Trial Title:
Zanubrutinib and Lisocabtagene Maraleucel for the Treatment of Richter's Syndrome
NCT ID:
NCT05873712
Condition:
Recurrent Transformed Chronic Lymphocytic Leukemia
Refractory Transformed Chronic Lymphocytic Leukemia
Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma
Recurrent Transformed B-Cell Non-Hodgkin Lymphoma
Recurrent Transformed Non-Hodgkin Lymphoma
Refractory Transformed Non-Hodgkin Lymphoma
Refractory Transformed B-cell Non-Hodgkin Lymphoma
Refractory Transformed
Conditions: Official terms:
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Large B-Cell, Diffuse
Recurrence
Cyclophosphamide
Fludarabine
Zanubrutinib
Conditions: Keywords:
Richter's Transformation
Richter's Syndrome
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo collection of blood samples
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo BM biopsy
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT and/or PET/CT
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Given IV
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
(-)-Cyclophosphamide
Other name:
2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
Other name:
Carloxan
Other name:
Ciclofosfamida
Other name:
Ciclofosfamide
Other name:
Cicloxal
Other name:
Clafen
Other name:
Claphene
Other name:
CP monohydrate
Other name:
CTX
Other name:
CYCLO-cell
Other name:
Cycloblastin
Other name:
Cycloblastine
Other name:
Cyclophospham
Other name:
Cyclophosphamid monohydrate
Other name:
Cyclophosphamide Monohydrate
Other name:
Cyclophosphamidum
Other name:
Cyclophosphan
Other name:
Cyclophosphane
Other name:
Cyclophosphanum
Other name:
Cyclostin
Other name:
Cyclostine
Other name:
Cytophosphan
Other name:
Cytophosphane
Other name:
Cytoxan
Other name:
Fosfaseron
Other name:
Genoxal
Other name:
Genuxal
Other name:
Ledoxina
Other name:
Mitoxan
Other name:
Neosar
Other name:
Revimmune
Other name:
Syklofosfamid
Other name:
WR- 138719
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Given IV
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
Fluradosa
Intervention type:
Procedure
Intervention name:
Leukapheresis
Description:
Given IV
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
Leukocytopheresis
Other name:
Therapeutic Leukopheresis
Intervention type:
Biological
Intervention name:
Lisocabtagene Maraleucel
Description:
Given IV
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
Anti-CD19-CAR Genetically Engineered Autologous T Lymphocytes JCAR017
Other name:
Anti-CD19-CAR Genetically Engineered Autologous T-lymphocytes JCAR017
Other name:
Autologous Anti-CD19-EGFRt-4-1BB-zeta-modified CAR CD8+ and CD4+ T-lymphocytes JCAR017
Other name:
Breyanzi
Other name:
JCAR 017
Other name:
JCAR017
Intervention type:
Procedure
Intervention name:
Lymph Node Biopsy
Description:
Undergo lymph node biopsy
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
Biopsy of Lymph Node
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET/CT
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron emission tomography (procedure)
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Intervention type:
Drug
Intervention name:
Zanubrutinib
Description:
Given PO
Arm group label:
Treatment (zanubrutinib, liso-cel)
Other name:
BGB-3111
Other name:
Brukinsa
Other name:
BTK-InhB
Summary:
This phase II trial tests how well zanubrutinib and lisocabtagene maraleucel (liso-cel)
work together in treating patients with Richter's syndrome. Richter's syndrome occurs
when chronic lymphocytic leukemia and/or small lymphocytic leukemia transforms into an
aggressive lymphoma, which is a cancer of the lymph nodes. Zanubrutinib is a class of
medication called a kinase inhibitor. These drugs work by preventing the action of
abnormal proteins that tell cancer cells to multiply, which helps stop the spread of
cancer. Liso-cel is a type of treatment known as chimeric antigen receptor (CAR) T cell
therapy. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type
of immune system cell) are changed in the laboratory so they will attack cancer cells. T
cells are taken from a patient's blood. Then the gene for a special receptor that binds
to a certain protein on the patient's cancer cells is added to the T cells in the
laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large
numbers of the CAR T cells are grown in the laboratory and given to the patient by
infusion for treatment of certain cancers. Giving zanubrutinib and liso-cell together may
kill more cancer cells in patients with Richter's syndrome.
