Optimizing Lymphodepletion to Improve Outcomes in Patients Receiving Cell Therapy With Kymriah

NCT06003179 | Withdrawn Phase 1 DMC

• 1 other identifier: OZM-123
• Study Type: interventional
• Target: N/A
• 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 lymphodepletion (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 chimeric antigen receptor T (CAR T) cell therapy.

Conditions

Lymphoma, Large B-Cell, Diffuse

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) for chemo plus radiation as 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 (JULIET) 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 end of study completion, approximately 2 years

Secondary Outcomes (6)

• overall response rate (ORR) at 12 months of chemo rads

  baseline to 12 months post CAR-T

• complete response (CR) rate at 12 months of chemo rads

  baseline to 12 months post CAR-T

• progression free survival (PFS) at 12 months of chemo rads

  baseline to 12 months post CAR-T

• ORR at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen

  baseline to 12 months post CAR-T

• CR rate at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen

  baseline to 12 months post CAR-T

Other Outcomes (1)

• Assessments

  During lymphodepleting therapy

Study Arms (6)

Cyclophosphamide and fludarabine, standard dose

ACTIVE COMPARATOR

Fludarabine 25mg/m2 Cyclophosphamide 250mg/m2 Days -4, -3, -2

Drug: Cyclophosphamide; Drug: Fludarabine

Cyclophosphamide and fludarabine, standard dose with radiation

EXPERIMENTAL

Fludarabine 25mg/m2 Cyclophosphamide 250mg/m2 Days -6, -5, -4 2 Gy in 2 Fractions Days -3, -2

Radiation: TLI; Drug: Fludarabine

Cyclophosphamide (intermediate dose) and fludarabine

EXPERIMENTAL

Fludarabine 25mg/m2 Cyclophosphamide 500mg/m2 Days -4, -3, -2

Drug: Cyclophosphamide; Drug: Fludarabine

Cyclophosphamide (intermediate dose) and fludarabine with radiation

EXPERIMENTAL

Fludarabine 25mg/m2 Cyclophosphamide 500mg/m2 Days -6, -5, -4 2 Gy in 2 Fractions Days -3, -2

Drug: Cyclophosphamide; Radiation: TLI; Drug: Fludarabine

Cyclophosphamide (high dose) and fludarabine

EXPERIMENTAL

Fludarabine 25mg/m2 Cyclophosphamide 750mg/m2 Days -4, -3, -2

Drug: Cyclophosphamide; Drug: Fludarabine

Cyclophosphamide (high dose) and fludarabine with radiation

EXPERIMENTAL

Fludarabine 25mg/m2 Cyclophosphamide 750mg/m2 Days -6, -5, -4 2 Gy in 2 Fractions Days -3, -2

Drug: Cyclophosphamide; Radiation: TLI; Drug: Fludarabine

Interventions

Cyclophosphamide DRUG

Conditioning chemo at different doses

Also known as: Cytoxan, neosar

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

TLI RADIATION

radiation given with conditioning chemo

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

Fludarabine DRUG

Fludarabine given as part of standard treatment

Cyclophosphamide (high dose) and fludarabine; Cyclophosphamide (high dose) and fludarabine with radiation; Cyclophosphamide (intermediate dose) and fludarabine; Cyclophosphamide (intermediate dose) and fludarabine with radiation; Cyclophosphamide and fludarabine, standard dose; 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 relapse/refractory (R/R) large B cell lymphoma, including Primary mediastinal B-cell lymphoma (PMBCL), R/R DLBCL and transformation from Follicular lymphoma (FL).
• Radiographically documented measurable disease as per Lugano response criteria (i.e. longest transverse diameter of a lesion (LDi) \> 1.5 cm that is \[18F\] fluorodeoxyglucose (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:
• 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 Intensive care unit (ICU)/vasopressor support)) and has good performance status
• Patient does not have active central nervous system (CNS) disease
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at enrollment
• Patient has not received prior adoptive T-cell immunotherapy
• Patient is not human immunodeficiency virus (HIV) positive
• Patient did not receive prior allogeneic stem cell transplant
• Adequate bone marrow, renal, hepatic, pulmonary and cardiac function
• Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
• Sexually active males who accept to use a condom during intercourse during treatment and for 12 months after treatment as they should not father a child in this period. A condom is required to be used also by vasectomized men (as well as during intercourse with a male partner) in order to prevent delivery of the drug via seminal fluid

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 chronic lymphocytic leukemia (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 protocol defined treatments/therapies
• Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
• Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
• Active tuberculosis
• Subjects with detectable cerebrospinal fluid malignant cells or known CNS involvement; a history of prior treated CNS lymphoma which is not active at the time of relapse is permitted
• History or presence of significant non-malignant CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
• Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months of enrollment

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Study Officials

• John G Kuruvilla

  Princess Margaret Cancer Centre - University Health Network

  PRINCIPAL INVESTIGATOR

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 maximum tolerated dose (MTD) is determined, a cohort expansion phase to further characterize the toxicity and efficacy profile and determine the recommended phase 2 dose (RP2D). The study will enroll approximately 20-40 patients in the dose escalation stage (Part 1), and approximately 20 further patients at cohort expansion (Part 2).

Study Record Dates

• First Submitted: July 10, 2023
• First Posted: August 21, 2023
• Study Start: April 5, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2028
• Last Updated: November 12, 2024

Record last verified: 2024-11

Locations

CA (1)