Overview
Optimizing lymphoDepletion to Improve Outcomes In Patients Receiving Cell Therapy With Yescarta
Status:
Recruiting
Recruiting
Trial end date:
2027-06-01
2027-06-01
Target enrollment:
0
0
Participant gender:
All
All
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.Phase:
Phase 1Accepts Healthy Volunteers?
NoDetails
Lead Sponsor:
University Health Network, TorontoTreatments:
Cyclophosphamide
Criteria
Inclusion Criteria:1. Age ≥ 18 years at the time of informed consent
2. Life expectancy ≥ 12 weeks
3. Biopsy-proven and histologically confirmed R/R large B cell lymphoma, including R/R
DLBCL, transformation from FL, and R/R PMBCL.
4. Radiographically documented measurable disease as per Lugano response criteria (i.e.
LDi > 1.5 cm that is FDG avid).
5. 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
6. 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
7. Patient does not have active CNS disease
8. 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
9. ECOG performance status 0 or 1 at enrollment
10. Patient has not received prior adoptive T-cell immunotherapy
11. Patient is not HIV positive
12. Patient did not receive prior allogeneic stem cell transplant
13. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function
14. 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)
15. Sexually active males who accept to use a condom during intercourse during treatment
and for 6 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
16. Must have an apheresis product of non-mobilized cells accepted for manufacturing.
Exclusion Criteria:
1. Persisting disease bulk (defined as ≥10 cm) on restaging imaging following bridging
therapy.
2. 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
3. History of Richter's transformation of CLL
4. History of allogeneic stem cell transplant
5. Received < 2 lines of therapy for large B cell lymphoma
6. Prior CD19 targeted therapy
7. 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).
- Treatment with systemic immunostimulatory agents (including but not limited to
interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is
shorter, prior to the infusion of axicabtagene ciloleucel
8. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy
9. 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.
10. 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.
11. Active tuberculosis
12. Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube,
indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter).
Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter
are permitted
13. 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
14. 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
15. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
16. 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
17. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or
blood vessel compression
18. History of autoimmune disease, requiring systemic immunosuppression and/or systemic
disease modifying agents within the last 2 years.
19. 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.
20. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of
enrollment
21. Any medical condition likely to interfere with assessment of safety or efficacy of
study treatment
22. History of severe immediate hypersensitivity reaction to tocilizumab or any of the
agents used in this study
23. 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
24. Women of childbearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of chemotherapy on the fetus or infant.
25. Subjects of either sex who are not willing to practice birth control from the time of
consent and at least 6 months after axicabtagene ciloleucel infusion
26. In the investigators judgment, the subject is unlikely to complete all protocol-
required study visits or procedures, including followup visits, or comply with the
study requirements for participation.