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

NCT07725406 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 23-10026672
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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

Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL); Relapsed or Refractory Multiple Myeloma (MM)

Outcome Measures

Primary Outcomes (1)

• Incidence of Dose-Limiting Toxicities (DLTs)

  This outcome measures the number of participants experiencing a dose-limiting toxicity (DLT) at each LD-TBI dose level, within 28 days following CAR T-cell infusion. This measure is used to assess the safety and tolerability of the treatment regimen across escalating radiation dose levels and to determine the maximum tolerated dose (MTD).

  Through Day 28 post-CAR T cell infusion

Secondary Outcomes (10)

• Incidence and Severity of Cytokine Release Syndrome (CRS)

  12 months post-LDTBI and CAR T cell therapy combination

• Incidence and Severity of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

  12 months post-LDTBI and CAR T cell therapy combination

• Incidence and Severity of Immune Effector Cell-Associated Hemophagocytic Syndrome (IEC-HS)

  12 months post-LDTBI and CAR T cell therapy combination

• Incidence of Delayed Immune Effector Cell-Associated Hematotoxicity (ICAHT)

  12 months post-LDTBI and CAR T cell therapy combination

• Incidence and Severity of Treatment-Related Adverse Events

  From Lymphodepletion (Day -5) through Day 360

Study Arms (10)

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; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Lisocabtagene Maraleucel; Other: Axicabtagene Ciloleucel; Radiation: Low-Dose Total Body Irradiation

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; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Lisocabtagene Maraleucel; Other: Axicabtagene Ciloleucel; Radiation: Low-Dose Total Body Irradiation

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; Drug: Lymphodepleting chemotherapy: Bendamustine; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Ciltacabtagene Autoleucel; Radiation: Low-Dose Total Body Irradiation

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; Drug: Lymphodepleting chemotherapy: Bendamustine; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Ciltacabtagene Autoleucel; Radiation: Low-Dose Total Body Irradiation

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; Drug: Lymphodepleting chemotherapy: Bendamustine; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Ciltacabtagene Autoleucel; Radiation: Low-Dose Total Body Irradiation

Part 2: LBCL: Expansion Cohort at MTD

EXPERIMENTAL

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; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Lisocabtagene Maraleucel; Other: Axicabtagene Ciloleucel; Radiation: Low-Dose Total Body Irradiation

Part 2: LBCL: Expansion Cohort Below MTD

EXPERIMENTAL

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; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Lisocabtagene Maraleucel; Other: Axicabtagene Ciloleucel; Radiation: Low-Dose Total Body Irradiation

Part 2: MM: Expansion Cohort at MTD

EXPERIMENTAL

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; Drug: Lymphodepleting chemotherapy: Bendamustine; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Ciltacabtagene Autoleucel; Radiation: Low-Dose Total Body Irradiation

Part 2: MM: Expansion Cohort Below MTD

EXPERIMENTAL

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; Drug: Lymphodepleting chemotherapy: Bendamustine; Drug: Lymphodepleting chemotherapy: Fludarabine; Other: Ciltacabtagene Autoleucel; Radiation: Low-Dose Total Body Irradiation

Interventions

Lymphodepleting chemotherapy: Cyclophosphamide DRUG

Lymphodepleting chemotherapy given in combination with fludarabine on Days -5 to -3.

Part 1: LBCL: Dose Level +1 (2.0 Gy); Part 1: LBCL: Dose Level -1 (0.5 Gy); Part 1: LBCL: Dose Level 0 (1.0 Gy, Starting Dose); Part 1: MM: Dose Level +1 (2.0 Gy); Part 1: MM: Dose Level -1 (0.5 Gy); Part 1: MM: Dose Level 0 (1.0 Gy, Starting Dose); Part 2: LBCL: Expansion Cohort Below MTD; Part 2: LBCL: Expansion Cohort at MTD; Part 2: MM: Expansion Cohort Below MTD; Part 2: MM: Expansion Cohort at MTD

Lymphodepleting chemotherapy: Bendamustine DRUG

Alternative lymphodepleting chemotherapy given on Days -5 to -4, for participants receiving ciltacabtagene autoleucel.

