Back to resultsLow Dose Radiation as Bridging Therapy in Relapsed B-Cell Non-Hodgkin Lymphoma
Primary Purpose
DLBCL - Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma, Follicular Lymphoma
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Bridging radiation therapy
Liso-cel
Post-infusion radiation
Sponsored by
About this trial
This is an interventional treatment trial for DLBCL - Diffuse Large B Cell Lymphoma
Eligibility Criteria
Inclusion Criteria: Biopsy-proven relapsed or progressive diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or DLBCL arising from indolent lymphoma meeting an FDA-approved (Food and Drug Administration-approved) indication for liso-cel infusion Presence of disease on imaging including at least one disease site safe for radiation as determined by treating radiation oncologist Willingness to participate in clinical trial and provide informed consent Adequate organ function as assessed by standard institution protocols and United States (US) prescribing information label for comorbidities, heart, and lung function to undergo FDA-approved CAR T-cell therapy as determined by institution Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Age 19 years or older, there is no upper limit to the age Exclusion Criteria: Subject is unsafe for radiation therapy as determined by investigator and/or radiation oncologist Diagnosis is primary central nervous system (CNS) lymphoma (secondary CNS lymphoma with additional systemic site is allowed) Requirement for concurrent high dose methotrexate Secondary active malignancy that has not been in remission for at least 2 years. This excludes non-melanoma skin cancer, definitively treated stage 1 solid tumor with low risk or recurrence, and curatively treated localized prostate cancer. Pregnant or nursing women Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as determined by investigator Unwillingness to follow procedures required in the protocol Inadequate organ or hematologic conditions that prohibit the use of lymphodepleting chemotherapy Use of lymphoma-directed therapy within 14 days of T-cell pheresis
Sites / Locations
- University of Nebraska Medical CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Single arm
Arm Description
Subjects will receive 4 gray (Gy) radiation in 2 fractions in the bridging period following lymphocyte pheresis, prior to lymphodepleting chemotherapy and chimeric antigen receptor (CAR) T-cell infusion. Post CAR T-cell infusion radiation therapy will be allowed as determined by study investigator but prespecified at time of radiation oncology consultation.
Outcomes
Primary Outcome Measures
Feasibility of the intervention in the proposed study population
The percentage of subjects who receive a chimeric antigen receptor (CAR) T-cell infusion after receiving bridging radiation therapy. A one-sided Binomial test will be conducted to assess whether acceptable percentage (>70% vs <70%) of patients receive CAR T-cell perfusion after undergoing the radiation therapy.
Secondary Outcome Measures
Incidence of treatment-emergent adverse events to assess the safety of the proposed intervention
Assessed via the incidence of combined Grade 3 and 4 cytokine release syndrome (CRS) or immune effector cell associated neurotoxicity syndrome (ICANS) events as measured by the American Society of Transplant and Cellular Therapy (ASTCT) consensus grading. The grading scale ranges from Grade 1 to 4, with a higher grade indicating a worse outcome. Assessed from the cumulative CRS and ICANS events occurring by the D+30 visit.
Evaluate the response to the study intervention of radiation and CAR T-cell therapy
Response rate will be assessed via PET/CT (positron emission tomography/computed tomography) using Lugano criteria. Overall response rate (ORR) will be defined as the proportion of patients with either a complete response (CR) or a partial response (PR) at D+100. For ORR, CR, and PR: two-sided exact binomial 95% confidence interval of response rate will be constructed to assess the precision of the point estimate.
Evaluate progression-free survival (PFS) following the study intervention
PFS will be measured using the Kaplan-Meier method. Disease progression will be measured according to clinical and imaging assessment (Lugano criteria) and will require biopsy confirmation.
Evaluate duration of response (DOR) following CAR T-cell therapy
DOR will be summarized using the Kaplan-Meier method, but only for patients who have achieved a response of at least partial response. DOR is defined by time of first response (D+30 visit) to disease progression, start of new antineoplastic therapy due to efficacy concerns, or death from any cause.
Evaluate overall survival (OS) following study intervention
OS will be analyzed by the Kaplan-Meier method. Subjects alive at last follow up will be censored.
Evaluate the rate of prolonged cytopenias following the intervention
The rate of prolonged cytopenias will be measured as a proportion of subjects with Grade 3 or higher hematologic toxicities per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria at the D+100 visit. The 95% confidence interval will be estimated.
The CTCAE v5.0 grading system ranges from Grade 0 to 5, with a higher grade indicating a worse outcome.
Monitor overall safety and toxicity of the intervention
Toxicity will be graded using CTCAE v5.0 guidelines. Grade 3 or higher toxicities will be tabulated using percentages at each follow up. The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading system ranges from Grade 0 to 5, with a higher grade indicating a worse outcome.
Monitor Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) toxicity events
Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) toxicity events will be collected for all grades as measured by American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria.
