Low-Dose TBI Plus CAR T-Cell Therapy for Relapsed/Refractory DLBCL and Multiple Myeloma | NCT07725406

NCT07725406

Overview

NCT ID: NCT07725406
Lead Sponsor: Weill Medical College of Cornell UniversityOTHER
Official Title: A Phase Ib, Dose-Escalation Study of Augmented Lymphodepletion and CAR T-cell Priming With Low-dose Total Body Irradiation in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphomas and Multiple Myeloma Receiving Treatment With Commercial CD19 or BCMA-directed CAR T-cell Therapies
Brief Summary: This is a clinical trial to evaluate the safety of combining CAR T-cell therapy with low-dose total body irradiation (LD-TBI) in patients with previously treated large B-cell lymphoma (LBCL) or multiple myeloma (MM). The investigators' hypothesis is that the combination will make the immune system more active in fighting cancer by increasing the display of antigens and activating pathways that lead to cell death, including death receptors like FAS and TRAIL2. This approach is expected to help the CAR T cells grow and last longer, leading to stronger anti-tumor effects and more cancer cell deaths. Participants will receive LDTBI treatment before their CAR T cell therapy and will be followed up for 2 years.
Conditions

Status and Timeline

Status: Not yet recruiting
Last Update Posted: Jul 24, 2026Actual
Start Date: Aug 1, 2026Estimated
Primary Completion Date: Aug 1, 2028Estimated
Completion Date

Participation Criteria

Ages Eligible for Study: Adult (18-64)Older Adult (65+)
Sexes Eligible for Study: All
Accepts Healthy Volunteers?: No
Eligibility Criteria: Inclusion Criteria:

For Diffuse Large B-Cell Lymphoma (DLBCL) Cohort:

Diagnosis of DLBCL that is refractory to first-line chemoimmunotherapy, relapses within 12 months of first-line chemoimmunotherapy, relapses after 12 months in a transplant-ineligible patient, or is relapsed/refractory after two or more lines of systemic therapy. Eligible histologies include DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from indolent lymphoma (follicular lymphoma, marginal zone lymphoma, or chronic lymphocytic leukemia)

Age ≥18 years

ECOG performance status ≤2

Measurable disease on PET/CT or CT per Lugano Criteria

Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥45 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction >40%

For Multiple Myeloma (MM) Cohort:

Relapsed or refractory multiple myeloma after ≥1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, with disease refractory to lenalidomide (progression within 60 days of last lenalidomide dose)

Age ≥18 years

ECOG performance status ≤2

Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥30 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction >40%

Exclusion Criteria:

For DLBCL Cohort:

History of previous total body irradiation

Prior CAR T-cell therapy

Clonal cytopenia of uncertain significance (CCUS)

Prior history of myeloid malignancies (MDS/AML or MPN), T-cell lymphoblastic lymphoma/leukemia, or B-cell acute lymphoblastic leukemia

Current or prior CNS involvement by lymphoma

Significant cardiovascular impairment (CHF greater than NYHA Class II, uncontrolled hypertension, unstable angina, MI or stroke within 6 months, or cardiac ventricular arrhythmia)

Decompensated cirrhosis

Active HIV, hepatitis B, or hepatitis C infection

Active uncontrolled systemic fungal, bacterial, or viral infection

Pregnancy

For MM Cohort:

History of previous total body irradiation

History of myelodysplastic syndrome, CCUS, or concurrent active hematological malignancy with bone marrow involvement

Active HIV, hepatitis B, or hepatitis C infection

Active uncontrolled systemic fungal, bacterial, or viral infection

Prior CAR T-cell therapy

Active or history of CNS myeloma or leptomeningeal infiltration

Pregnancy

Study Plan

Study Type: Interventional
Phase: Phase 1
Enrollment: 32Estimated
Primary Purpose: Treatment
Allocation: Non-Randomized
Interventional Model: Sequential Assignment
Masking: None (Open Label)

