A Phase I/II Trial of 'Re-Priming' Radiation Therapy for Relapsed/Refractory Non-Hodgkin Lymphoma Patients in Incomplete Response After Chimeric Antigen Receptor T-cell (CAR-T) Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 2
- 主要终点
- Incidence of Treatment-Related Adverse Events as Assessed by CTCAE v5.0, ASTCT Consensus Guidelines for CRS, and ASTCT ICANS Consensus Guidelines for Neurotoxicity [Phase 1: Safety and Tolerability]
研究概览
简要总结
This is a single-arm open-label phase I/II trial studying the safety and efficacy of focal 're-priming' radiation therapy (RT) to FDG-avid residual sites of disease in relapsed/refractory non-Hodgkin lymphoma (R/R NHL) patients with incomplete response (IR) to CAR T-cell therapy (CAR-T) by day 30 post-CAR-T PET/CT. We hypothesize that focal 're-priming' RT will be safe (phase I) and improve conversion to metabolic complete response (CR) by day 90 post-CAR-T PET/CT from 29% (historical control) to 58% (phase II).
详细描述
Early clinical trials of CAR-T in R/R NHL suggest that only ~40% of patients achieve CR by day 30 PET/CT evaluation. Of those who do not, the large majority (~70%) ultimately fail, while ~30% convert to CR after a median time of 64 days (range, 49-424). This group of patients, who have incomplete response on day 30 PET/CT after CAR-T and thus are most likely to fail CAR-T alone, may be the ideal target for early therapeutic intervention to 're-prime' CAR-T and convert them from IR to CR.
Preclinical and early clinical studies suggest potential immune augmentation when combining RT with CAR-T. Therefore, we propose a phase I/II clinical trial investigating the impact of RT to poor responding sites of disease after CD19-directed CAR-T in R/R NHL patients who are likely to fail CAR-T alone. We hypothesize that focal RT to residual FDG-avid sites of disease on day 30 PET/CT will improve the number of patients who convert to CR by day 90 PET/CT both through local cytotoxic effects as well as local and systemic synergistic effects through 're-priming' of CAR T-cells.
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
- •Age ≥ 18 years.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening
- •Biopsy-proven histological high-grade non-Hodgkin lymphoma, such as diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma.
- •Prior treatment with any CD19-directed CAR T-cell therapy, such as tisagenlecleucel (tisa-cel, Kymriah), axicabtagene ciloleucel (axi-cel, Yescarta), or lisocabtagene maraleucel (liso-cel).
- •Incomplete response noted on day 30 PET post-CAR-T, defined as not achieving CR per Lugano 2014 classification
- •Ability to understand and the willingness to sign a written informed consent
- •All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- •7.1 A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
- •Has not undergone a hysterectomy or bilateral oophorectomy; or
- •Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
排除标准
- •Prior "definitive" radiation therapy (40-50 Gy EQD2 with an α/β of 10) to one or more sites of incomplete response as noted on day 30 post-CAR-T PET/CT scan within the past one year. Prior "palliative" radiation therapy (<40 Gy EQD2) permissible at discretion of treating physician.
- •Intracranial site of incomplete response as noted on day 30 post-CAR-T PET/CT scan or any active central nervous system involvement by malignancy.
- •Active grade 3 or higher CRS or neurotoxicity related to CAR-T.
- •Patients with prior history of auto-immune disease or other contraindication to RT.
- •Patients with life expectancy < 3 months.
- •Psychiatric illness/social situations that would limit compliance with study requirements.
- •Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
结局指标
主要结局
Incidence of Treatment-Related Adverse Events as Assessed by CTCAE v5.0, ASTCT Consensus Guidelines for CRS, and ASTCT ICANS Consensus Guidelines for Neurotoxicity [Phase 1: Safety and Tolerability]
时间窗: 4 Months post CAR-T
To determine the dose-limiting toxicity (DLT) and maximally tolerated dose (MTD) of RT to sites of incomplete response after CAR-T in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). DLT rate will be defined by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade 4 or higher hematologic, grade 3 or higher dermatitis/burn, pneumonitis, enteritis, or other toxicity attributable to RT, as well as new grade 3 or higher cytokine release syndrome (CRS) per American Society for Transplantation and Cellular Therapy (ASTCT) consensus guidelines or grade 3 or higher neurotoxicity per ASTCT immune effector cell-associated neurotoxicity syndrome (ICANS) consensus guidelines for adults. For those who had prior stem cell transplant (SCT), DLT will also be defined by grade C or D graft-versus-host-disease (GVHD) per International Bone Marrow Transplant Registry (IBMTR) grading system.
Rate of Metabolic Complete Response (CR) on Day 90 Post-CAR-T PET/CT scan per Lugano 2014 Classification [Phase 2: Efficacy]
时间窗: Day 90 post CAR-T
To assess the efficacy of adding RT to sites of incomplete response after CAR-T in R/R NHL patients by determining the rate of metabolic complete response (CR) at day 90 post-CAR-T PET/CT scan, assessed per Lugano 2014 classification.
次要结局
- Progression free survival (PFS)(1 year)
- Response rates of individual sites(Day 90 PET post-CAR-T)
- Duration of response (DOR) in Participants with Any Response as Noted on Day 90 Post-CAR-T PET/CT(1 year)
- Overall survival (OS)(1 year)
研究者
Kiran Kumar
Principal Investigator, Assistant Professor, Chief of Lymphoma & Pediatrics Radiation Oncology Service
University of Texas Southwestern Medical Center