Acalabrutinib With DA-EPOCH-R or R-CHOP for People With Untreated Diffuse Large B-cell Lymphoma

Background: Gene-expression profiling (GEP) has identified two dominant molecular subtypes, activated B cell like (ABC) and germinal center B cell like (GCB), that arise by distinct mechanisms, have distinct prognoses, and respond differently to targeted therapy Recently, genetic subtypes of DLBCL have been described within molecular subtypes that have distinct genotypic, epigenetic, and clinical characteristics providing biologic rationale for precision medicine strategies in DLBCL Frontline treatment of DLBCL is either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or infusional rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (DA-EPOCH-R) but up to 40% of patients are not cured with frontline treatment Bruton s tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR)-signaling cascade and selective BTK inhibitors have clinical activity preferentially in ABC-DLBCL Acalabrutinib is a selective, small molecule, next-generation BTK inhibitor approved for relapsed mantle cell lymphoma and demonstrated activity in DLBCL The molecular characterization of tumors that respond to DLBCL BTK inhibitors is incomplete; although responses occur more commonly in ABC-DLBCL, cases of GCB-DLBCL show minor responses, and no information is available within genetic subtypes of DLBCL Patients with minor responses during 2-week window of treatment with acalabrutinib (100mg BID) as a single agent may benefit from acalabrutinib added to standard combination therapy as part of frontline therapy Objectives: To determine the response rate, including minor response (MR), to acalabrutinib administered for 14 days in molecular and genetic subtypes of untreated DLBLC (ABC, GCB, unclassified, genetic subtypes) Eligibility: Histologically confirmed DLBCL or high-grade B-cell lymphoma Primary mediastinal B-cell lymphoma (PMBL) and CNS involvement excluded Stages II-IV HIV negative or positive Available FFPE or fresh frozen biopsy Adequate organ function Age \>= 18 years Design: Open-label, single center, non-randomized phase 2 study, with enrollment of 100 untreated DLBCL patients. It is estimated that there may be 50% who are ABC (\~50 patients), and 50% who are GCB or unclassified (\~50 patients). The accrual ceiling will be set at 132 to allow for inevaluable patients and to account for screen fails. The study will start with an initial 2-week window of treatment with acalabrutinib (100mg BID) as a single agent, with collection and assessment of molecular correlates as well as response rates (by imaging) by molecular subtype Treatment with chemoimmunotherapy (R-CHOP or DA-EPOCH-R) either alone or in combination with acalabrutinib will depend on response during window; those with less than 25% reduction during window will receive chemoimmunotherapy alone, while those with at least a 25% reduction in tumor lesions (sum of the products of the longest diameter) will receive combination therapy of chemoimmunotherapy with acalabrutinib (100mg BID on days 1-10 of each cycle); those with clinical progression during window will move immediately to chemoimmunotherapy Secondary objectives include: integrative genomic analysis of all untreated DLBCL that respond or are resistant to acalabrutinib for 14 days, event-free survival (EFS), assessment of progression free survival (PFS) and overall survival (OS) of combination therapy of acalabrutinib and chemoimmunotherapy and investigation of the safety and tolerability of acalabrutinib added to R-CHOP or DA-EPOCH-R in untreated DLBCL.