NCT04196491已完成1 期
A Phase 1, Open-label, Multicenter Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (KarMMa-4)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Celgene
- 入组人数
- 13
- 试验地点
- 22
- 主要终点
- Adverse Events (AEs)
研究概览
简要总结
This is a multicenter, open-label, phase 1, single arm study intended to determine the optimal target dose and safety of bb2121 in subjects with HR (R-ISS Stage III per IMWG criteria) NDMM. Subjects should have received 3 Cycles of standard induction therapy prior to undergoing leukapheresis procedure to collect autologous mononuclear cells for manufacture of the drug product (bb2121). Following manufacture of the drug product, subjects will receive fourth cycle of induction therapy followed by lymphodepleting therapy with fludarabine and cyclophosphamide prior to bb2121 infusion. Maintenance therapy is recommended for all subjects who have received bb2121 infusion and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later.
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
- •Subjects must satisfy all of the following criteria to be enrolled in the study:
- •Subject is newly diagnosed and has symptomatic Multiple Myeloma (MM) prior to initiating induction anti-myeloma therapy
- •Subject is ≥ 18 years of age at the time of initial diagnosis of MM
- •Subject has measurable disease at initial diagnosis by
- •M-protein and/or
- •Light chain MM without measurable disease in the serum or urine
- •Subject has high-risk MM at the time of initial diagnosis of MM per R-ISS Stage III as defined by IMWG:
- •ISS Stage III and cytogenetic abnormalities with t(4; 14) and/or del(17p); and/or t(14:16) by iFISH; or;
- •ISS Stage III and serum LDH > ULN
- •Subject has Eastern Cooperative Oncology Group performance ≤ 1
- •Subjects has received ≤ to 3 cycles of the following induction anti-myeloma therapy prior to enrollment:
- •Cycle 1: one of the following regimens (RVd, KRd, CyBorD, D-RVd and D-KRd)
- •Cycle 2 to Cycle 3: either KRd or RVd (Cycle 3 must be without dexamethasone)
排除标准
- •The presence of any of the following will exclude a subject from enrollment: The presence of any of the following will exclude a subject from enrollment:
- •At initial diagnosis, screening and prior to initiation of induction therapy for MM:
- •Subject has non-secretory MM
- •During Screening:
- •Subject received any treatments for MM other than up to 3 cycles of induction therapy per protocol
- •Subject has any of the following laboratory abnormalities:
- •Absolute neutrophil count < 1,000/μL
- •Platelet count < 50,000 mm3
- •Hemoglobin < 8 g/dL (< 4.9 mmol/L)
- •Serum creatinine clearance < 45 mL/min
- •Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
- •Serum aspartate aminotransferase or alanine aminotransferase > 2.5 × upper limit of normal
- •Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert's syndrome
- •INR or aPTT > 1.5 × ULN
- •Subject has history or presence of clinically significant CNS pathology
- •Subjects has high risk for developing deep vein thrombosis or pulmonary embolus and are unable or unwilling to undergo anti-thrombotic therapy
- •Subject has peripheral neuropathy of > Grade 2 severity according to the NCI CTCAE Version 4.03 with bortezomib based induction regimen
- •Subjects has moderate or severe pulmonary hypertension
- •Subject has intolerance to components of induction regimen (KRd or RVd) or has any contraindication to one or the other drug
- •Subject has not recovered from induction therapy-related toxicities (non-hematologic) to < grade 1 CTCAE at the time of screening
- •Subject has prior history of deep vein thrombosis or pulmonary embolus (PE) within 6 months of starting study treatment
- •Subject has cardiac conditions such as:
- •Echocardiogram or multi gated acquisition assessment of left ventricular ejection fraction < 45%
- •Subject has a history of clinically significant cardiovascular disease or clinically significant ECG abnormalities
- •Subject has Pulmonary conditions such as:
- •Subject has known chronic obstructive pulmonary with a forced expiratory vol in 1 sec 50% of predicted normal.
- •Inadequate pulmonary function defined as oxygen saturation < 92 % on room air
- •Subject needs ongoing treatment with chronic immunosuppressants
- •Subject has history of primary immunodeficiency
- •Subject is seropositive for human immunodeficiency virus, chronic or active hepatitis B or active hepatitis A or C
研究组 & 干预措施
Dose Escalation
Experimental
- bb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 800 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy with a planned starting dose of 450 x 10^6 CAR+ T cells.
- Lenalidomide maintenance therapy is recommended for all patients and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later
干预措施: bb2121 (Biological)
Dose Escalation
Experimental
- bb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 800 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy with a planned starting dose of 450 x 10^6 CAR+ T cells.
- Lenalidomide maintenance therapy is recommended for all patients and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later
干预措施: Fludarabine (Drug)
Dose Escalation
Experimental
- bb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 800 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy with a planned starting dose of 450 x 10^6 CAR+ T cells.
- Lenalidomide maintenance therapy is recommended for all patients and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later
干预措施: Cyclophosphamide (Drug)
Dose Escalation
Experimental
- bb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 800 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy with a planned starting dose of 450 x 10^6 CAR+ T cells.
- Lenalidomide maintenance therapy is recommended for all patients and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later
干预措施: Lenalidomide (Drug)
结局指标
主要结局
Adverse Events (AEs)
时间窗: Approximately 2 years after last subject bb2121 infused
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.
Dose-limiting toxicity (DLT) rates
时间窗: Up to completion of DLT period after last subject bb2121 infused
DLTs will be assessed during the DLT interval (ie, within 21 days immediately after bb2121 infusion). DLTs are defined as any bb2121 related Grade 3 to 5 toxicity.
次要结局
- Pharmacokinetics - Cmax(Approximately 2 years after last subject bb2121 infused)
- Proportion of subjects who achieved Complete Response (CR) Rate(Approximately 2 years after last subject bb2121 infused)
- Duration of Response (DoR)(Approximately 2 years after last subject bb2121 infused)
- Feasibility of initiating maintenance(Approximately 2 years after last subject bb2121 infused)
- Overall Response Rate (ORR)(Approximately 2 years after last subject bb2121 infused)
- Time to Complete Response (TCR)(Approximately 2 years after last subject bb2121 infused)
- Time to start maintenance(Approximately 2 years after last subject bb2121 infused)
- Progression-free Survival (PFS)(Approximately 2 years after last subject bb2121 infused)
- Overall Survival (OS)(Approximately 2 years after last subject bb2121 infused)
- Pharmacokinetics - Tmax(Approximately 2 years after last subject bb2121 infused)
- Pharmacokinetics - AUC(Approximately 2 years after last subject bb2121 infused)
研究者
研究点 (22)
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