The ASTCT consensus criteria grading system ranges from Grade 1 to 4, with a higher grade indicating a worse outcome.
Full Information
NCT ID
NCT05621096
First Posted
October 27, 2022
Last Updated
September 28, 2023
Sponsor
University of Nebraska
Collaborators
Bristol-Myers Squibb
1. Study Identification
Unique Protocol Identification Number
NCT05621096
Brief Title
Low Dose Radiation as Bridging Therapy in Relapsed B-Cell Non-Hodgkin Lymphoma
Official Title
Feasibility of Low Dose Radiation as Bridging Therapy for Lisocabtagene Maraleucel in Relapsed B-Cell Non-Hodgkin Lymphoma
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 21, 2023 (Actual)
Primary Completion Date
July 2025 (Anticipated)
Study Completion Date
July 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Nebraska
Collaborators
Bristol-Myers Squibb
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The goal of this clinical trial is to learn about treatment for people with B-cell lymphoma that did not respond to treatment or that has gotten worse after treatment. The aim of this trial is to answer the following questions:
If it is realistic to give people radiation treatment before they receive a chimeric antigen receptor (CAR) T-cell treatment for their cancer
If it is safe to give people radiation treatment before they receive a CAR T-cell treatment for their cancer
Detailed Description
This is a pilot study to evaluate the feasibility of low-dose radiation therapy in the bridging period between chimeric antigen receptor (CAR) T-cell collection, manufacturing, and infusion (vein-to-vein) in patients with relapsed and refractory aggressive B-cell lymphoma.
Emerging cellular immunotherapies including CAR T-cell therapy have produced remarkable outcomes for this population. The Food and Drug Administration (FDA) has recently approved lisocabtagene maraleucel (liso-cel) for the management of people with relapsed and refractory B-cell lymphoma. Unfortunately, many patients undergoing liso-cel infusion will suffer progression or relapse with devastating consequences. The object of this study is to identify a novel means to enhance liso-cel activity to improve overall outcomes. The investigators hypothesize that the addition of radiation therapy targeting selected sites as bridging therapy prior to lymphodepleting chemotherapy and liso-cel infusion will be effective at improving responses for patients with relapsed and refractory B-cell lymphoma.
Results from this study will provide key justification to expand this therapeutic approach into a larger phase II clinical trial powered to examine the efficacy of this approach.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
DLBCL - Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma, Follicular Lymphoma, Mediastinal Large B-cell Lymphoma, Indolent B-Cell Non-Hodgkin Lymphoma, Relapsed Non-Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
33 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Single arm
Arm Type
Experimental
Arm Description
Subjects will receive 4 gray (Gy) radiation in 2 fractions in the bridging period following lymphocyte pheresis, prior to lymphodepleting chemotherapy and chimeric antigen receptor (CAR) T-cell infusion. Post CAR T-cell infusion radiation therapy will be allowed as determined by study investigator but prespecified at time of radiation oncology consultation.
Intervention Type
Radiation
Intervention Name(s)
Bridging radiation therapy
Intervention Description
Days -20 to -7: Patients will receive 2 fractions of 2 gray (Gy) for a total of 4 Gy received.
Intervention Type
Biological
Intervention Name(s)
Liso-cel
Other Intervention Name(s)
Chimeric antigen receptor (CAR) T-cell product
Intervention Description
Day 0: Patients will receive an infusion of liso-cel CAR T-cell product.
Prior to the liso-cell infusion (Days -5 to -3), patients will receive lymphodepleting chemotherapy using fludarabine 30mg/m2 and cyclophosphamide 300mg/m2 per institutional standard procedures.
Intervention Type
Radiation
Intervention Name(s)
Post-infusion radiation
Intervention Description
Days 30 to 80: Patients eligible for post-infusion radiation will receive a total dose of up to 32 Gy.
Primary Outcome Measure Information:
Title
Feasibility of the intervention in the proposed study population
Description
The percentage of subjects who receive a chimeric antigen receptor (CAR) T-cell infusion after receiving bridging radiation therapy. A one-sided Binomial test will be conducted to assess whether acceptable percentage (>70% vs <70%) of patients receive CAR T-cell perfusion after undergoing the radiation therapy.
Time Frame
Up to 90 days
Secondary Outcome Measure Information:
Title
Incidence of treatment-emergent adverse events to assess the safety of the proposed intervention
Description
Assessed via the incidence of combined Grade 3 and 4 cytokine release syndrome (CRS) or immune effector cell associated neurotoxicity syndrome (ICANS) events as measured by the American Society of Transplant and Cellular Therapy (ASTCT) consensus grading. The grading scale ranges from Grade 1 to 4, with a higher grade indicating a worse outcome. Assessed from the cumulative CRS and ICANS events occurring by the D+30 visit.
