Trial Title:
Optimizing lymphoDepletion to Improve Outcomes In Patients Receiving Cell Therapy With Yescarta
NCT ID:
NCT05950802
Condition:
DLBCL - Diffuse Large B Cell Lymphoma
Conditions: Official terms:
Lymphoma, Large B-Cell, Diffuse
Cyclophosphamide
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
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 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)
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Higher dose than traditional conditioning chemo
Arm group label:
Cyclophosphamide (intermediate dose) and fludarabine
Arm group label:
Cyclophosphamide (intermediate dose) and fludarabine with radiation
Arm group label:
Cyclophosphamide and fludarabine, standard dose with radiation
Other name:
cytoxin, neosar
Intervention type:
Radiation
Intervention name:
TLI
Description:
radiation given with conditioning chemo
Arm group label:
Cyclophosphamide (intermediate dose) and fludarabine with radiation
Arm group label:
Cyclophosphamide and fludarabine, standard dose with radiation
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.
Detailed 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 18-24 patients in the dose escalation stage (Part 1), and approximately 20
further patients at cohort expansion (Part 2). There will be four dose escalation
cohorts, in two study arms. There are two dosing cohorts in each study arm. Patients in
Arm 1 will receive the ZUMA-1 chemotherapy LD regimen with or without TLI, and in Arm 2,
an intermediate dose of Cy with a fixed dose of Flu, with or without TLI, will be given.
The cohorts in Arm 1 will enroll concurrently, and enrollment into Arm 2 will begin after
Arm 1 has enrolled all patients and data review by the Trial Steering Committee (TSC).
For accrual into Cohort 2, Arm 1, there will be a 15-day staggered enrollment for the
first 2 patients. Staggered enrollment with another 15-day delay may be considered for
enrollment into Cohorts 3 and 4, Arm 2, after review by the TSC. Following completion of
accrual to Arm 1, a 30 day dose-limiting toxicity (DLT) window will be observed, prior to
review by the TSC and commencement of enrollment into Arm 2.
Criteria for eligibility:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Princess Margaret Cancer Centre
Address:
City:
Toronto
Country:
Canada
Status:
Recruiting
Contact:
Last name:
John Kuruvilla
Phone:
4169462821
Email:
LymphomaClinicalTrials@uhn.ca
Start date:
July 14, 2023
Completion date:
June 2027
Lead sponsor:
Agency:
University Health Network, Toronto
Agency class:
Other
Source:
University Health Network, Toronto
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05950802
