Back to results'Re-Priming' RT After Incomplete Response to CAR-T in R/R NHL
Primary Purpose
Non-Hodgkin Lymphoma
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Focal radiation therapy (RT)
Sponsored by
About this trial
This is an interventional treatment trial for Non-Hodgkin Lymphoma focused on measuring CAR-T, Radiation therapy, NHL, DLBCL, RT
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening (See Section 13, Appendix A).
- 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 classification37.
- 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).
Exclusion Criteria:
- Prior radiation therapy to one or more sites of incomplete response as noted on day 30 post-CAR-T PET/CT scan within the past one year.
- 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.
Sites / Locations
- UT Southwestern Medical CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Radiation Therapy to all residual FDG-avid sites*
Arm Description
All patients enrolled in the trial will receive focal radiation therapy (RT) to all* residual FDG-avid sites per Lugano criteria (Lugano 4-5) as noted on day 30 post-CAR-T PET/CT scan. *If >5 distinct sites, physician discretion will be allowed as to how many sites are treated, with recommendation that at least all symptomatic and bulky (>=7.5 cm in largest dimension) sites be treated.
Outcomes
Primary Outcome Measures
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]
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]
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.
Secondary Outcome Measures
Response rates of individual sites
To determine the rates of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and overall response rate (ORR) of all irradiated and un-irradiated sites on 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
To determine the duration of response (DOR) for patients who have any response as noted on day 90 PET post-CAR-T, defined as time from day 90 post-CAR-T PET/CT to first PET/CT scan showing progression.
Progression free survival (PFS)
To determine the progression free survival (PFS) for all patients at 1-year post-CAR-T
Overall survival (OS)
To determine the overall survival (OS) for all patients all patients at 1-year post-CAR-T
Full Information
NCT ID
NCT04601831
First Posted
October 9, 2020
Last Updated
July 17, 2023
Sponsor
University of Texas Southwestern Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT04601831
Brief Title
'Re-Priming' RT After Incomplete Response to CAR-T in R/R NHL
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 23, 2020 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Texas Southwestern Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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).
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Hodgkin Lymphoma
Keywords
CAR-T, Radiation therapy, NHL, DLBCL, RT
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Single-arm, open label, seamless phase I/II study
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Radiation Therapy to all residual FDG-avid sites*
Arm Type
Experimental
Arm Description
All patients enrolled in the trial will receive focal radiation therapy (RT) to all* residual FDG-avid sites per Lugano criteria (Lugano 4-5) as noted on day 30 post-CAR-T PET/CT scan.
*If >5 distinct sites, physician discretion will be allowed as to how many sites are treated, with recommendation that at least all symptomatic and bulky (>=7.5 cm in largest dimension) sites be treated.
Intervention Type
Radiation
Intervention Name(s)
Focal radiation therapy (RT)
Intervention Description
Radiation therapy for phase II:
"Definitive" 40-50 Gy EQD2 (i.e. 30 Gy in 5 fractions)
Hypofractionated regimen (i.e. 5 fractions in 1-2 weeks) recommended, but other fractionation schemes (10-20 fractions in 2-4 weeks) allowed.
Primary Outcome Measure Information:
Title
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]
Description
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.
Time Frame
60 DAYS
Title
Rate of Metabolic Complete Response (CR) on Day 90 Post-CAR-T PET/CT scan per Lugano 2014 Classification [Phase 2: Efficacy]
Description
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.
Time Frame
Day 90 post CAR-T
Secondary Outcome Measure Information:
Title
Response rates of individual sites
Description
To determine the rates of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and overall response rate (ORR) of all irradiated and un-irradiated sites on day 90 PET post-CAR-T.
Time Frame
Day 90 PET post-CAR-T
Title
Duration of response (DOR) in Participants with Any Response as Noted on Day 90 Post-CAR-T PET/CT
Description
To determine the duration of response (DOR) for patients who have any response as noted on day 90 PET post-CAR-T, defined as time from day 90 post-CAR-T PET/CT to first PET/CT scan showing progression.
Time Frame
1 year
Title
Progression free survival (PFS)
Description
To determine the progression free survival (PFS) for all patients at 1-year post-CAR-T
Time Frame
1 year
Title
Overall survival (OS)
Description
To determine the overall survival (OS) for all patients all patients at 1-year post-CAR-T
Time Frame
1 year
Other Pre-specified Outcome Measures:
Title
Level of Circulating CAR-T cells in the Peripheral Blood as Measured by Digital PCR and/or Flow Cytometry
Description
To evaluate cellular kinetics data (peak expansion, persistence, etc.) through peripheral blood measurement of circulating CAR T-cells with digital polymerase chain reaction (PCR) and/or flow cytometry before and after RT, as well at day 90 post-CAR-T, to assess the impact of RT on CAR-T expansion and persistence.
Time Frame
1 year
Title
Biomarkers in serum and tumor samples
Description
To analyze biomarkers in serum and tumor samples (optional) to assess for association and predictive value of response to RT after CAR-T.
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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).
Exclusion Criteria:
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sarah Neufeld
Phone
2146458525
Email
sarah.hardee@utsouthwestern.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kajal Desai
Phone
2146458525
Email
kajal.desai@utsouthwestern.edu
Facility Information:
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sarah Hardee
Phone
214-645-8525
Email
sarah.hardee@utsouthwestern.edu
First Name & Middle Initial & Last Name & Degree
Kajal Desai
Phone
2146458301
Email
Kajal.Desai@UTSouthwestern.edu
First Name & Middle Initial & Last Name & Degree
Kiran Kumar, MD
12. IPD Sharing Statement
Learn more about this trial
'Re-Priming' RT After Incomplete Response to CAR-T in R/R NHL
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