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

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

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.

Detailed description

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.

Interventions

• Drug Lymphodepleting chemotherapy: Cyclophosphamide
  Lymphodepleting chemotherapy given in combination with fludarabine on Days -5 to -3.
• Drug Lymphodepleting chemotherapy: Bendamustine
  Alternative lymphodepleting chemotherapy given on Days -5 to -4, for participants receiving ciltacabtagene autoleucel.
• Drug Lymphodepleting chemotherapy: Fludarabine
  Lymphodepleting chemotherapy given in combination with cyclophosphamide on Days -5 to -3.
• Other Lisocabtagene Maraleucel
  Commercial CD19-directed CAR T-cell therapy administered intravenously on Day 0, at least 4 hours after completion of LD-TBI.
• Other Axicabtagene Ciloleucel
  Commercial CD19-directed CAR T-cell therapy administered intravenously on Day 0, at least 4 hours after completion of LD-TBI.
• Other Ciltacabtagene Autoleucel
  Commercial BCMA-directed CAR T-cell therapy administered intravenously on Day 0, at least 4 hours after completion of LD-TBI.
• Radiation Low-Dose Total Body Irradiation
  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.

Primary outcome measures

• Incidence of Dose-Limiting Toxicities (DLTs) [Time frame: Through Day 28 post-CAR T cell infusion]

Secondary outcome measures (10)

• Incidence and Severity of Cytokine Release Syndrome (CRS) [Time frame: 12 months post-LDTBI and CAR T cell therapy combination]
• Incidence and Severity of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) [Time frame: 12 months post-LDTBI and CAR T cell therapy combination]
• Incidence and Severity of Immune Effector Cell-Associated Hemophagocytic Syndrome (IEC-HS) [Time frame: 12 months post-LDTBI and CAR T cell therapy combination]
• Incidence of Delayed Immune Effector Cell-Associated Hematotoxicity (ICAHT) [Time frame: 12 months post-LDTBI and CAR T cell therapy combination]
• Incidence and Severity of Treatment-Related Adverse Events [Time frame: From Lymphodepletion (Day -5) through Day 360]
• Overall Response Rate (ORR) [Time frame: At Days +30, +90, +180, and +365 post-CAR T-cell infusion]
• Overall Survival (OS) [Time frame: 12 months post-LDTBI and CAR T cell therapy combination]
• Progression-Free Survival (PFS) [Time frame: 12 months post-LDTBI and CAR T cell therapy combination]
• Duration of Response (DoR) [Time frame: Assessed throughout study follow-up (up to 2 years)]
• Adverse Event of Interest [Time frame: From CAR T-cell infusion (Day 0) through Day 360]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Weill Cornell Medicine/NewYork-Presbyterian Hospital — New York

Identifiers

NCT: NCT07725406 · 23-10026672

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