Lymphodepletion With Low Dose Total Body Irradiation Before Standard of Care Tisagenlecleucel for the Treatment of Relapsed and Recurrent Large B-cell Lymphoma

A Phase I Trial of Lymphodepletion Intensification With Low Dose Total Body Irradiation With Dose Expansion for Standard-of-Care Tisagenlecleucel in Patients With Large B-Cell Lymphoma

This phase I trial tests the safety, side effects, and best dose of total body irradiation (TBI) in combination with standard of care lymphodepletion with cyclophosphamide and fludarabine before tisagenlecleucel (Tisa-cel) and how well the combination works in patients with large B-cell lymphoma (LBCL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). TBI is a common treatment that sends radiation (for example, through x-rays) to the entire body. Lymphodepleting chemotherapy, such as cyclophosphamide and fludarabine, along with TBI helps kill cancer cells in the body and helps prepare the body for the Tisa-cel infusion. Tisagenlecleucel is made using a patient's T cells (a type of immune system cell). A gene for a special receptor called chimeric antigen receptor (CAR) is added to the T cells in the laboratory. These changed T cells called CAR T cells are grown in large numbers in the laboratory and given to the patient by infusion. Tisa-cel binds to a protein called CD19, which is found on some leukemia and lymphoma cells. This helps the body's immune system kill cancer cells. Tisa-cel is a type of CAR T-cell therapy. Giving low dose TBI in combination with standard of care lymphodepletion therapy and Tisa-cel may be safe, tolerable, and/or effective in treating patients with relapsed or refractory (R/R) LBCL.

Study Overview

• Status: Not yet recruiting
• Conditions: Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Procedure: Biospecimen Collection; Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: Leukapheresis; Procedure: Positron Emission Tomography; Procedure: Computed Tomography; Biological: Tisagenlecleucel; Radiation: Total-Body Irradiation

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the safety and maximum tolerated dose (MTD) of total body irradiation (TBI) as lymphodepletion intensification for Tisa-cel in R/R large B-cell lymphoma.

SECONDARY OBJECTIVE:

I. To determine the efficacy, toxicity, and pharmacokinetics of Tisa-cel with intensified lymphodepletion by low dose TBI.

II. To compare pharmacokinetics of Tisa-cel with intensified to historic control from JULIET trial, provided by Novartis and Navigate.

EXPLORATORY OBJECTIVE:

I. Compare the clinical outcomes of Tisa-cel with intensified lymphodepletion by TBI with institutional and Center for International Blood and Marrow Transplant Research (CIBMTR) historic control real world of evidence of standard-of-care Tisa-cel in LBCL.

CORRELATIVE OBJECTIVES:

I. To describe the T-cell phenotype, exhaustion, and activation induced cell death markers marker of Tisa-cel with intensified lymphodepletion by low dose total body irradiation.

II. To describe the cytokine profile, immune profile and circulating tumor deoxyribonucleic acid (ctDNA) dynamics following of Tisa-cel with intensified lymphodepletion by low dose total body irradiation.

III. To investigate tumor microenvironment and mechanism of resistance to CAR-T19 in the biopsy at progression post-CAR-T19.

OUTLINE: This is a dose-escalation study of TBI in combination with standard of care lymphodepletion and Tisa-cel followed by a dose-expansion study.

Patients undergo leukapheresis and receive lymphodepleting chemotherapy with cyclophosphamide intravenously (IV) and fludarabine IV on days -5 to -3 per standard of care. Patients also undergo low dose TBI on day -2 and receive standard of care Tisa-cel IV over 5-30 minutes on day 0. Additionally, patients undergo blood sample collection, positron emission tomography (PET)/computed tomography (CT) or CT throughout the study.

After completion of study treatment, patients are followed up at days 1-7, 10, 14, 17, 21, 30, 45, 60, 75, 90, 120, 150, 180 and 270, at 1 year after Tisa-cel infusion then for up to year 15 per standard of care.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ohio State University Comprehensive Cancer Center; Phone Number: 800-293-5066; Email: OSUCCCClinicaltrials@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
      • Principal Investigator: Nathan Denlinger, DO
      • Contact: Nathan Denlinger, DO; Phone Number: 614-293-3316; Email: Nathan.Denlinger@osumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Eligible for standard of care anti-CD19 CAR-T treatment with Tisa-cel
• Age ≥ 18 years
• Biopsy-confirmed relapsed or refractory large B-cell lymphoma after 2 lines of prior therapy
• Qualitative CD19 expression by either immunohistochemistry (IHC) or flow cytometry
• Measurable disease prior to lymphodepletion as determined by Lugano criteria
• Non-RT bridging therapy allowed, but requires re-staging prior to lymphodepletion (LD) to confirm measurable disease
• Adequate performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2
• Platelets above 75K
• Hemoglobin above 8.0 g/dL without transfusion within 1 week
• Absolute neutrophil count (ANC) above 1,000 without granulocyte colony-stimulating factor (G-CSF) within 1 week
• Total bilirubin < 1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) =< 3 x ULN
• Glomerular filtration rate (GFR) > 60 ml/min calculated by the Cockcroft - Gault formula
• Oxygen saturation (SpO2) > 92% without supplemental oxygen
• Ejection fraction more than 45%
• Patients must have the ability to understand and the willingness to sign a written informed consent document
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 12 months after Tisa-cel and until CAR T-cells are no longer present by quantitative polymerase chain reaction (qPCR) on two consecutive tests
• A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptive s that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

