Trial Title:
Lisocabtagene Maraleucel, Nivolumab and Ibrutinib for the Treatment of Richter's Transformation
NCT ID:
NCT05672173
Condition:
Recurrent Transformed Chronic Lymphocytic Leukemia
Refractory Transformed Chronic Lymphocytic Leukemia
Richter Syndrome
Conditions: Official terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Cyclophosphamide
Nivolumab
Fludarabine
Ibrutinib
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:
Biopsy
Description:
Undergo tumor biopsy
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood specimen collection
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, 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 bone marrow biopsy and/or aspiration
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo PET/CT
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
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 (nivolumab, ibrutinib, chemotherapy, 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 (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
Fluradosa
Intervention type:
Drug
Intervention name:
Ibrutinib
Description:
Given PO
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
BTK Inhibitor PCI-32765
Other name:
CRA-032765
Other name:
Imbruvica
Other name:
PCI-32765
Intervention type:
Biological
Intervention name:
Lisocabtagene Maraleucel
Description:
Given IV
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, 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:
Biological
Intervention name:
Nivolumab
Description:
Given IV
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
BMS-936558
Other name:
CMAB819
Other name:
MDX-1106
Other name:
NIVO
Other name:
Nivolumab Biosimilar CMAB819
Other name:
ONO-4538
Other name:
Opdivo
Intervention type:
Procedure
Intervention name:
Pheresis
Description:
Undergo apheresis
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
Apheresed
Other name:
Apheresis
Other name:
Blood Component Removal
Other name:
Collection, Apheresis/Leukapheresis
Other name:
Hemapheresis
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET/CT
Arm group label:
Treatment (nivolumab, ibrutinib, chemotherapy, liso-cel)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Summary:
This phase II trial tests how well adding lisocabtagene maraleucel (liso-cel) to
nivolumab and ibrutinib works in treating patients with Richter's transformation.
Liso-cel is in a class of medications called autologous cellular immunotherapy, a type of
medication prepared by using cells from patient's own blood. It works by causing the
body's immune system (a group of cells, tissues, and organs that protects the body from
attack by bacteria, viruses, cancer cells and other substances that cause disease) to
fight the cancer cells. Nivolumab is in a class of medications called monoclonal
antibodies. It works by helping the immune system to slow or stop the grown of cancer.
Ibrutinib is in a class of medications called kinase inhibitors. It works by blocking the
action of the abnormal protein that signals cancer cells to multiply. This helps stop the
spread of cancer cells. Giving ibrutinib and nivolumab with Liso-cel may kill more cancer
cells in patients with Richter's transformation.
Detailed description:
PRIMARY OBJECTIVES:
I. Evaluate the complete response (CR) rate after cycle 3 following lisocabtagene
maraleucel (liso-cel) in combination with nivolumab and ibrutinib to treat patients with
Richter's transformation (RT).
II. Assess the Unacceptable toxicities (UT) rate within the first 28 days during cycle 1
following liso-cel infusion. (Safety lead-in only)
SECONDARY OBJECTIVES:
I. Assess the safety of liso-cel, nivolumab and ibrutinib to treat patients with RT.
II. Estimate the best CR rate. III. Estimate the best overall response rate (ORR). IV.
Estimate duration of response (DOR) at 2 years. V. Assess minimal residual disease (MRD)
post liso-cel in participants with CLL at baseline.
VI. Estimate progression free survival (PFS) at 2 years. VII. Estimate overall survival
(OS) at 2 years.
EXPLORATORY OBJECTIVES:
I. Evaluate predictive biomarkers of response (genetic and immune) in peripheral blood,
apheresis product, infusion product and circulating tumor (ct)DNA.
II. Evaluate the ability of MRD assessed by ctDNA analysis to predict PFS. III. Evaluate
changes in the lymph node microenvironment during nivolumab therapy, with an optional
pre-CAR T cell infusion lymph node biopsy.
IV. Evaluate the effect of liso-cel on CD19 expression on tumor cells at disease
progression.
OUTLINE:
Patients receive ibrutinib orally (PO), nivolumab intravenously (IV), fludarabine IV,
cyclophosphamide IV, and liso-cel IV on study. Patients also undergo apheresis, positron
emission tomography (PET)/computed tomography (CT), collection of blood samples, and bone
marrow biopsy on study. Patients may receive low-moderate intensity chemotherapy in
combination with the study induction therapy per treating physician discretion with
approval of study principal investigator.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Documented informed consent of the participant
- Agreement for confirmatory pre-treatment tumor biopsy
- If a patient does not have an easily accessible lymph node to biopsy without
excessive risk in the opinion of the investigator, archival biopsy material
reviewed by a hematopathologist at the enrolling site for study eligibility and
baseline correlatives may be acceptable with approval from the Study principal
investigator (PI)
- Age: >= 18 years
- Eastern cooperative oncology group (ECOG) <= 2
- Histologically confirmed Richter's Transformation (RT)
- Relapsed / refractory following >=2 prior lines of systemic therapy; OR refractory
to first-line chemoimmunotherapy; OR relapsed within 12 months of first line
chemoimmunotherapy; OR relapsed after first line of chemoimmunotherapy and not
eligible for hematopoietic stem cell transplantation due to comorbidities or age
- Eligible to receive liso-cel and ibrutinib per package inserts
- Fully recovered from the acute toxic effects (except alopecia) to <= Grade 1 to
prior anti-cancer therapy
- Absolute neutrophil count (ANC) >= 750/mm^3 unless there is bone marrow involvement
- Platelets >= 75,000/mm^3 unless there is bone marrow involvement
- Total bilirubin =< 1.5 X ULN (unless has Gilbert's disease)
- Aspartate aminotransferase (AST) =< 2.5 x ULN
- Alanine aminotransferase (ALT) =< 2.5 x ULN
- Creatinine clearance of >= 30 mL/min per 24 hour urine test or the Cockcroft-Gault
formula
- International Normalized Ratio (INR) OR Prothrombin (PT) =< 1.5 x ULN
- Activated Partial Thromboplastin Time (aPTT) =< 1.5 x ULN
- Left ventricular ejection fraction (LVEF) >= 40%
- Note: To be performed within 28 days prior to Day 1 of protocol therapy.
- Seronegative for HCV*, active HBV (Surface Antigen Negative), and syphilis (RPR)
- If positive, Hepatitis C RNA quantitation must be performed OR
- If seropositive for HCV or HBV, nucleic acid quantitation must be performed.
Viral load must be undetectable
- Meets other institutional and federal requirements for infectious disease titer
requirements
- Note: Infectious disease testing to be performed within 28 days prior to Day 1
of protocol therapy
- Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
- If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- Agreement by females and males of childbearing potential* to use an effective method
of birth control or abstain from heterosexual activity for the course of the study
through at least 5 months after the last dose of protocol therapy
- Childbearing potential defined as not being surgically sterilized (men and
women) or have not been free from menses for > 1 year (women only)
Exclusion Criteria:
- Subjects who previously received PD1 or PD-L1 inhibitor therapy
- Autologous stem cell transplant within 3 months prior to Day 1 of protocol therapy
- Allogeneic stem cell transplant within 3 months prior to Day 1 of protocol therapy
and no active graft versus host disease (GVHD) or need for immunosuppressants
- Chemotherapy, radiation therapy, immunotherapy within 14 days prior to Day 1 of
protocol therapy
- Strong CYP3A inducers within 14 days prior to Day 1 of protocol therapy
- Warfarin within 5 days prior to Day 1 of protocol therapy
- Current requirement for oxygen supplementation
- Concurrent use of systemic steroids or chronic use of immunosuppressant medications.
Recent or current use of inhaled steroids is not exclusionary. Physiologic
replacement of steroids (prednisone =< 7.5 mg /day or equivalent) is allowed
throughout the study. Use of "bridging" steroids, to control disease, after
leukapheresis and until 3 days prior to CAR T cell infusion, is allowed
- Subjects with lymphoma only involving the central nervous system
- Class III/IV cardiovascular disability according to the New York Heart Association
(NYHA) Classification
- Subjects with clinically significant arrhythmia or arrhythmias not stable on medical
management within two weeks of screening
- Subjects with a known history or prior diagnosis of optic neuritis or other
immunologic or inflammatory disease affecting the central nervous system, including
seizure disorder
- Subjects with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to study agent
- Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
- History of stroke or intracranial hemorrhage within 6 months prior to screening
- History of other malignancies, except for malignancy surgically resected (or treated
with other modalities) with curative intent, basal cell carcinoma of the skin or
localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer;
malignancy treated with curative intent with no known active disease present for >=
3 years
- Clinically significant uncontrolled illness
- Active infection requiring antibiotics
- Known history of immunodeficiency virus (HIV)
- Females only: Pregnant or breastfeeding
- Subjects with an active, known or suspected autoimmune disease. Subjects with type I
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis) not requiring systemic treatment, well controlled
asthma and/or mild allergic rhinitis (seasonal allergies) are eligible
- Any other condition that would, in the Investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
City of Hope Medical Center
Address:
City:
Duarte
Zip:
91010
Country:
United States
Status:
Recruiting
Contact:
Last name:
Tanya Siddiqi
Phone:
626-803-3458
Email:
tsiddiqi@coh.org
Investigator:
Last name:
Tanya Siddiqi
Email:
Principal Investigator
Start date:
June 2, 2023
Completion date:
September 10, 2025
Lead sponsor:
Agency:
City of Hope Medical Center
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
City of Hope Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05672173
