Protocol H125001: An Open-Label Phase 1/2 Study of JCARH125, BCMA-targeted Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 165
- 试验地点
- 39
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity in Phase 1 and Phase 1 Anakinra
研究概览
简要总结
This is an open-label, multicenter, Phase 1/2 study to determine the safety and efficacy of JCARH125, a CAR T-cell product that targets B-cell maturation antigen (BCMA), in adult subjects with relapsed and/or refractory multiple myeloma. The study will include a Phase 1 part to determine the recommended dose of JCARH125 in subjects with relapsed and/or refractory multiple myeloma, followed by a Phase 2 part to further evaluate the safety and efficacy of JCARH125 at the recommended dose. The safety and tolerability of JCARH125 in subjects who receive prophylactic treatment with anakinra will be evaluated in a separate Phase 1 cohort. The antitumor activity of JCARH125 in subjects who have been previously treated with BCMA-directed therapy will be evaluated in separate Phase 2a cohorts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 multiple myeloma (MM) with relapsed and/or refractory (R/R) disease. Participants must have received at least 3 prior anti-myeloma treatment regimens. Participants must have previously received all of the following therapies and must be refractory to the last line of therapy prior to entering the study (not applicable to Phase 2a):
- •Autologous stem cell transplant
- •A regimen that included an immunomodulatory agent (eg, thalidomide, lenalidomide, pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib), either alone or in combination
- •Anti-CD38 (eg, daratumumab) as part of a combination regimen or as a monotherapy
- •Subjects who have received prior allogeneic stem cell transplant or donor lymphocyte infusion at least 100 days before enrollment with no signs of acute or chronic graft-versus-host disease (GVHD) will be considered eligible. Subjects who were not candidates to receive one or more of the above treatments (ie, contraindicated) are eligible.
- •Subjects must have measurable disease.
- •Subject must be willing to provide fresh bone marrow biopsy samples during Screening (and prior to study treatment, if required).
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Adequate renal, bone marrow, hepatic, pulmonary, and cardiac function
- •Phase 2a cohorts only - Subjects with R/R MM who have been previously treated with prior BCMA-directed anti-myeloma therapy, achieved at least a partial response (PR) and progressed on the following treatment:
- •Subjects who have received prior BCMA-directed CAR T-cell therapy. The last CAR T-cell therapy must have been received at least 6 months prior to JCARH125 screening.
- •Subjects who have received prior BCMA-directed T-cell engager therapy.
- •Subjects who have received prior BCMA-directed antibody-drug conjugate therapy.
排除标准
- •Subjects with known active or history of CNS involvement by malignancy
- •Subjects with solitary plasmacytoma; active or history of plasma cell leukemia (PCL); Waldenstrom's macroglobulinemia; Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasmaproliferative disorder, Skin changes (POEMS) syndrome; or symptomatic amyloidosis
- •Subjects who are considered eligible to receive and have not refused an autologous stem cell transplant
- •History of another primary malignancy that has not been in remission for at least 3 years. The following are exempt from the 3-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.
- •Require systemic immunosuppressive therapies (eg, calcineurin inhibitors, methotrexate, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-IL-6 or anti-IL-6 receptor [IL-6R])
- •Prior CAR T-cell or other genetically-modified T-cell therapy (not applicable for subjects enrolled in Phase 2a cohorts)
- •Prior treatment with a BCMA-targeted agent (not applicable for subjects enrolled in Phase 2a cohorts)
- •History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
- •Untreated or active infection at time of initial screening, at the time of leukapheresis, within 72 hrs before lymphodepletion, or 5 days before JCARH125 infusion.
- •History of any of the following cardiovascular conditions within 6 months of screening: Class III or IV heart failure as defined by the New York Heart Association (NYHA), myocardial infarction, unstable angina, uncontrolled or symptomatic atrial arrhythmias, any ventricular arrhythmias, or other clinically significant cardiac disease
- •Subjects with known hypersensitivity to E Coli-derived proteins (only applicable to subjects in Phase 1 Anakinra Cohort)
- •History of severe immediate hypersensitivity reaction to any of the protocol-mandated or recommended agents used in this study
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity in Phase 1 and Phase 1 Anakinra
时间窗: From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)
TEAE is defined as an AE that starts any time from initiation of JCARH125 administration through and including 90 days following the JCARH125 infusion graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Any AE occurring after the initiation of another anticancer treatment will not be considered a TEAE. Grade 3=Severe; Grade 4=Life-threatening; and Grade 5=death.