Detailed description:
PRIMARY OBJECTIVE:
I. To evaluate the efficacy of the combination of zanubrutinib and lisocabtagene
maraleucel (liso-cel) for the treatment of Richter's syndrome (RS).
SECONDARY OBJECTIVES:
I. To describe the safety profile of the combination of zanubrutinib and liso-cel for RS.
II. To evaluate duration of the efficacy of the combination of zanubrutinib and liso-cel
for RS
CORRELATIVE OBJECTIVES:
I. Describe T-cell subsets before and after zanubrutinib initiation, as well as post
liso-cel infusion.
II. To describe the persistence of liso-cel. III. To describe the tumor microenvironment
post liso-cel infusion at relapse. IV. Investigate the correlation between inflammatory
cytokines and measures of inflammation and outcomes and rates of adverse events including
cytokine release syndrome (CRS).
V. Investigate chronic lymphocytic leukemia (CLL) persistence post treatment.
OUTLINE:
Patients receive zanubrutinib orally (PO), undergo leukaphereis, and receive fludarabine
intravenously (IV), cyclophosphamide IV, and liso-cel IV on study. Patients also undergo
bone marrow (BM) biopsy and lymph node biopsy at screening and follow up, and undergo
collection of blood samples and computed tomography (CT), positron emission tomography
(PET)/CT, and/or magnetic resonance imaging (MRI) throughout the trial.
After study completion, patients are followed for 24 months, and then every 6 months
until disease progression or death.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Diagnosis of RS - occurrence of diffuse large B-cell lymphoma (DLBCL) in patients
with antecedent or concurrent CLL/SLL (CLL/SLL diagnosis per IWCLL 2018 criteria).
- Must have relapsed/refractory disease as defined by one of the following:
- Participants must have undergone >= 1 prior systemic therapeutic regimen
administered for >= 1 cycle for either CLL or RS, and have had either
documented disease progression to the most recent treatment regimen, or
refractory disease. OR
- Developed RS while receiving treatment for CLL
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Total bilirubin =< 2.0 times the institutional upper limit of normal (unless
documented Gilbert's syndrome)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =<
2.5 x institutional upper limit of normal
- Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal
- Creatinine clearance >= 30 mL/min
- Using 24-hour creatinine clearance or standard Cockcroft-Gault equation
- Absolute lymphocyte count > 100/uL at screening
- Left ventricular ejection fraction >= 40% by multigated acquisition (MUGA) or
echocardiogram (ECHO)
- Adequate bone marrow independent of growth factor support or infusion support at
screening unless evidence shows that the cytopenia(s) is due to marrow involvement
by CLL/small lymphocytic lymphoma (SLL). If cytopenias are due to disease in the
bone marrow any degree of anemia or thrombocytopenia are allowed, absolute
neutrophil count (ANC) must be >= 500
- Absolute neutrophil count (ANC) >= 1000/mm^3 (independent of growth factor support
or infusion support at screening unless evidence shows that the cytopenia[s] is due
to marrow involvement by CLL/SLL). If cytopenias are due to disease in the bone
marrow any degree of anemia or thrombocytopenia are allowed, ANC must be >= 500
- Platelets >= 30,000/mm^3 (independent of growth factor support or infusion support
at screening unless evidence shows that the cytopenia[s] is due to marrow
involvement by CLL/SLL). If cytopenias are due to disease in the bone marrow any
degree of anemia or thrombocytopenia are allowed
- Hemoglobin >= 7 g/dL (independent of growth factor support or infusion support at
screening unless evidence shows that the cytopenia[s] is due to marrow involvement
by CLL/SLL). If cytopenias are due to disease in the bone marrow any degree of
anemia or thrombocytopenia are allowed
- Radiographically measurable lymphadenopathy (or measurable extra-nodal disease) per
Lugano criteria
- Must meet all institutional standards for receiving CAR T-cell therapy
- Subjects (or legal guardians) must have the ability to understand and the
willingness to sign a written informed consent document
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
per year, initiated prior to first dose of study drug, during the treatment period
and for at least 1 year after the CAR-T cell infusion or 1 month after last dose of
zanubrutinib, whichever is longer.
