Selinexor Maintenance Post CAR-T Cell Therapy for Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Tolerability as measured by rate of patients who received > 80% of cumulative selinexor dose during the study period
研究概览
简要总结
The outcomes in patients with relapsed multiple myeloma refractory to triple-therapy (anti-CD38, immunomodulatory drugs (IMiD) and proteasome inhibitors (PI)) remain poor. These patients are eligible for chimeric antigen receptor T-cells (CAR-T), which rely on redirecting autologous T-cells to clear myeloma cells by targeting B-cell maturation antigen (BCMA). BCMA CAR-T therapy is not curative, and unlike autologous stem cell transplant, there is currently no standard for maintenance therapy post CAR-T which could potentially increase MRD rates and extend progression-free survival.
Selinexor is an exportin (XPO1) inhibitor with direct anti-tumor effect used often as an adjunct with other agents as bridging therapy prior to CAR-T. As selinexor does not affect T-cell yields or fitness, T-cell collection on selinexor for CAR-T manufacturing is safe.
The aim of this study is to evaluate the safety and toxicity of selinexor in triple-exposed or refractory multiple myeloma patients with high-risk features (adverse risk cytogenetics, less than complete response (CR) post CAR-T, or extramedullary disease) following BCMA CAR-T therapy. The investigators hypothesize that selinexor as maintenance therapy following CAR-T has the potential to act synergistically with CAR-T cells leading to more durable responses.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Diagnosis of triple-class exposed or refractory multiple myeloma (MM). Diagnosis must be histologically confirmed. Patients with multiple myeloma with local amyloid deposition in the bone marrow are eligible. Only the following risk categories will be enrolled:
- •High risk myeloma, defined by the presence of at least one of the following features:
- •Deletion 17p and/or TP53 alteration:
- •Deletion of 17p with a cancer clonal fraction (CCF) ≥20%, assessed on CD138-positive/purified plasma cells, AND/OR
- •TP53 mutation identified using a validated next-generation sequencing (NGS)-based assay.
- •High-risk IgH translocation with chromosome 1 abnormality:
- •Presence of t(4;14), t(14;16), or t(14;20) in combination with either gain/amplification of 1q (1q+) and/or deletion of 1p
- •Chromosome 1p32 deletion patterns:
- •Monoallelic deletion of 1p32 occurring with gain/amplification of 1q, OR
- •Biallelic deletion of 1p
- •Elevated β2-microglobulin without renal dysfunction:
- •Serum β2-microglobulin ≥5.5 mg/L in the setting of normal renal function, defined as serum creatinine <1.2 mg/dL.
- •Presence of extramedullary disease prior to receiving CAR-T OR
- •Standard risk myeloma with MRD-positive (MRD+) disease at MRD draw around Day 58-60 post CAR-T.
- •Received standard of care ciltacabtagene autoleucel (cilta-cel; Carvykti).
- •Able to monitor disease response by ClonoSEQ MRD testing.
- •At least 18 years of age.
- •ECOG performance status ≤
- •Adequate bone marrow and organ function as defined below:
- •Absolute neutrophil count ≥ 1.0 K/cumm
- •Platelets ≥ 50 K/cumm
- •Hemoglobin ≥ 8.5 g/dL without blood transfusion within 7 days before C1D
- •Total bilirubin ≤ 1.5 x IULN; patients with Gilbert's syndrome must have a total bilirubin < 3 x IULN.
- •AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
- •Calculated creatinine clearance ≥ 15 mL/min by Cockcroft-Gault
- •The effects of selinexor on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to C1D1 of selinexor, for the duration of study participation, and for 90 days after completion of selinexor. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
- •Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
排除标准
- •MM with active CNS involvement.
- •Confirmed progressive disease by IMWG after CAR-T administration.
- •Unresolved cytokine release syndrome (CRS) or CAR-T neurologic toxicity.
- •Any unresolved non-hematologic grade ≥ 3 treatment-related toxicity from CAR-T.
- •Administration or planned administration of any other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy which would be considered a treatment of multiple myeloma from Day 28 post-CAR-T cell therapy through discontinuation from study treatment. Note: patients may be on corticosteroids if they are being given for disorders other than multiple myeloma (e.g., adrenal insufficiency, rheumatoid arthritis)
- •Has received selinexor or another XPO1 inhibitor post-CART.
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- •Prior organ transplant requiring immunosuppressive therapy.
- •Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
- •Currently receiving any other investigational agents.
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor or other agents used in the study.
- •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.
- •Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to C1D1 of selinexor (patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 of selinexor may enroll); active, unstable cardiovascular function, as indicated by the presence of symptomatic ischemia, uncontrolled clinically significant conduction abnormalities (e.g. patients with ventricular or atrial 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), congestive heart failure of NYHA class ≥ 3 or known left ventricular ejection fraction of < 40%, or myocardial infraction within 3 months prior to C1D1 of selinexor therapy.
- •Major surgery within 28 days prior to C1D1 of selinexor
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of C1D1 of selinexor.
- •HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
- •Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
- •History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
研究组 & 干预措施
Selinexor
Patients with high risk of relapse will receive maintenance selinexor starting at Day 30 (high risk MM patients) or after Day 58 (for MRD+ patients) post-cilta-cel infusion and will continue selinexor for up to 12 cycles. Selinexor will be given weekly on Days 1, 8, 15, and 22 of each 28-day cycle. The first 3 to 6 patients enrolled will be part of the safety run-in cohort; these patients will be monitored for dose-limiting toxicities during Cycle 1.
干预措施: Selinexor (Drug)
结局指标
主要结局
Tolerability as measured by rate of patients who received > 80% of cumulative selinexor dose during the study period
时间窗: Through completion of selinexor treatment (estimated to be 12 months)
Rate of non-hematologic grade ≥ 3 treatment-related adverse events (excluding conditioning and CAR-T related adverse events) according to CTCAE v 5.0
时间窗: From start of selinexor through 30 days after the last dose of selinexor (estimated to be 13 months)
Tolerability as measured by rate of patients who received > 80% of cumulative selinexor dose during the study period
时间窗: Through completion of selinexor treatment (estimated to be 12 months)
次要结局
- Rate of MRD negativity by clonoSEQ sensitive to 10-5(At 12 months after CAR-T infusion)
- Rate of complete response (CR) and stringent CR (sCR) by IMWG response criteria(At 12 months after CAR-T infusion)
- Progression-free survival (PFS)(At 12 months after CAR-T infusion)
- Time to progression (TTP)(Through completion of follow-up (estimated to be 24 months))
- Duration of response (DOR)(Through completion of follow-up (estimated to be 24 months))
- Rate of complete response (CR) and stringent CR (sCR) by IMWG response criteria(At 6 months after CAR-T infusion)
- Rate of MRD negativity by clonoSEQ sensitive to 10-5(At 6 months after CAR-T infusion)
- Progression-free survival (PFS)(At 6 months after CAR-T infusion)
- Rate of MRD negativity by clonoSEQ sensitive to 10-5(At 12 months after CAR-T infusion)
- Rate of complete response (CR) and stringent CR (sCR) by IMWG response criteria(At 12 months after CAR-T infusion)
- Progression-free survival (PFS)(At 12 months after CAR-T infusion)
- Time to progression (TTP)(Through completion of follow-up (estimated to be 24 months))
- Duration of response (DOR)(Through completion of follow-up (estimated to be 24 months))