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

Phase 1Not Yet RecruitingNCT07725406

Weill Medical College of Cornell University32 enrolled

Overview

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.

This is a single-center, open-label, non-randomized, Phase Ib trial evaluating dose escalation of low-dose total body irradiation (LD-TBI) combined with standard-of-care CAR T-cell therapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) or multiple myeloma (MM). The study includes two disease-specific cohorts: Cohort 1 (LBCL) receives commercial CD19-directed CAR T-cell therapy (axicabtagene ciloleucel or lisocabtagene maraleucel), and Cohort 2 (MM) receives commercial BCMA-directed CAR T-cell therapy (ciltacabtagene autoleucel). In CAR T-cell therapy, T-cells are removed via apheresis, modified to target the tumor, and infused back into the patient after lymphodepleting chemotherapy. On the same day as CAR T-cell infusion, prior to infusion, patients receive a single dose of LD-TBI. Each cohort follows a standard 3+3 dose-escalation design (Part 1) to identify the maximum tolerated dose (MTD) across three planned dose levels (0.5 Gy, 1.0 Gy starting dose, and 2.0 Gy), based on dose-limiting toxicities occurring within 28 days of treatment. Once the MTD is identified, an expansion cohort (Part 2) of up to 10 additional participants per cohort will be randomized 1:1 to the MTD or a dose level below it to further evaluate safety and activity. Approximately 16-22 participants are anticipated per disease cohort. Participants will be followed for up to 2 years after treatment.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Interventions

Lymphodepleting chemotherapy: CyclophosphamideDRUG

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

Lymphodepleting chemotherapy: BendamustineDRUG

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

Lymphodepleting chemotherapy: FludarabineDRUG

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

Lisocabtagene MaraleucelOTHER

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

Axicabtagene CiloleucelOTHER

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

Ciltacabtagene AutoleucelOTHER

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

Low-Dose Total Body IrradiationRADIATION

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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).

Time frame: Through Day 28 post-CAR T cell infusion

Secondary Outcomes

Incidence and Severity of Cytokine Release Syndrome (CRS)

This outcome measures the number of participants experiencing CRS of any grade, and the maximum CRS grade (1-4) observed per participant, per ASTCT Consensus Criteria. This measure is used to assess the incidence and severity of this expected immune-related toxicity following combined LD-TBI and CAR T-cell therapy.

Time frame: 12 months post-LDTBI and CAR T cell therapy combination

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

This outcome measures the number of participants experiencing ICANS of any grade, and the maximum ICANS grade (1-4) observed per participant, per ASTCT Consensus Criteria. This measure is used to assess the incidence and severity of neurologic toxicity following combined LD-TBI and CAR T-cell therapy.

Time frame: 12 months post-LDTBI and CAR T cell therapy combination

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

This outcome measures the number of participants experiencing IEC-HS of any grade, and the maximum IEC-HS grade (1-5) observed per participant, per ASTCT criteria. This measure is used to assess the incidence and severity of this rare but serious immune-related toxicity.

Time frame: 12 months post-LDTBI and CAR T cell therapy combination

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

This outcome measures the number of participants experiencing delayed ICAHT, per EHA/EBMT consensus criteria. This measure is used to assess the incidence of prolonged blood count abnormalities following CAR T-cell therapy.

Time frame: 12 months post-LDTBI and CAR T cell therapy combination

Incidence and Severity of Treatment-Related Adverse Events

This outcome measures the number of participants experiencing at least one treatment-related adverse event, summarized by event term and maximum CTCAE v5.0 grade (1-5) per participant. This measure is used to characterize the overall safety profile of combined LD-TBI and CAR T-cell therapy.

Time frame: From Lymphodepletion (Day -5) through Day 360

Overall Response Rate (ORR)

This outcome measures the counts and proportion of response to treatment for participants achieving a partial response (PR), VGPR (for MM only) and complete response (CR), per Lugano Criteria (LBCL) or IMWG criteria (MM). This measure is used to estimate the preliminary anti-tumor activity of combined LD-TBI and CAR T-cell therapy.

Time frame: At Days +30, +90, +180, and +365 post-CAR T-cell infusion

Overall Survival (OS)

This outcome measures the probability of survival over time, estimated by the Kaplan-Meier method, from start of treatment to death from any cause. This measure is used to estimate the overall survival associated with combined LD-TBI and CAR T-cell therapy.

Time frame: 12 months post-LDTBI and CAR T cell therapy combination

Progression-Free Survival (PFS)

This outcome measures the probability of remaining free of disease progression over time, estimated by the Kaplan-Meier method, from start of treatment to disease progression or death from any cause, whichever occurs first. This measure is used to estimate the durability of disease control with combined LD-TBI and CAR T-cell therapy.

Time frame: 12 months post-LDTBI and CAR T cell therapy combination

Duration of Response (DoR)

This outcome measures the median duration of response, estimated by the Kaplan-Meier method, from first documentation of complete or partial response until disease progression or relapse. This measure is used to estimate how durable a response to combined LD-TBI and CAR T-cell therapy is among participants who respond.

Time frame: Assessed throughout study follow-up (up to 2 years)

Adverse Event of Interest

This outcome measures the incidence of pre-specified adverse events of interest following combined LD-TBI and CAR T-cell therapy. Adverse events of interest include parkinsonism (in participants receiving ciltacabtagene autoleucel), prolonged cytopenias, infections after Day +28, and immune effector cell-associated hemophagocytic syndrome (IEC-HS).

Time frame: From CAR T-cell infusion (Day 0) through Day 360

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts