study of Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Bortezomib and Dexamethasone (Vd) in Patients With Relapsed or Refractory Multiple Myeloma (RRMM)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 402
- 试验地点
- 156
- 主要终点
- SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC)
研究概览
简要总结
This Phase 3, 2-arm, randomized, active comparator-controlled, open-label, multicenter study will compare the efficacy and health-related quality of life (HR-QoL) and assess the safety of selinexor plus bortezomib (Velcade) plus low-dose dexamethasone (SVd) versus bortezomib plus low-dose dexamethasone (Vd) in adult patients with RRMM who have received 1 to 3 prior anti-multiple myeloma (MM) regimens. Crossover from the Vd Arm to a treatment that includes selinexor (i.e., SVdX or SdX) will be allowed at the point of IRC-confirmed objective disease progression per the IMWG criteria for patients in the Vd Arm.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Histologically confirmed MM with measurable disease per IMWG guidelines as defined by at least 1 of the following:
- •Serum M-protein ≥ 0.5 g/dL (> 5 g/L) by serum protein electrophoresis (SPEP) or for immunoglobulin (Ig) A myeloma, by quantitative serum IgA levels; or
- •Urinary M-protein excretion at least 200 mg/24 hours; or
- •Serum free light chain (FLC) ≥ 100 mg/L, provided that the serum FLC ratio is abnormal (normal FLC ratio: 0.26 to 1.65).
- •Had at least 1 prior anti-MM regimen and no more than 3 prior anti-MM regimens. Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 anti-MM regimen.
- •Documented evidence of progressive MM (based on the Investigator's determination according to the modified IMWG response criteria) on or after their most recent regimen.
- •Prior treatment with bortezomib or other Proteasome Inhibitor (PI) is allowed, provided all of the following criteria are met:
- •Best response achieved with prior bortezomib at any time was ≥ PR and with the last PI (PI therapy (alone or in combination) was ≥ PR, AND
- •Participant did not discontinue bortezomib due to ≥ Grade 3 related toxicity, AND
- •Must have had at least a 6-month PI-treatment-free interval prior to Cycle 1 Day 1 (C1D1) of study treatment.
- •Must have an ECOG Status score of 0, 1, or
- •Written informed consent in accordance with federal, local, and institutional guidelines.
- •Age ≥18 years.
- •Resolution of any clinically significant non-hematological toxicities (if any) from previous treatments to ≤ Grade 1 by C1D
- •Patients with chronic, stable Grade 2 non-hematological toxicities may be included following approval from the Medical Monitor.
- •Adequate hepatic function within 28 days prior to C1D
- •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 (estimated creatinine clearance [CrCl] of ≥20 mL/min, calculated using the formula of Cockroft and Gault):
- •(140-Age) × Mass (kg)/(72 × creatinine mg/dL) Multiply by 0.85 if the patient is female, or if CrCl is ≥20 mL/min as measured by 24-hour urine collection.
- •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
- •Prior exposure to a SINE compound (i.e. an XPO-1 inhibitor), including selinexor.
- •Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to randomization. Cancer treated with curative intent for >5 years previously and without evidence of recurrence will be allowed.
- •Has any concurrent medical condition or disease (e.g., 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 C1D
- •Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.
- •Active plasma cell leukemia.
- •Documented systemic light chain amyloidosis.
- •MM involving the central nervous system.
- •Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.
- •Spinal cord compression.
- •Greater than Grade 2 neuropathy or ≥ Grade 2 neuropathy with pain at baseline, regardless of whether or not the patient is currently receiving medication
- •Known intolerance, hypersensitivity, or contraindication to glucocorticoids.
- •Radiation, chemotherapy, or immunotherapy or any other anticancer therapy (including investigational therapies) ≤ 2 weeks prior to C1D
- •Localized radiation to a single site at least 1 week before C1D1 is permitted. Glucocorticoids within 2 weeks of C1D1 are permitted. Patients on long-term glucocorticoids during Screening do not require a washout period but must be able to tolerate the specified dexamethasone dose in this study.
