'Re-Priming' RT After Incomplete Response to CAR-T in R/R NHL
Study Details
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Radiation Therapy to all residual FDG-avid sites* 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. |
Radiation: Focal radiation therapy (RT)
Radiation therapy- 2 dose levels:
"Definitive" 40-50 Gy EQD2 (i.e. 30 Gy in 5 fractions), or if de-escalation needed,
"Palliative" 20-32.5 Gy EQD2 (i.e. 20 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.
|
Outcome Measures
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] [60 DAYS]
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] [60 DAYS]
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 [Day 90 PET post-CAR-T]
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 [1 year]
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) [1 year]
To determine the progression free survival (PFS) for all patients at 1-year post-CAR-T
- Overall survival (OS) [1 year]
To determine the overall survival (OS) for all patients all patients at 1-year post-CAR-T
Other Outcome Measures
- Level of Circulating CAR-T cells in the Peripheral Blood as Measured by Digital PCR and/or Flow Cytometry [1 year]
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.
- Biomarkers in serum and tumor samples [1 year]
To analyze biomarkers in serum and tumor samples (optional) to assess for association and predictive value of response to RT after CAR-T.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥ 18 years.
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Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening (See Section 13, Appendix A).
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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.
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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).
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Incomplete response noted on day 30 PET post-CAR-T, defined as not achieving CR per Lugano 2014 classification37.
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Ability to understand and the willingness to sign a written informed consent
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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:
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Has not undergone a hysterectomy or bilateral oophorectomy; or
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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:
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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.
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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.
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Active grade 3 or higher CRS or neurotoxicity related to CAR-T.
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Patients with prior history of auto-immune disease or other contraindication to RT.
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Patients with life expectancy < 3 months.
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Psychiatric illness/social situations that would limit compliance with study requirements.
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Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UT Southwestern Medical Center | Dallas | Texas | United States | 75390 |
Sponsors and Collaborators
- University of Texas Southwestern Medical Center
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2020-1106