Time Frame
Up to 120 days
Title
Evaluate the response to the study intervention of radiation and CAR T-cell therapy
Description
Response rate will be assessed via PET/CT (positron emission tomography/computed tomography) using Lugano criteria. Overall response rate (ORR) will be defined as the proportion of patients with either a complete response (CR) or a partial response (PR) at D+100. For ORR, CR, and PR: two-sided exact binomial 95% confidence interval of response rate will be constructed to assess the precision of the point estimate.
Time Frame
Up to 190 days
Title
Evaluate progression-free survival (PFS) following the study intervention
Description
PFS will be measured using the Kaplan-Meier method. Disease progression will be measured according to clinical and imaging assessment (Lugano criteria) and will require biopsy confirmation.
Time Frame
Measured from first day of apheresis to death or disease progression, whichever comes first, up to two years
Title
Evaluate duration of response (DOR) following CAR T-cell therapy
Description
DOR will be summarized using the Kaplan-Meier method, but only for patients who have achieved a response of at least partial response. DOR is defined by time of first response (D+30 visit) to disease progression, start of new antineoplastic therapy due to efficacy concerns, or death from any cause.
Time Frame
Up to 2 years
Title
Evaluate overall survival (OS) following study intervention
Description
OS will be analyzed by the Kaplan-Meier method. Subjects alive at last follow up will be censored.
Time Frame
Up to 2 years
Title
Evaluate the rate of prolonged cytopenias following the intervention
Description
The rate of prolonged cytopenias will be measured as a proportion of subjects with Grade 3 or higher hematologic toxicities per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria at the D+100 visit. The 95% confidence interval will be estimated.
The CTCAE v5.0 grading system ranges from Grade 0 to 5, with a higher grade indicating a worse outcome.
Time Frame
Up to 190 days
Title
Monitor overall safety and toxicity of the intervention
Description
Toxicity will be graded using CTCAE v5.0 guidelines. Grade 3 or higher toxicities will be tabulated using percentages at each follow up. The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading system ranges from Grade 0 to 5, with a higher grade indicating a worse outcome.
Time Frame
Up to 270 days
Title
Monitor Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) toxicity events
Description
Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) toxicity events will be collected for all grades as measured by American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria.
The ASTCT consensus criteria grading system ranges from Grade 1 to 4, with a higher grade indicating a worse outcome.
Time Frame
Up to 270 days
Other Pre-specified Outcome Measures:
Title
Prospectively bank serum and peripheral blood mononuclear cells (PBMCs)
Description
Storage for subsequent correlative analyses in future research. No analysis plan is provided.
Time Frame
Up to 270 days
Title
Prospectively bank stool samples for future gut microbiome exploratory analyses
Description
Sample storage at indicated timepoints. No specific analysis is intended on this protocol
Time Frame
Up to 270 days
Title
Evaluate in-field versus out-of-field disease progression following radiation therapy
Description
Proportion of individual disease sites with local progression by Lugano criteria defined by within the treated radiation field versus outside the treated radiation field
Time Frame
Up to 270 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Biopsy-proven relapsed or progressive diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or DLBCL arising from indolent lymphoma meeting an FDA-approved (Food and Drug Administration-approved) indication for liso-cel infusion
Presence of disease on imaging including at least one disease site safe for radiation as determined by treating radiation oncologist
Willingness to participate in clinical trial and provide informed consent
Adequate organ function as assessed by standard institution protocols and United States (US) prescribing information label for comorbidities, heart, and lung function to undergo FDA-approved CAR T-cell therapy as determined by institution
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Age 19 years or older, there is no upper limit to the age
Exclusion Criteria:
Subject is unsafe for radiation therapy as determined by investigator and/or radiation oncologist
Diagnosis is primary central nervous system (CNS) lymphoma (secondary CNS lymphoma with additional systemic site is allowed)
Requirement for concurrent high dose methotrexate
Secondary active malignancy that has not been in remission for at least 2 years. This excludes non-melanoma skin cancer, definitively treated stage 1 solid tumor with low risk or recurrence, and curatively treated localized prostate cancer.
Pregnant or nursing women
Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as determined by investigator
Unwillingness to follow procedures required in the protocol
Inadequate organ or hematologic conditions that prohibit the use of lymphodepleting chemotherapy
Use of lymphoma-directed therapy within 14 days of T-cell pheresis
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Maribeth A Hohenstein, RN
Phone
402-559-9053
Email
mahohens@unmc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher R D'Angelo, MD
Organizational Affiliation
University of Nebraska
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maribeth A Hohenstain, RN
Phone
402-559-9053
Email
mahohens@unmc.edu
12. IPD Sharing Statement
Learn more about this trial
Low Dose Radiation as Bridging Therapy in Relapsed B-Cell Non-Hodgkin Lymphoma
We'll reach out to this number within 24 hrs