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

Sponsor

University Health Network, Toronto (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06003179

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Large B-Cell, Diffuse	Drug: Cyclophosphamide Radiation: TLI Drug: Fludarabine	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

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).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).

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Optimizing Lymphodepletion to Improve Outcomes in Patients Receiving Anti-CD19 CAR T Cell Therapy With Kymriah/tIsagenlecleucel (LOKI)

Anticipated Study Start Date :

Aug 1, 2023

Anticipated Primary Completion Date :

Aug 1, 2026

Anticipated Study Completion Date :

Aug 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Cyclophosphamide and fludarabine, standard dose Fludarabine 25mg/m2 Cyclophosphamide 250mg/m2 Days -4, -3, -2	Drug: Cyclophosphamide Conditioning chemo at different doses Other Names: Cytoxan, neosar Drug: Fludarabine Fludarabine given as part of standard treatment
Experimental: Cyclophosphamide and fludarabine, standard dose with radiation Fludarabine 25mg/m2 Cyclophosphamide 250mg/m2 Days -6, -5, -4 2 Gy in 2 Fractions Days -3, -2	Radiation: TLI radiation given with conditioning chemo Drug: Fludarabine Fludarabine given as part of standard treatment
Experimental: Cyclophosphamide (intermediate dose) and fludarabine Fludarabine 25mg/m2 Cyclophosphamide 500mg/m2 Days -4, -3, -2	Drug: Cyclophosphamide Conditioning chemo at different doses Other Names: Cytoxan, neosar Drug: Fludarabine Fludarabine given as part of standard treatment
Experimental: Cyclophosphamide (intermediate dose) and fludarabine with radiation Fludarabine 25mg/m2 Cyclophosphamide 500mg/m2 Days -6, -5, -4 2 Gy in 2 Fractions Days -3, -2	Drug: Cyclophosphamide Conditioning chemo at different doses Other Names: Cytoxan, neosar Radiation: TLI radiation given with conditioning chemo Drug: Fludarabine Fludarabine given as part of standard treatment
Experimental: Cyclophosphamide (high dose) and fludarabine Fludarabine 25mg/m2 Cyclophosphamide 750mg/m2 Days -4, -3, -2	Drug: Cyclophosphamide Conditioning chemo at different doses Other Names: Cytoxan, neosar Drug: Fludarabine Fludarabine given as part of standard treatment
Experimental: Cyclophosphamide (high dose) and fludarabine with radiation Fludarabine 25mg/m2 Cyclophosphamide 750mg/m2 Days -6, -5, -4 2 Gy in 2 Fractions Days -3, -2	Drug: Cyclophosphamide Conditioning chemo at different doses Other Names: Cytoxan, neosar Radiation: TLI radiation given with conditioning chemo Drug: Fludarabine Fludarabine given as part of standard treatment

Outcome Measures

Primary Outcome Measures

MTD and dose limiting toxicity (DLT) for chemo plus radiation as lymphodepletion [baseline through end of study completion, approximately 2 years]
(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

Secondary Outcome Measures

overall response rate (ORR) at 12 months of chemo rads [baseline to 12 months post CAR-T]
To assess the ORR at 12 months of a combination chemo-radiation LD regimen (standard dose Flu/Cy + TLI) in patients receiving CAR T cell therapy for R/R DLBCL.
complete response (CR) rate at 12 months of chemo rads [baseline to 12 months post CAR-T]
To assess the CR rate of a combination chemo-radiation LD regimen (standard dose Flu/Cy + TLI) in patients receiving CAR T cell therapy for R/R DLBCL.
progression free survival (PFS) at 12 months of chemo rads [baseline to 12 months post CAR-T]
To assess the PFS rate at 12 months of a combination chemo-radiation LD regimen (standard dose Flu/Cy + TLI) in patients receiving CAR T cell therapy for R/R DLBCL.
ORR at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen [baseline to 12 months post CAR-T]
To assess the ORR at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen in patients receiving CAR T cell therapy for R/R DLBCL
CR rate at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen [baseline to 12 months post CAR-T]
To assess the CR rate at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen in patients receiving CAR T cell therapy for R/R DLBCL
PFS at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen [baseline to 12 months post CAR-T]
To assess the PFS rate at 12 months of an intermediate dose iCy/Flu +/- TLI LD regimen in patients receiving CAR T cell therapy for R/R DLBCL

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 PMBCL, R/R DLBCL and transformation from FL.
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:
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
Patient does not have active CNS disease
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
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
Must have an apheresis product of non-mobilized cells accepted for manufacturing.

Exclusion Criteria:

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 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
Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression
History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years.
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment
Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study
Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of chemotherapy on the fetus or infant.
Subjects of either sex who are not willing to practice birth control from the time of consent and at least 6 months after tisagenlecleucel infusion
In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

University Health Network, Toronto

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

University Health Network, Toronto

ClinicalTrials.gov Identifier:

NCT06003179

Other Study ID Numbers:

OZM-123

First Posted:

Aug 21, 2023

Last Update Posted:

Aug 21, 2023

Last Verified:

Aug 1, 2023

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Lymphoma, Large B-Cell, Diffuse

Cyclophosphamide

Fludarabine

Study Results

No Results Posted as of Aug 21, 2023