Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Most people
with this cancer can be cured. But those who are not cured have a poor prognosis. Researchers
want to add another drug to standard treatment see if it can improve the cure rate.
To see if the drug acalabrutinib given with rituximab and standard combination chemotherapy
can improve the cure rate of aggressive B-cell lymphomas such as diffuse large B-cell
People ages 18 and older with an aggressive B-cell lymphomas that have not been treated
Participants will be screened with:
Blood and urine tests
Bone marrow biopsy: A needle will remove marrow from the participant s hipbone.
Lumbar puncture: If necessary, a needle will remove fluid from the participant s spinal
Participants will take the study drug for up to 14 days. It is a pill taken 2 times a day.
Then they will have more scans. They will get rituximab and chemotherapy. They may get these
drugs through a needle in an arm vein. Or they may them through a tube placed in a vein in
their chest or in their neck. They might also keep taking the study drug. Each treatment
cycle lasts 21 days. They will have up to 6 cycles.
Participants may have 4 doses of another drug injected into their spinal fluid.
Participants will have repeats of the screening tests throughout the study.
Participants will have a follow-up visit 30 days after their last treatment, then every 3
months for 2 years, then every 6 months for 3 years, and then yearly.
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, second-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 GCBDLBCL 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
-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,
Histologically confirmed DLBCL or high-grade B-cell lymphoma
Primary mediastinal B-cell lymphoma (PMBL) and CNS involvement excluded
HIV negative or positive
Available FFPE or fresh frozen biopsy
Adequate organ function
Age >=18 years
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
Secondary objectives include integrative genomic analysis of all untreated DLBCL that
respond or are resistant to acalabrutinib for 14 days, event-free survival (EFS),
progression free survival (PFS) and overall survival (OS) of combination therapy of
acalabrutinib and chemoimmunotherapy will be assessed
Diffuse Large B-Cell Lymphoma,
non-hodgkin's lymphoma (nhl),
diffuse large cell lymphoma,
diffuse large b cell lymphoma
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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