- •Prior autologous stem cell transplantation < 1 month or allogeneic stem cell transplantation < 4 months prior to C1D
- •Active graft versus host disease (after allogeneic stem cell transplantation) at C1D
- •Pregnant or breastfeeding females.
- •Body Surface Area < 1.4 m² at baseline, calculated by the Dubois or Mosteller method.
- •Life expectancy of < 4 months.
- •Major surgery within 4 weeks prior to C1D
- •Active, unstable cardiovascular function:
- •Symptomatic ischemia, or
- •Uncontrolled clinically significant conduction abnormalities (e.g., patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with first-degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or
- •Congestive heart failure of New York Heart Association Class ≥ 3 or known left ventricular ejection fraction < 40%, or
- •Myocardial infarction within 3 months prior to C1D
- •Known active human immunodeficiency virus (HIV) infection or HIV seropositivity
- •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.
- •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.
- •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, including providing 24-hour urine samples for urine protein electrophoresis at the required time points.
研究组 & 干预措施
SVd Arm: Selinexor + Bortezomib + Dexamethasone
Participants received a fixed oral dose of 100 milligrams (mg) selinexor tablets (5 tablets of 20 mg each) once weekly (QW) on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with subcutaneous (SC) injection of 1.3 milligrams per square meter (mg/m^2) bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone twice weekly (BIW) on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Selinexor (Drug)
SVd Arm: Selinexor + Bortezomib + Dexamethasone
Participants received a fixed oral dose of 100 milligrams (mg) selinexor tablets (5 tablets of 20 mg each) once weekly (QW) on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with subcutaneous (SC) injection of 1.3 milligrams per square meter (mg/m^2) bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone twice weekly (BIW) on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Bortezomib (Drug)
SVd Arm: Selinexor + Bortezomib + Dexamethasone
Participants received a fixed oral dose of 100 milligrams (mg) selinexor tablets (5 tablets of 20 mg each) once weekly (QW) on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with subcutaneous (SC) injection of 1.3 milligrams per square meter (mg/m^2) bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone twice weekly (BIW) on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Dexamethasone (Drug)
Vd Arm: Bortezomib + Dexamethasone
Participants received SC injection of 1.3 mg/m^2 bortezomib on Days 1, 4, 8, and 11 of each 21-day cycle for the first 8 cycles, followed by greater than or equal to (>=) 9 cycles on Days 1, 8, 15, and 22 of each 35-day cycle, and received oral dose of 20 mg dexamethasone BIW on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for the first 8 cycles and for cycles >= 9 on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Bortezomib (Drug)
Vd Arm: Bortezomib + Dexamethasone
Participants received SC injection of 1.3 mg/m^2 bortezomib on Days 1, 4, 8, and 11 of each 21-day cycle for the first 8 cycles, followed by greater than or equal to (>=) 9 cycles on Days 1, 8, 15, and 22 of each 35-day cycle, and received oral dose of 20 mg dexamethasone BIW on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for the first 8 cycles and for cycles >= 9 on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Dexamethasone (Drug)
SVdX Arm: Selinexor + Bortezomib + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were able to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with SC injection of 1.3 mg/m^2 bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Selinexor (Drug)
SVdX Arm: Selinexor + Bortezomib + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were able to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with SC injection of 1.3 mg/m^2 bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Bortezomib (Drug)
SVdX Arm: Selinexor + Bortezomib + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were able to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle, along with SC injection of 1.3 mg/m^2 bortezomib QW on Days 1, 8, 15, and 22 of each 35-day cycle, and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Dexamethasone (Drug)
