Optimizing lymphoDepletion to Improve Outcomes In Patients Receiving Cell Therapy With Yescarta

NCT05950802 | Recruiting Phase 1 DMC

• 1 other identifier: OZM-124
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1b study of participants with Diffuse Large B Cell Lymphoma (DLBCL). The purpose of this study is to identify an optimized lymphodenpletion (LD) regimen by evaluating standard and intermediate doses of Fludarabine (Flu) / Cyclophosphamide (Cy) with or without a fixed dose of total lymphoid irradiation (TLI) in the setting of standard of care CAR T cell therapy.

Conditions

DLBCL - Diffuse Large B Cell Lymphoma

Outcome Measures

Primary Outcomes (1)

• safety and tolerability of chemo rads as conditioning chemo

  To assess the safety and tolerability of a combination chemo-radiation lymphodepletion (LD) regimen (Fludarabine (Flu)/Cyclophosphamide (Cy) + total lymphoid irradiation (TLI ) in patients receiving standard of care CAR T cell therapy for relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL), by establishing the maximum tolerated doses (MTD) of standard (ZUMA-1) dose Flu/Cy + TLI, and of intermediate dose iCy/Flu +/- TLI, and the dose limiting toxicities (DLT) of standard dose Flu/Cy + TLI, and of intermediate dose iCy/Flu +/- TLI

  baseline through Day 30

Secondary Outcomes (3)

• Overall response rate

  baseline through day 365

• Complete response

  baseline through day 365

• Progression free survival

  baseline through day 365

Study Arms (4)

Cyclophosphamide and fludarabine, standard dose

NO INTERVENTION

Fludarabine 30mg/m2 Cyclophosphamide 500mg/m2 Days -4, -3, -2

Cyclophosphamide and fludarabine, standard dose with radiation

EXPERIMENTAL

Fludarabine 30mg/m2 Cyclophosphamide 500mg/m2 Days -6, -5, -4, and 2 Gy in 2 Fractions Days -3, -2

Drug: Cyclophosphamide; Radiation: TLI

Cyclophosphamide (intermediate dose) and fludarabine

EXPERIMENTAL

Fludarabine 30mg/m2 Cyclophosphamide 750mg/m2 Days -4, -3, -2

Drug: Cyclophosphamide

Cyclophosphamide (intermediate dose) and fludarabine with radiation

EXPERIMENTAL

Fludarabine 30mg/m2 Cyclophosphamide 750mg/m2 Days -6, -5, -4, and 2 Gy in 2 Fractions Days -3, -2

Drug: Cyclophosphamide; Radiation: TLI

Interventions

Cyclophosphamide DRUG

Higher dose than traditional conditioning chemo

Also known as: cytoxin, neosar

Cyclophosphamide (intermediate dose) and fludarabine; Cyclophosphamide (intermediate dose) and fludarabine with radiation; Cyclophosphamide and fludarabine, standard dose with radiation

TLI RADIATION

radiation given with conditioning chemo

Cyclophosphamide (intermediate dose) and fludarabine with radiation; Cyclophosphamide and fludarabine, standard dose with radiation

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years at the time of informed consent
• Life expectancy ≥ 12 weeks
• Biopsy-proven and histologically confirmed R/R large B cell lymphoma, including R/R DLBCL, transformation from FL, and R/R PMBCL.
• Radiographically documented measurable disease as per Lugano response criteria (i.e. LDi \> 1.5 cm that is FDG avid).
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic cancer therapy at the time the subject provides consent
• Eligible for standard of care CAR T cell therapy, specifically, relapsed or refractory large B cell lymphoma after two or more lines of systemic therapy, and subjects must have received adequate first-line therapy including at a minimum:
• Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and
• An anthracycline containing chemotherapy regimen
• Patient does not have active CNS disease
• Patient is sufficiently stable to facilitate planned CAR T-cell therapy (e.g. not rapidly progressing on temporizing therapy, no significant compromise of vital organ functions (intubation, dialysis, requiring ICU/vasopressor support)) and has good performance status
• ECOG performance status 0 or 1 at enrollment
• Patient has not received prior adoptive T-cell immunotherapy
• Patient is not HIV positive
• Patient did not receive prior allogeneic stem cell transplant
• Adequate bone marrow, renal, hepatic, pulmonary and cardiac function

You may not qualify if:

• Persisting disease bulk (defined as ≥10 cm) on restaging imaging following bridging therapy.
• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years
• History of Richter's transformation of CLL
• History of allogeneic stem cell transplant
• Received \< 2 lines of therapy for large B cell lymphoma
• Prior CD19 targeted therapy
• Subject has received or undergone the following:
• o Therapeutic doses of corticosteroids (defined as \>20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis.
• Physiologic steroid replacement, topical, and inhaled steroids are permitted.
• Cytotoxic chemotherapeutic agents that are not considered lymphotoxic, and intrathecal (IT) chemotherapy must be stopped ≥ 7 days prior to leukapheresis.
• Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide \> 300 mg/m2, ifosfamide, bendamustine) 4 weeks prior to leukapheresis.
• Experimental agents within 4 weeks prior to signing the ICF, unless no response or PD is documented on the experimental therapy and at least 5 half-lives have elapsed prior to leukapheresis.
• Ibrutinib, lenalidomide and PI3K inhibitor within 5 half-lives prior to leukapheresis
• Immunosuppressive therapies within 4 weeks prior to leukapheresis (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin thalidomide, immunosuppressive antibodies such as anti-tumor necrosis factor \[TNF\], anti-IL6, or anti- IL6R)
• Radiation within 6 weeks of leukapheresis. Subject must have progressive disease in irradiated lesions or have additional nonirradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated PET-positive lesions are present, is allowed up to 2 weeks prior to leukapheresis (discuss with sponsor).

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Princess Margaret Cancer Centre

Toronto, Ontario, Canada

RECRUITING

MeSH Terms

Conditions

Dendritic Cell Sarcoma, Interdigitating

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Histiocytic Disorders, Malignant; Neoplasms by Histologic Type; Neoplasms; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Design

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

Model Details: Patients will be enrolled in two stages: the dose escalation stage to assess the safety and tolerability of a modified LD regimen, and once the MTD is determined, a cohort expansion phase to further characterize the toxicity and efficacy profile and determine the RP2D. The study will enroll approximately 18-24 patients in the dose escalation stage (Part 1), and approximately 20 further patients at cohort expansion (Part 2)

Study Record Dates

• First Submitted: June 29, 2023
• First Posted: July 18, 2023
• Study Start: July 14, 2023
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027
• Last Updated: December 8, 2025

Record last verified: 2025-12

Locations

CA (1)