Radiation Post-CAR T in Refractory Lymphoma

Study Overview
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Brief Summary
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This study is evaluating the safety and efficacy of using radiotherapy in participants who have refractory lymphoma shortly after receiving CAR T cell therapy (axicel or tisacel).

Detailed Description
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This research study is a Pilot Study, which is the first time investigators are examining this intervention after administration of CAR T cell therapy. This research study looks to systematically investigate the safety and efficacy of radiotherapy following CAR T cell therapy (axicel or tisacel) in refractory lymphoma. CAR T cell therapy involves genetically modifying T cells to target tumor cells for death. Radiotherapy is a standard treatment offered with refractory lymphoma and uses high-energy x rays, or particles, to destroy or damage cancer cells. Few have received CAR T cell therapy prior to radiation therapy and this study aims to gather more information on radiotherapy following CAR T cell therapy as a treatment option and its potential to improve participants immune system's response to cancer cells as well as its interaction with CAR T cell therapy to better treat refractory lymphoma. The research study procedures include screening for eligibility, enrollment, biopsy following radiation, post-treatment period, and long-term follow-up. Participants will receive radiotherapy at a dose and schedule determined by the study doctor. Participants will be followed for up to 24 months after completion of study treatment. It is expected that about 20 people will take part in this research study.

Official Title
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Radiation Therapy To Enhance CAR T Efficacy Early in Post-CAR T Cell Therapy Refractory Lymphoma: A Pilot Study

Conditions
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Hematologic Malignancy, Refractory Lymphoma

Intervention / Treatment
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* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be able to undergo biopsy. Biopsy will be obtained for patients to exclude possibility of false negative residual FDG avidity on PET/CT that is not substantially increased relative to pre-CAR-T PET/CT. Exceptions are allowed for patients who have clearly progressive disease for whom delaying radiation therapy to obtain a biopsy may worsen outcome (such as cases of cord compression), and for patients for whom the risks of biopsy are high (such as patients with evidence for CNS involvement). Biopsy-confirmed refractory disease within 30-90 days following commercial axicabtagene ciloleucel or tisagenlecleucel therapy for a hematologic malignancy (these include relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma). Of note, 'refractory' refers to patients who had early refractory disease after CAR-T cell therapy and not to patients who have received CAR-T for refractory disease, but had complete response to CAR-T cell therapy. At least 1 measurable lesion according to the Lugano criteria1. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy The following criteria pertain to pattern of progression: Patients may have one refractory lesion without other residual or progressive disease as per PET/CT Patients may have more than one refractory lesion, but with evidence for at least partial response of at least one other lesion as per PET/CT Patients with more than one site of refractory disease without evidence for at least partial response of at least one other lesion are eligible if they are: A. Symptomatic from a refractory lesion (such as cord compression or focal pain) or B. Have disease that can locally affect the spinal canal or brain if left untreated. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia and prolonged cytopenias that are not expected to worsen during RT) if there is concern for overlap of anticipated radiation-related toxicity and toxicity from prior therapy due to where the RT field is located. Age 18 or older Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Any medical condition likely to interfere with assessment of safety or efficacy of RT Patients with more than one site of disease without any evidence for response to CAR T cell therapy who are not focally symptomatic due to progressive disease or do not have disease that can locally affect the spinal canal or brain if left untreated Women of child-bearing potential who are pregnant because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential. In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy<br>Participants must have received CAR-T infusion within the last 90 days prior to completing a study screening and enrollment process. Participants will be enrolled within 28 days after screening is complete and radiotherapy will occur within 14 days after study enrollment. Radiotherapy will be administered based on a dose and schedule pre-determined by the study doctor. | Radiation: Radiotherapy<br>* Radiotherapy at pre-determined dose and schedule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0 | Rate and severity of RT-related toxicity as per CTCAE v5.0 criteria during RT or within the first 30 days of completing RT. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | The competing-risk analysis method will be used to estimate the cumulative incidence of relapse. The cumulative incidence of relapse in the presence of non-disease related mortality (the competing risk) will be estimated along with 2-sided 95% confidence intervals at 3-month intervals. Among subjects who experience an objective response, DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per Lugano criteria or death regardless of cause. Subjects not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing. | First objective response (which is subsequently confirmed) to disease progression per Lugano criteria or death regardless of cause or up to 2 years | 
| Objective response rate (ORR) per IRRC | ORR per IRRC is defined as the incidence of either a complete response or a partial response by Lugano criteria as determined by the IRRC. All subjects that do not meet the criteria for an objective response by the analysis data cutoff date will be considered non-responders. | defined as the incidence of either a complete response or a partial response by Lugano criteria or up to 2 years | 
| Progression-free Survival (PFS) | Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for progression free survival time. Estimates of the proportion of subjects alive and progression-free at 3-month intervals will be provided. PFS is defined as the time from RT completion date to the date of disease progression per Lugano criteria or death from any cause. Subjects not meeting the criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date. | Time from RT completion date to the date of disease progression per Lugano criteria or death from any cause up to 2 years | 
| Overall All Survival | Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for OS. Estimates of the proportion of subjects alive at 3-month intervals will be provided | OS is defined as the time from RT completion to the date of death up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematologic Malignancy, Refractory Lymphoma, CAR T cell therapy, Radiotherapy