- A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (< 12 continuous months of amenorrhea
with no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus). Examples of contraceptive
methods with a failure rate of < 1% per year include bilateral tubal ligation,
male sterilization, hormonal contraceptives that inhibit ovulation,
hormone-releasing intrauterine devices, and copper intrauterine devices
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures, and agreement to refrain from donating sperm, as defined
below:
- With female partners of childbearing potential, men must remain abstinent or
use a condom plus an additional contraceptive method that together result in a
failure rate of < 1% per year during the treatment period and for at least 1
year after the anti-CD19 CAR-T cell infusion or 1 month after last dose of
zanubrutinib, whichever is longer. Men should avoid fathering a child and
refrain from donating sperm during this same period.
- With pregnant female partners, men must remain abstinent or use a condom during
the treatment period and for at least 1 year after the human anti- CD19 CAR-T
cell infusion or 1 month post last dose of zanubrutinib, whichever is longer,
to avoid potential embryonal or fetal exposure. The reliability of sexual
abstinence should be evaluated in relation to the duration of the clinical
trial and the preferred and usual lifestyle of the patient. Periodic abstinence
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception
Exclusion Criteria:
- A history of treatment including any of the following: prior CD19 directed therapy,
treatment with alemtuzumab within 6 months before enrollment, prior allogeneic
hematopoietic stem cell transplant (SCT) or donor lymphocyte infusion (DLI) within 2
months prior to enrollment
- Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD),
or requiring immunosuppressive drugs for treatment of GVHD, or have taken
calcineurin inhibitors within 4 weeks prior to consent
- Inadequate recovery from adverse events related to prior therapy to grade =< 1
(excluding grade 2 alopecia, neuropathy, and hypertension)
- Is unable to swallow oral medication, or has significant gastrointestinal disease
that would limit absorption of oral medication
- Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand
disease)
- Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic
purpura (ITP)
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
screening
- Clinically significant cardiovascular disease such as symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification. Note: Subjects with controlled atrial
fibrillation/flutter can enroll on study
- Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists
- Prothrombin time (PT)/international normalized ratio (INR) or activated partial
thromboplastin time (PTT) (in the absence of lupus anticoagulant) > 2 x upper limit
normal (ULN)
- Treatment with a moderate or strong CYP3A inhibitor or inducer within 7 days prior
to first dose of zanubrutinib
- Patients may not have an active intercurrent disease or concurrent malignancy that
is expected to limit survival to < 5 years
- Human immunodeficiency virus (HIV) seropositivity at screening
- Subjects with uncontrolled intercurrent illness including, but not limited to
ongoing or active infection, unstable angina pectoris, pulmonary abnormalities or
psychiatric illness/social situations that would limit compliance with study
requirements
- Pregnant or breastfeeding women are excluded from this study because CAR-T cell
therapy may be associated with the potential for teratogenic or abortifacient
effects. Women of childbearing potential must have a negative serum pregnancy test.
Because there is an unknown, but potential risk for adverse events in nursing
infants secondary to treatment of the mother with CAR-T cells, breastfeeding should
be discontinued. These potential risks may also apply to other agents used in this
study
- Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia
on any bone marrow biopsy prior to initiation of therapy
- Serologic status reflecting active hepatitis B or C infection at screening. Patients
that are positive for hepatitis B core antibody, hepatitis B surface antigen
(HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction
(PCR) at screening. PCR positive patients will be excluded
- History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus
erythematosus) with requirement of immunosuppressive medication within 6 months
- Chronic use of corticosteroids >= 20mg prednisone equivalent PO daily
- Live vaccines given in 28 days prior to lymphodepleting chemotherapy
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Ohio State University Comprehensive Cancer Center
Address:
City:
Columbus
Zip:
43210
Country:
United States
Status:
Recruiting
Contact:
Last name:
Adam S. Kittai, MD
Phone:
614-366-4567
Email:
Adam.Kittai@osumc.edu
Investigator:
Last name:
Adam S. Kittai, MD
Email:
Principal Investigator
Start date:
July 28, 2023
Completion date:
December 31, 2025
Lead sponsor:
Agency:
Adam Kittai
Agency class:
Other
Source:
Ohio State University Comprehensive Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05873712
http://cancer.osu.edu