Number of Participants Receiving Prophylactic Anakinra With Grade ≥2 Cytokine Release Syndrome (CRS) in Phase 1 and Phase 1 Anakinra
时间窗: From first infusion to up to aproximately 61 months
Number of participants receiving prophylactic anakinra with grade ≥ 2 CRS relative to the number of participants treated at the recommended Phase 2 dose (RP2D) in the Phase 1 dose escalation portion of the trial with grade ≥ 2 CRS. CRS grade is defined by the most severe symptom (excluding fever). Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening
Number of Participants With Dose-Limiting Toxicity (DLT) in Phase 1
时间窗: From day 1 to day 22 following JCARH125 infusion (Up to 21 days)
DLT is defined as adverse events (AEs) that occur within 21 days following JCARH125 infusion and meet any of the following criteria: * Treatment-emergent Grade ≥3 allergic reactions related to JCARH125; * Treatment-emergent Grade 3 seizures, regardless of attribution, that do not resolve to Grade ≤2 within 3 days in participants who have no evidence of central nervous system (CNS) involvement of Multiple Myeloma or other CNS pathology; * Treatment-emergent autoimmune toxicity Grade ≥3, regardless of attribution (excluding B-cell aplasia); * Treatment-emergent Grade 3 CRS that does not resolve to Grade ≤2 within 72 hours; * Any other treatment-emergent Grade 3 AE related to JCARH125 that does not resolve to Grade ≤2 within 7 days; * Any treatment-emergent Grade 4 AE related to JCARH125 that does not resolve to Grade ≤2 within 7 days; * Treatment-emergent Grade 4 Cytokine Release Syndrome of any duration; * Any treatment-emergent Grade 5 toxicity not due to the underlying malignancy
Number of Participants With Clinically Significant Laboratory Abnormalities by Severity in Phase 1 and Phase 1 Anakinra
时间窗: From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)
Clinically significant laboratory abnormalities are assessed by investigator and are reported as treatment-emergent adverse event (TEAE). TEAE is defined as an AE that starts any time from initiation of JCARH125 administration through and including 90 days following the JCARH125 infusion graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Any AE occurring after the initiation of another anticancer treatment is not considered a TEAE. Grade 3=Severe; Grade 4=Life-threatening.
Time to Onset of Grade ≥2 Cytokine Release Syndrome (CRS) in Phase 1 and Phase 1 Anakinra
时间窗: From JCARH125 infusion to the first onset of Grade ≥2 CRS (Up to approximately 61 months)
Time to first onset of Grade ≥2 CRS in participants receiving prophylactic anakinra relative to onset of Grade ≥ 2 CRS in participants treated at the RP2D(s) in the Phase 1 dose escalation portion of the trial. Time to onset is calculated from the latest JCARH125 infusion prior to the first onset of Grade \>= 2 CRS. CRS grade is defined by the most severe symptom (excluding fever). Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening
Number of Participants Receiving Prophylactic Anakinra With no Cytokine Release Syndrome (CRS) Occurring on Days 1-3 in Phase 1 Anakinra
时间窗: Day 1, 2, 3
The number of participants receiving prophylactic anakinra with no CRS occurring on study days 1, 2, or 3. CRS grade is defined by the most severe symptom (excluding fever). Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening
Overall Response Rate (ORR) in Phase 2 and Phase 2a
时间窗: From the time of the JCARH125 infusion until disease progression, end of study, or the start of another anticancer therapy or stem cell transplant (Up to aproximately 61 months)
ORR is defined as stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), according to IMWG criteria. Participants without any reported disease response assessments will be considered non-responders. sCR=complete response plus normal free light chain ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR=negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow aspirates. When the only method to measure disease is by serum FLC levels, CR can be defined as a normal FLC ratio of 0.26 to 1.65; VGPR=serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein level plus urine M-protein level \< 100 mg/24 h; PR=≥ 50% reduction of serum M protein plus reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg/24 h
次要结局
- Area Under the Concertation-Time Curve (AUC) From Time Day 1 to Day 29 [AUC (0-28 Days)](From JCARH125 infusion through 28 days after the infusion)
- Number of Participants With Pharmacokinetics Persistence(Day 29, 60, 90, 180, 270, 365, 545, 730)
- Overall Response Rate (ORR) in Phase 1 and Phase 1 Anakinra(From the time of the JCARH125 infusion until disease progression, end of study, or the start of another anticancer therapy or stem cell transplant (Up to 61 approximately months))
- Time to Maximum Observed Concentration (Tmax)(From JCARH125 infusion through the day 29 visit)
- Duration of Complete Response (DoCR) in Phase 2 and 2a(From first response to the date of progression or death due to any cause, whichever occurs first (Up to approixmately 61 months))
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity in Phase 2 and Phase 2a(From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days))
- Maximum Observed Concentration (Cmax)(From JCARH125 infusion through the day 29 visit)
- Duration of Response (DoR) in Phase 2 and 2a(From first response to the date of progression or death due to any cause, whichever occurs first (Up to approixmately 61 months))
- Number of Participants With Clinically Significant Laboratory Abnormalities by Severity in Phase 2 and Phase 2a(From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days))
- Progression Free Survival (PFS) in Phase 2 and Phase 2a(Form date of first infusion to the date of disease progression, or death, due to any reason (Up to approximately 61 months))
- Duration of Hospitalization From JCARH125 Administration in Phase 2(From JCARH125 infusion to up to approximately 61 months)
- Complete Response Rate (CRR)(From the time of the JCARH125 infusion until disease progression, end of study, or the start of another anticancer therapy or stem cell transplant (Up to aproximately 61 months))
- Overall Survival (OS) in Phase 2 and Phase 2a(Form date of first infusion to the date of death due to any reason (Up to apprixamtely 61 months))
- Change From Baseline in the Total Score of European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ-MY20) in Phase 2(Baseline and visit 24 month)
- Time to Response (TTR) in Phase 2 and Phase 2a(Form date of first infusion to the date of disease progression, or death, due to any reason (Up to approximately 61 months))
- Change From Baseline (EQ-5D-5L) Index Score in Phase 2(Baseline and visit 24 month)
- Reasons for Hospitalization From JCARH125 Administration in Phase 2(From JCARH125 infusion to up to approximately 61 months)
- Time to Complete Response (TTCR) in Phase 2 and Phase 2a(Form date of first infusion to the date of disease progression, or death, due to any reason (Up to approximately 61 months))
- Change From Baseline in the Total Score of European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) in Phase 2(Baseline and visit 24 month)