This phase II trial studies the side effects of acalabrutinib, obinutuzumab, and glofitamab and how well they work together for treating patients with mantle cell lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Acalabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers such as mantel cell lymphoma at abnormal levels. This may help keep cancer cells from growing and spreading. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Glofitamab is a class of medications called bispecific antibodies. Bispecific antibodies are designed to simultaneously bind to T cells and cancer cell antigens, leading to T-cell activation, proliferation, and cancer cell death. Giving acalabrutinib, obinutuzumab, and glofitamab together may be a safe and effective treatment for patients with relapsed or refractory mantle cell lymphoma.
PRIMARY OBJECTIVES: I. Evaluate the safety and tolerability of a regimen combining acalabrutinib and glofitamab in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). (Safety Lead-In) II. Estimate the complete response (CR) rate in R/R MCL patients treated with acalabrutinib plus glofitamab. (Phase 2) SECONDARY OBJECTIVES: I. Estimate the minimal residual disease (MRD) negativity rate, time to response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and patient-reported quality of life measures (HRQOL) in R/R MCL patients treated with acalabrutinib plus glofitamab. II. Evaluate the toxicity of acalabrutinib plus glofitamab for R/R MCL. EXPLORATORY OBJECTIVES: I. Examine the prognostic value of MRD assessment by next-generation sequencing (NGS) and circulating cell-free tumor deoxyribonucleic acid (DNA) (ctDNA) assessment in patients with R/R MCL treated with acalabrutinib combined with glofitamab. II. Examine the immune reconstitution, T-cell fitness, and immunomodulatory effects in patients with R/R MCL treated with acalabrutinib combined with glofitamab. III. Examine the evolution of tumor genetic profile and microenvironment in patients with R/R MCL treated with acalabrutinib combined with glofitamab. OUTLINE: Patients receive acalabrutinib orally (PO) twice daily (BID) of each cycle, obinutuzumab intravenously (IV) on days 1 and 7 of cycle 1 only, and glofitamab IV over 2-4 hours on days 8 and 15 of cycle 1 and day 1 of subsequent cycles. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with MRD positive complete response (CR), partial response (PR), or stable disease (SD) after 12 cycles of protocol therapy may continue receiving single agent acalabrutinib per standard of care during the follow-up phase of the study. Patients also undergo a echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening, as well as positron emission tomography (PET)/computed tomography (CT) or CT, and blood specimen collection throughout the trial. Patients may also undergo bone marrow biopsies throughout the trial. Upon completion of study treatment, patients are followed up at 30 days and then every 3 months for response and bi-annually for survival, for up to 4 years from start of treatment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Given PO
Undergo blood sample collection
Undergo bone marrow biopsies
Undergo PET/CT or CT
Undergo ECHO
Given IV
Undergo MUGA
Given IV
Undergo PET/CT
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of unacceptable adverse events (AEs) (safety lead-in)
Defined as AEs that is at least possibly related to study treatment and not related to underlying lymphoma. Toxicities will be graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Cytokine release syndrome (CRS) severity will be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading Criteria. Observed toxicities will be summarized by type, severity, and attribution.
Time frame: During the first 2 cycles of treatment (cycle= 21 days)
Complete response (CR) rate (phase 2)
The proportion of response-evaluable participants that achieve a best response of CR after the start of protocol therapy and prior to disease progression and/or start of other anti-lymphoma therapy. Will be estimated along with the 95% exact binomial confidence interval.
Time frame: Up to 4 years from start of treatment.
Minimal residual disease (MRD) negatively rate
MRD will be assessed by next generation sequencing
Time frame: Up to 4 years from start of treatment
Time to response
Will be estimated along with the 95% exact binomial confidence interval.
Time frame: From start of protocol treatment to the first achievement of partial response (PR) or CR, assessed up to 4 years from start of treatment
Duration of response
Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation.
Time frame: Defined as the time from the first achievement of PR or CR to time of progressive disease or death, whichever earlier, assessed up to 4 years from start of treatment
Progression-free survival
Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation.
Time frame: From start of protocol treatment to time of disease relapse/progression or death due to any cause, whichever occurs earlier, assessed up to 4 years from start of treatment
Overall survival
Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation.
Time frame: From start of protocol treatment to time of death due to any cause, assessed up to 4 years from start of treatment
Patient-reported quality of life (QOL) measures
Measured by the item/domain/total scores from Functional Assessment of Cancer Therapy - Lymphoma and EuroQol-5 Dimension. QOL measures and their changes will be summarized by each timepoint and longitudinally.
Time frame: Up to 4 years from start of treatment
Incidence of AEs
Toxicities will be graded by NCI CTCAE v5.0.CRS severity will be graded according to the ASTCT CRS Consensus Grading Criteria. Observed toxicities will be summarized by type, severity, and attribution.
Time frame: Up to 4 years from start of treatment
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