'Re-Priming' RT After Incomplete Response to CAR-T in R/R NHL

• ClinicalTrials.gov Identifier: NCT04601831
• Recruitment Status: Recruiting
• First Posted: October 26, 2020
• Last Update Posted: January 3, 2022
• Sponsor: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Kiran Kumar, University of Texas Southwestern Medical Center

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
Non-Hodgkin Lymphoma	Radiation: Focal radiation therapy (RT)	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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single-arm, open label, seamless phase I/II study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of 'Re-Priming' Radiation Therapy (RT) for Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL) Patients in Incomplete Response After Chimeric Antigen Receptor T-cell (CAR-T) Therapy
• Actual Study Start Date: December 23, 2020
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2024

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 :

1. 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] [ Time Frame: 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.

2. Rate of Metabolic Complete Response (CR) on Day 90 Post-CAR-T PET/CT scan per Lugano 2014 Classification [Phase 2: Efficacy] [ Time Frame: 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 :

1. Response rates of individual sites [ Time Frame: 1 year ]
   To determine the response rate of all individual irradiated and un-irradiated sites
2. Duration of response (DOR) in Participants with Any Response as Noted on Day 90 Post-CAR-T PET/CT [ Time Frame: 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.
3. Progression free survival (PFS) [ Time Frame: 1 year ]
   To determine the progression free survival (PFS) for all patients at 1-year post-CAR-T
4. Overall survival (OS) [ Time Frame: 1 year ]
   To determine the overall survival (OS) for all patients all patients at 1-year post-CAR-T

Other Outcome Measures:

1. Level of Circulating CAR-T cells in the Peripheral Blood as Measured by Digital PCR and/or Flow Cytometry [ Time Frame: 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.
2. Biomarkers in serum and tumor samples [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥ 18 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening (See Section 13, Appendix A).
3. 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.
4. 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).
5. Incomplete response noted on day 30 PET post-CAR-T, defined as not achieving CR per Lugano 2014 classification37.
6. Ability to understand and the willingness to sign a written informed consent
7. 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:

1. 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.
2. 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.
3. Active grade 3 or higher CRS or neurotoxicity related to CAR-T.
4. Patients with prior history of auto-immune disease or other contraindication to RT.
5. Patients with life expectancy < 3 months.
6. Psychiatric illness/social situations that would limit compliance with study requirements.
7. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
8. 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

Contacts

Contact: Sarah Hardee; 2146458525; sarah.hardee@utsouthwestern.edu

Contact: Kajal Desai; 2146458525; kajal.desai@utsouthwestern.edu

Locations

United States, Texas

UT Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75390

Contact: sarah Hardee 214-645-8525 sarah.hardee@utsouthwestern.edu

Contact: Kajal Desai 2146458301 Kajal.Desai@UTSouthwestern.edu

Principal Investigator: Kiran Kumar, MD

Sponsors and Collaborators

University of Texas Southwestern Medical Center

More Information

• Responsible Party: Kiran Kumar, Principal Investigator, Assistant Professor, Chief of Lymphoma & Pediatrics Radiation Oncology Service, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT04601831
• Other Study ID Numbers: 2020-1106
• First Posted: October 26, 2020
• Last Update Posted: January 3, 2022
• Last Verified: December 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kiran Kumar, University of Texas Southwestern Medical Center:

CAR-T; Radiation therapy; NHL; DLBCL; RT

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases