Phase II, Single-Arm, Open-label, Multicenter Study Evaluating the Efficacy of Adjunctive Zanubrutinib and CAR T-Cell Therapy in Aggressive B-Cell Non-Hodgkin's Lymphoma
Overview
- Phase
- Phase 2
- Intervention
- Chimeric Antigen Receptor T-Cell Therapy
- Conditions
- Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation
- Sponsor
- Northwestern University
- Enrollment
- 24
- Locations
- 2
- Primary Endpoint
- Change in 6-month complete response rates
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This phase II trial studies the effect of zanubrutinib and CAR T-cell therapy in treating patients with aggressive B-cell non-Hodgkin's lymphoma or transformed indolent B-cell lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize CAR, a protein on the surface of cancer cells. These CAR-specific T cells may help the body's immune system identify and kill cancer cells. Giving zanubrutinib together with CAR T-cell therapy may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVE: I. To determine efficacy of adjunctive zanubrutinib with chimeric antigen receptor T (CAR T)-cell therapy as defined by an improvement in 6-month complete response rates (CR) (defined per 2014 Lugano criteria) as compared to historical rates, in patients treated with CAR T-cell therapy (with a prior lead-in zanubrutinib) followed by maintenance zanubrutinib. SECONDARY OBJECTIVES: I. To determine the conversion rates of partial (PR) to complete response (CR), defined per Lugano criteria (2014), in patients with partial response to initial CAR T-cell therapy (with a prior lead-in zanubrutinib) who are administered maintenance zanubrutinib. II. To determine the overall response rate (ORR), using Lugano criteria (2014), in patients treated with CAR T-cell therapy (with a prior lead-in zanubrutinib) who are administered maintenance zanubrutinib. III. To determine progression free survival (PFS), in patients treated with CAR T-cell therapy (with a prior lead-in zanubrutinib) who are administered maintenance zanubrutinib. IV. To determine the overall survival (OS) rate in patients treated with CAR T-cell therapy (with a prior lead-in zanubrutinib) who are administered maintenance zanubrutinib. V. Toxicity assessment. EXPLORATORY OBJECTIVES: I. To determine the impact on quality of life using the health-related quality of life outcome questionnaire European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ C-30), in patients treated with CAR T-cell therapy (with a prior lead-in zanubrutinib) who are administered maintenance zanubrutinib. II. To measure disease-specific symptoms and/or treatment-related concerns in patients treated with CAR T-cell therapy (with a prior lead-in zanubrutinib) who are administered maintenance zanubrutinib. III. To evaluate CAR T-cell polyfunctionality with the administration of zanubrutinib lead-in and maintenance treatment. IV. To identify changes in immune cell subsets and cytokines with administration of zanubrutinib lead-in and maintenance. V. To characterize potential mechanisms of loss of response by measuring changes in programmed cell death ligand-1 /2 (PD-L1/L2) and CD19 on tumor tissue. OUTLINE: LEAD- IN PHASE: Patients receive zanubrutinib orally (PO) twice daily (BID) for 7-14 days in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive standard of care CAR T-cell therapy intravenously (IV) at 4 weeks. MAINTENANCE PHASE: Patients receive zanubrutinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have a histo-pathologically confirmed diagnosis of an aggressive B-cell non-Hodgkin lymphoma or transformed indolent B-cell lymphoma that is recurrent or refractory to standard therapy and with intent to treat with standard of care CAR T-cell therapy (meeting Food and Drug Administration \[FDA\] approved indications for the respective CAR T-cell construct being used). Standard of care /FDA approved CARTs for this population include axicabtagene ciloleucel, tisagenlecleucel or lisocabtagene maraleucel, any of which may be used for this study and provider dependent. For the purpose of this study, aggressive B-cell NHL histologies should conform to the label indications for the respective CART being utilized. Accordingly, CART eligible histologies include the following groups according to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms
- •High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
- •High-grade B-cell lymphoma, not otherwise specified (NOS)
- •Diffuse large B-cell lymphoma (DLBCL), NOS
- •Diffuse large B-cell lymphoma (DLBCL), NOS; Germinal center B-cell type
- •Diffuse large B-cell lymphoma (DLBCL), NOS; Activated B-cell type
- •Large B-cell lymphoma with IRF4 rearrangement
- •T-cell/histiocyte-rich large B-cell lymphoma (subtype of DLCBL)
- •Primary cutaneous DLBCL, leg type (subtype of DLCBL)
- •Epstein-Barr virus (EBV)+ DLBCL, NOS (subtype of DLCBL)
Exclusion Criteria
- •Patients who are receiving any other investigational agents are not eligible
- •Patients who require treatment with moderate or strong CYP3A inducers =\< 7 days prior to treatment with zanubrutinib lead-in are not eligible
- •Patients requiring systemic treatment with corticosteroids (\> 10mg daily prednisone equivalents) or other immunosuppressive medications including anti-neoplastic therapies =\< 7 days prior to treatment with zanubrutinib lead-in are not eligible
- •Please note: Steroids for treatment of lymphoma and/or management of CAR T-cell toxicities are allowed from time of apheresis until 90 days post CAR T-cell therapy. In the event that steroids are deemed necessary for CAR T-cell toxicities after 90 days, this may be done upon discussion with the principal investigator (PI)
- •Patients with evidence of active disease in the central nervous system (CNS) defined as either the presence of active lesions on magnetic resonance imaging (MRI) obtained within 4 weeks prior to registration or progressive neurological decline are not eligible
- •Patients are not eligible if they have uncontrolled intercurrent illness including, but not limited to
- •Ongoing or active infection
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Cardiac arrhythmia deemed clinically significant by the provider
Arms & Interventions
Treatment (zanubrutinib and CAR T-cell therapy)
LEAD- IN PHASE: Patients receive zanubrutinib PO BID for 7-14 days in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive standard of care CAR T-cell therapy IV at 4 weeks. MAINTENANCE PHASE: Patients receive zanubrutinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.
Intervention: Chimeric Antigen Receptor T-Cell Therapy
Treatment (zanubrutinib and CAR T-cell therapy)
LEAD- IN PHASE: Patients receive zanubrutinib PO BID for 7-14 days in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive standard of care CAR T-cell therapy IV at 4 weeks. MAINTENANCE PHASE: Patients receive zanubrutinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Treatment (zanubrutinib and CAR T-cell therapy)
LEAD- IN PHASE: Patients receive zanubrutinib PO BID for 7-14 days in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive standard of care CAR T-cell therapy IV at 4 weeks. MAINTENANCE PHASE: Patients receive zanubrutinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.
Intervention: Questionnaire Administration
Treatment (zanubrutinib and CAR T-cell therapy)
LEAD- IN PHASE: Patients receive zanubrutinib PO BID for 7-14 days in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive standard of care CAR T-cell therapy IV at 4 weeks. MAINTENANCE PHASE: Patients receive zanubrutinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.
Intervention: Zanubrutinib
Outcomes
Primary Outcomes
Change in 6-month complete response rates
Time Frame: At 6 months from initiation of maintenance zanubrutinib treatment
Defined per 2014 Lugano criteria. The proportion of patients with complete response at 6 months will be estimated among evaluable of patients, and reported along with the 95% two-sided Clopper-Pearson confidence interval. A one-sample exact binomial test will be used to compare the 6-month CR rate to the historic control rate of 35%.
Secondary Outcomes
- Overall response rate (ORR)(At day 90, 6, 12, 18, and 24 months from initiation of zanubrutinib maintenance therapy)
- Progression free survival(From registration until progression/recurrence of lymphoma or death from any cause, assessed at day 90, 6, 12, 18 and 24 months after initiation of zanubrutinib maintenance therapy)
- Conversion rates of partial response (PR) to CR(At day 90, 6, 12, 18, and 24 months from initiation of zanubrutinib maintenance therapy)
- Overall survival(From registration until death from any cause, assessed at day 90, 6, 12, 18 and 24 months)
- Incidence of adverse events(From the time of informed consent until one week post the lead- in treatment period, and then again from day 1 of maintenance treatment phase up to 30 days after treatment discontinuation)