Contacts and Locations

Central Contacts: Nicole Santos, MPHContact
nis7058@med.cornell.edu646-962-6827

Similar Studies

Participant Group/Arms

Part 1: LBCL: Dose Level -1 (0.5 Gy)Experimental

Participants with relapsed/refractory LBCL receive lymphodepletion followed by LD-TBI 0.5 Gy on Day 0, ≥4 hours before infusion of commercial CD19-directed CAR T-cell therapy. Used if de-escalation from Dose Level 0 is required due to dose-limiting toxicity.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Drug: Lymphodepleting chemotherapy: Fludarabine

Other: Lisocabtagene Maraleucel

Other: Axicabtagene Ciloleucel

Radiation: Low-Dose Total Body Irradiation

Part 1: LBCL: Dose Level 0 (1.0 Gy, Starting Dose)Experimental

Participants with relapsed/refractory LBCL receive lymphodepletion followed by LD-TBI 1.0 Gy (starting dose) on Day 0, ≥4 hours before infusion of commercial CD19-directed CAR T-cell therapy.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 1: LBCL: Dose Level +1 (2.0 Gy)Experimental

Participants with relapsed/refractory LBCL receive lymphodepletion followed by LD-TBI 2.0 Gy on Day 0, ≥4 hours before infusion of commercial CD19-directed CAR T-cell therapy. Used if Dose Level 0 is tolerated.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 1: MM: Dose Level -1 (0.5 Gy)Experimental

Participants with relapsed/refractory multiple myeloma receive lymphodepletion followed by LD-TBI 0.5 Gy on Day 0, ≥4 hours before infusion of commercial BCMA-directed CAR T-cell therapy. Used if de-escalation from Dose Level 0 is required.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 1: MM: Dose Level 0 (1.0 Gy, Starting Dose)Experimental

Participants with relapsed/refractory multiple myeloma receive lymphodepletion followed by LD-TBI 1.0 Gy (starting dose) on Day 0, ≥4 hours before infusion of commercial BCMA-directed CAR T-cell therapy.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 1: MM: Dose Level +1 (2.0 Gy)Experimental

Participants with relapsed/refractory multiple myeloma receive lymphodepletion followed by LD-TBI 2.0 Gy on Day 0, ≥4 hours before infusion of commercial BCMA-directed CAR T-cell therapy. Used if Dose Level 0 is tolerated.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 2: LBCL: Expansion Cohort at MTDExperimental

Expansion-cohort participants with relapsed/refractory LBCL are randomized 1:1 to LD-TBI at the MTD or one dose level below. This arm receives LD-TBI at the MTD (single dose, Day 0), preceded by lymphodepletion and followed ≥4 hours later by commercial CD19-directed CAR T-cell therapy.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 2: LBCL: Expansion Cohort Below MTDExperimental

Expansion-cohort participants with relapsed/refractory LBCL are randomized 1:1 to LD-TBI at the MTD or one dose level below. This arm receives LD-TBI one dose level below the MTD (single dose, Day 0), preceded by lymphodepletion and followed ≥4 hours later by commercial CD19-directed CAR T-cell therapy.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 2: MM: Expansion Cohort at MTDExperimental

Expansion-cohort participants with relapsed/refractory multiple myeloma are randomized 1:1 to LD-TBI at the MTD or one dose level below. This arm receives LD-TBI at the MTD (single dose, Day 0), preceded by lymphodepletion and followed ≥4 hours later by commercial BCMA-directed CAR T-cell therapy.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide

Part 2: MM: Expansion Cohort Below MTDExperimental

Expansion-cohort participants with relapsed/refractory multiple myeloma are randomized 1:1 to LD-TBI at the MTD or one dose level below. This arm receives LD-TBI one dose level below the MTD (single dose, Day 0), preceded by lymphodepletion and followed ≥4 hours later by commercial BCMA-directed CAR T-cell therapy.

Drug: Lymphodepleting chemotherapy: Cyclophosphamide