  • With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 12 months after Tisa-cel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. Men must refrain from donating sperm during this same period
  • With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after Tisa-cel infusion to avoid potential embryonal or fetal exposure. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
• For patients with prior irradiation: the study radiation oncologist co-investigator will review the patient's prior history of radiation to confirm that the investigational low dose total body irradiation is feasible and safe to respect the maximum cumulative organ radiation exposure

Exclusion Criteria:

• Active central nervous system (CNS) disease at screening or prior to lymphodepletion
• Prior therapy with autologous or allogenic CAR-T or CAR-natural killer (NK) cell therapy
• Prior anti-CD19 therapies (such as, but not limited to tafasitamab or loncastuximab)
• Prior allogeneic stem cell transplant
• Bridging therapy with radiation not allowed
• Any contra-indications to receive low-dose TBI, standard of care lymphodepleting chemotherapy or Tisa-cel per treating physician
• A minimum of 28 days must have elapsed between prior treatment with investigational agent(s) and start of lymphodepletion
• Uncontrolled major medical problem as infections
• Active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast). Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial (e.g. low Gleason score prostate cancer)
• Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study
• Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy
• Active hepatitis B or C as indicated by serology (for details please refer to Novartis Leukapheresis Reference Manual version [v] 4)
• Patients with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease
• History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of systemic immunosuppressive medication within 6 months
• Live vaccines given in 28 days prior to lymphodepleting chemotherapy
• Active substance use disorders

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (TBI, lymphodepletion, Tisa-cel); Patients undergo leukapheresis and receive lymphodepleting chemotherapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 per standard of care. Patients also undergo low dose TBI on day -2 and receive standard of care Tisa-cel IV over 5-30 minutes on day 0. Additionally, patients undergo blood sample collection, PET/CT or CT throughout the study.

Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; B 518; B518; WR 138719; WR138719; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Procedure: Leukapheresis; Undergo leukapheresis; Other Names: Leukocytopheresis; Therapeutic Leukopheresis; Leukocyte Adsorptive Apheresis; White Blood Cell Reduction Apheresis; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Computed Tomography; Undergo PET/CT or CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Biological: Tisagenlecleucel; Given IV; Other Names: CART19; CTL019; Kymriah; CART-19; CTL019 T-cells; Tisagenlecleucel-T; CTL 019; CTL-019; Tisa-cel; Radiation: Total-Body Irradiation; Undergo low dose TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Whole Body

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicities	Adverse events will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are graded using American Society for Transplantation and Cellular Therapy (ASTCT) Consensus grading.	Up to 30 days after infusion
Maximum tolerated dose or recommended phase 2 dose (RP2D)	Will define the dose as the RP2D for which the isotonic estimate of the toxicity rate is closest to the targeted toxicity rate (i.e., 25%). If there is a tie, the higher dose level when the isotonic estimate is lower than the targeted toxicity rate; and will choose the lower dose level when the isotonic estimate is greater than the targeted toxicity rate.	Up to 30 days after infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Frequency and nature of adverse events of different grades, overall and by dose levels will be described.	Up to 1 year
Complete remission rate	Will be evaluated with descriptive statistics with proportions used to describe response rates (complete and overall).	At days 30 and 90 from tisagenlecleucel (Tisa-cel) infusion
Objective response rate	Will be estimated with 95% confidence intervals.	At 30 and 90 days and 6 months
Median duration of response	Will be calculated using Kaplan Meier method, comparisons between groups will be done using the log rank test.	Up to 1 year
Progression-free survival	Will be analyzed using Lugano criteria. Will be calculated using Kaplan Meier method, comparisons between groups will be done using the log rank test.	From Tisa-cel infusion to clinical progression or death as a result of any cause, assessed at 6 months and 1 year
Overall survival	Will be analyzed using Lugano criteria.	From Tisa-cel infusion to death from any cause, assessed at 6 months and 1 year
Rate and grade of cytokine release syndrome	Will be evaluated using ASTCT Consensus grading.	Within the first 30 days post-infusion
Rate and grade of immune effector cell associated neurotoxicity syndrome	Will be evaluated using ASTCT Consensus grading.	Within the first 30 days post-infusion
Rates of grade IV cytopenias		At days 30 and 90 from Tisa-cel infusion

Collaborators and Investigators

• Sponsor: Nathan Denlinger
• Collaborators: Novartis
• Investigators: Principal Investigator: Nathan Denlinger, DO, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: June 23, 2026
• First Submitted That Met QC Criteria: June 23, 2026
• First Posted (Actual): June 30, 2026

Study Record Updates

• Last Update Posted (Actual): June 30, 2026
• Last Update Submitted That Met QC Criteria: June 23, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; Organic Chemicals; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Cytological Techniques; Hydrocarbons; Chemistry Techniques, Analytical; Spectrum Analysis; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Biological Therapy; Cytapheresis; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cyclophosphamide; Specimen Handling; Magnetic Resonance Spectroscopy; fludarabine; Leukapheresis; Whole-Body Irradiation; tisagenlecleucel; CTL019 chimeric antigen receptor
• Other Study ID Numbers: OSU-25255; NCI-2026-04299 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No