SdX Arm: Selinexor + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were unable to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Selinexor (Drug)
SdX Arm: Selinexor + Dexamethasone
Participants in the VD arm who had IRC-confirmed PD and were unable to tolerate continued bortezomib treatment had crossed over to receive fixed oral dose of 100 mg selinexor tablets (5 tablets of 20 mg each) QW on Days 1, 8, 15, 22, and 29 of each 35-day cycle and an oral dose of 20 mg of dexamethasone BIW on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle until PD confirmed by the IRC, investigator or participant decision to discontinue study treatment, pregnancy, unacceptable AEs or toxicity that could not be managed by supportive care, withdrawal of consent, death, or sponsor decision to terminate the study.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
SVd/Vd Arm: Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC)
时间窗: From date of randomization until IRC-confirmed documented PD or death, censored date, whichever occurred first (up to 33 months)
PFS was defined as time from date of randomization until the first date of IRC-confirmed PD, per International Myeloma Working Group (IMWG) response criteria, or death due to any cause, whichever occurs first. PD included increase of 25% from lowest confirmed response value in 1 or more of the following criteria: a) serum M-protein with absolute increase of \>= 0.5 gram per deciliter (g/dL); b) serum M-protein increase \>= 1 g/dL if the lowest M-component was \>=5 g/dL; c) urine M-protein (absolute increase must be \>= 200 mg per 24 hours); d) in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be greater than \[\>\] 10 mg/dL); e) in participants without measurable serum and urine M-protein levels and without measurable involved FLC levels: bone marrow plasma cell percentage irrespective of baseline status (absolute increase must be \>=10%).
次要结局
- SVd/Vd Arm: Number of Participants With at Least One Grade Greater Than or Equal to [>=] 2 Peripheral Neuropathy Events(From first dose of study treatment to 30 days after the last dose of study treatment inclusive, or the day before the start of new anti-MM treatment, whichever occurs first (up to 33 months))
- SVdX Arm: Overall Response Rate (ORR1) as Assessed by IRC During SVdX Treatment(From date of first SVdX treatment until disease progression or initiating a new MM treatment (up to 33 months))
- SVdX Arm: Progression Free Survival1 (PFS1) as Assessed by IRC During SVdX Treatment(From date of first SVdX treatment until IRC-confirmed documented PD or death or censored date, whichever occurred first (up to 33 months))
- SVd/Vd Arm: Percentage of Participants With Response Rate of Very Good Partial Response (VGPR) or Better Based on IRC Assessment(From date of randomization until confirmed PD or initiating a new MM treatment (up to 33 months))
- SVd/Vd Arm: Overall Response Rate (ORR) as Assessed by IRC(From date of randomization until disease progression or initiating a new MM treatment (up to 33 months))
- SVd/Vd Arm: Overall Survival (OS)(From date of randomization to the date of death or censored date, whichever occurred first (up to 45 months))
- SVd/Vd Arm: Duration of Response (DOR) as Assessed by IRC(From the first documentation of response to the first documentation of PD or death, whichever occurred first (up to 45 months))
- SVd/Vd Arm: Time-to-next-treatment (TTNT) in Participants Randomized to the SVd and Vd Arm Who Received Treatment After SVd/Vd(From date of randomization to start of next anti-MM treatment or death, whichever occurred first (up to 33 months))
- SVd/Vd Arm: Time To Response (TTR) in Participants Randomized to the SVd and Vd Arm(From randomization to the date of first IRC-confirmed PR or better (i.e., PR, VGPR, CR, or sCR), whichever occurred first (up to 33 months))
- SVd/Vd/SVdx Arm: Progression Free Survival 2 (PFS 2) in Participants Randomized to the SVd and Vd Arm Who Received Post-SVd/Vd/SVdX Treatment(From date of first dose of post-SVd/Vd/SVdX treatment to the date of first PD on post-SVd/Vd/SVdX treatment, or death due to any cause (up to 33 months))
- SVd/Vd Arm: Change From Baseline in Participant-Reported Peripheral Neuropathy (PN) Assessed by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire- Chemotherapy-Induced PN 20 (EORTC- QLQ-CIPN20) Total Scores(Svd Arm: Baseline up to End of treatment (EOT) (at Day 820); Vd Arm: Baseline up to EOT (at Day 848))