Part 1: MM: Dose Level +1 (2.0 Gy); Part 1: MM: Dose Level -1 (0.5 Gy); Part 1: MM: Dose Level 0 (1.0 Gy, Starting Dose); Part 2: MM: Expansion Cohort Below MTD; Part 2: MM: Expansion Cohort at MTD

Lymphodepleting chemotherapy: Fludarabine DRUG

Lymphodepleting chemotherapy given in combination with cyclophosphamide on Days -5 to -3.

Part 1: LBCL: Dose Level +1 (2.0 Gy); Part 1: LBCL: Dose Level -1 (0.5 Gy); Part 1: LBCL: Dose Level 0 (1.0 Gy, Starting Dose); Part 1: MM: Dose Level +1 (2.0 Gy); Part 1: MM: Dose Level -1 (0.5 Gy); Part 1: MM: Dose Level 0 (1.0 Gy, Starting Dose); Part 2: LBCL: Expansion Cohort Below MTD; Part 2: LBCL: Expansion Cohort at MTD; Part 2: MM: Expansion Cohort Below MTD; Part 2: MM: Expansion Cohort at MTD

Lisocabtagene Maraleucel OTHER

Commercial CD19-directed CAR T-cell therapy administered intravenously on Day 0, at least 4 hours after completion of LD-TBI.

Also known as: Liso-cel; Breyanzi

Part 1: LBCL: Dose Level +1 (2.0 Gy); Part 1: LBCL: Dose Level -1 (0.5 Gy); Part 1: LBCL: Dose Level 0 (1.0 Gy, Starting Dose); Part 2: LBCL: Expansion Cohort Below MTD; Part 2: LBCL: Expansion Cohort at MTD

Axicabtagene Ciloleucel OTHER

Commercial CD19-directed CAR T-cell therapy administered intravenously on Day 0, at least 4 hours after completion of LD-TBI.

Also known as: Axi-cel; Yescarta

Part 1: LBCL: Dose Level +1 (2.0 Gy); Part 1: LBCL: Dose Level -1 (0.5 Gy); Part 1: LBCL: Dose Level 0 (1.0 Gy, Starting Dose); Part 2: LBCL: Expansion Cohort Below MTD; Part 2: LBCL: Expansion Cohort at MTD

Ciltacabtagene Autoleucel OTHER

Commercial BCMA-directed CAR T-cell therapy administered intravenously on Day 0, at least 4 hours after completion of LD-TBI.

Also known as: Cilta-cel; Carvykti

Part 1: MM: Dose Level +1 (2.0 Gy); Part 1: MM: Dose Level -1 (0.5 Gy); Part 1: MM: Dose Level 0 (1.0 Gy, Starting Dose); Part 2: MM: Expansion Cohort Below MTD; Part 2: MM: Expansion Cohort at MTD

Low-Dose Total Body Irradiation RADIATION

A single dose of total body irradiation administered on Day 0, at least 4 hours before the start of CAR T-cell infusion. Dose level (0.5 Gy, 1.0 Gy, or 2.0 Gy) is determined by the assigned dose cohort.

Also known as: LD-TBI; TBI

Part 1: LBCL: Dose Level +1 (2.0 Gy); Part 1: LBCL: Dose Level -1 (0.5 Gy); Part 1: LBCL: Dose Level 0 (1.0 Gy, Starting Dose); Part 1: MM: Dose Level +1 (2.0 Gy); Part 1: MM: Dose Level -1 (0.5 Gy); Part 1: MM: Dose Level 0 (1.0 Gy, Starting Dose); Part 2: LBCL: Expansion Cohort Below MTD; Part 2: LBCL: Expansion Cohort at MTD; Part 2: MM: Expansion Cohort Below MTD; Part 2: MM: Expansion Cohort at MTD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%

You may not qualify if:

• 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

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (1)

Weill Cornell Medicine/NewYork-Presbyterian Hospital

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Recurrence; Lymphoma, Large B-Cell, Diffuse; Multiple Myeloma

Interventions

axicabtagene ciloleucel; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Investigative Techniques

Study Officials

• Caitlin Gribbin, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nicole Santos, MPH

CONTACT

646-962-6827; nis7058@med.cornell.edu

Caitlin Gribbin, MD

CONTACT

646-962-7950; ckg2001@med.cornell.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2026
• First Posted: July 24, 2026
• Study Start: August 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 31, 2033
• Last Updated: July 24, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)