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

  • STATUS
    Recruiting
  • End date
    Mar 31, 2028
  • participants needed
    132
  • sponsor
    National Cancer Institute (NCI)
Updated on 17 June 2022
platelet count
cancer
cyclophosphamide
chronic lymphocytic leukemia
hodgkin's disease
rituximab
filgrastim
vincristine
granulocyte colony stimulating factor
prednisone
leukemia
lymphocytic leukemia
gilbert's syndrome
etoposide
doxorubicin
colony stimulating factor
combination chemotherapy
neutrophil count
follicular lymphoma
diffuse large b-cell lymphoma
b-cell lymphoma
large b-cell lymphoma
r-chop
high grade b-cell lymphoma
acalabrutinib
da-epoch
chop regimen
r-chop regimen

Summary

Background

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.

Objective

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 lymphoma.

Eligibility

People ages 18 and older with an aggressive B-cell lymphomas that have not been treated

Design

Participants will be screened with:

Blood and urine tests

Physical exam

Medical history

Tumor biopsy

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 canal.

Imaging scans

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.

...

Description

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.

Details
Condition Non-Hodgkin's Lymphoma, Diffuse Large B-Cell Lymphoma, DLBCL, NHL
Treatment Rituximab, CHOP, acalabrutinib, DA-EPOCH
Clinical Study IdentifierNCT04002947
SponsorNational Cancer Institute (NCI)
Last Modified on17 June 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients must have a confirmed histologic diagnosis of an aggressive B-cell lymphoma with morphologic appearance of DLBCL or high-grade B-cell lymphoma (HGBL) confirmed by the Laboratory of Pathology, NCI, with no prior treatment for DLBCL or HGBL. The following subtypes are included
DLBCL, NOS, Activated B-cell type (ABC)
DLBCL, NOS, Germinal center B-cell type (GCB)
T-cell/histiocyte-rich large B-cell lymphoma
Primary cutaneous DLBCL, leg-type
EBV+ DLBCL, NOS
DLBCL associated with chronic inflammation
ALK+ large B-cell lymphoma
High-grade B-cell lymphoma, NOS
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
NOTE: Presence of concomitant indolent lymphomas such as follicular lymphoma, marginal
zone lymphomas, monoclonal B-cell lymphocytosis or chronic lymphocytic leukemia/small
lymphocytic lymphoma that are best categorized as composite or transformed lymphomas
are allowed
A formalin-fixed tissue block or 15 slide of tumor sample (archival or fresh) must be
available for performance of correlative studies
NOTE: Tumor tissue may be from any previously collected tissue and adequacy is at the
discretion of the Principal Investigator. Patients must be willing to have a tumor
biopsy if adequate archival tissue is not available (i.e., post-enrollment and prior
to treatment)
Measurable lymph nodes or masses of at least 1.5 centimeters (cm) on baseline CT or
MRI
Stage II, III, or IV disease as classified by the Ann Arbor Classification
Age greater than or equal to 18 years
investigator
ECOG performance status less than or equal to 2
absolute neutrophil count >=1,000/mcL
Adequate organ and marrow function as defined below unless dysfunction is felt to be
hemoglobin >= 8 g/dL (transfusions permitted to meet criteria)
secondary to lymphoma involvement as determined by the treating investigator
Platelets >= 75,000/mcL (transfusions not permitted)
Serum creatinine <= 2.0 mg/dL
total bilirubin <= 1.5 X institutional ULN (or <= 3 X institutional ULN for
OR
patients with documented Gilberts syndrome or cholestatic obstruction or
involvement by lymphoma)
AST(SGOT)/ALT(SGPT) <= 3 X institutional ULN (<= 5 x ULN for patients with
cholestatic obstruction or involvement by lymphoma
Creatinine clearance >=40 mL/min/1.73 m2 for patients with creatinine levels above 2
mg/dL
RBC transfusions and use of G-CSF will be allowed in order to meet eligibility
parameters
NOTE: In patients without bone marrow involvement, transfusions of RBCs are permitted
to achieve the criterion hemoglobin of 8g/dl, but transfusions of platelets are not
permitted to achieve the criterion platelet count of >75,000/mcL. In patients with
bone marrow involvement, all transfusions are permissible at the discretion of the
Effects of acalabrutinib on the developing human fetus are unknown. For these reasons
the following measures apply
Women of childbearing potential must have a negative serum or urine pregnancy
test within 7 days prior to enrollment
Women of childbearing potential (WOCBP) who are sexually active must agree to
highly-effective contraception prior to study entry, for the duration of study
participation, and for at least 2 days after the last dose of acalabrutinib or 12
months after the last dose of combined chemotherapy, whichever is later. Male
subjects must use highly effective contraception prior to study entry, for the
duration of study participation, and for 12 months after the last dose of
combined chemotherapy; there is no contraception timing requirement post-last
dose of acalabrutinib alone if male subject does not initiate chemotherapy on
study after the acalabrutinib window
Participants must not be planning to conceive or father children within the
projected duration of the trial, starting with the pre-screening/screening visit
through 2 days after the last dose of acalabrutinib or 12 months after the last
dose of combined chemotherapy, whichever is later
Ability of patient to understand and the willingness to sign a written informed
consent document
Any HIV status will be included in this study; status must be confirmed prior to
enrollment

Exclusion Criteria

Patients who meet histologic criteria for the following subtypes are excluded
Primary DLBCL of the central nervous system (PCNSL)
Primary mediastinal B-cell lymphoma (PMBL)
Plasmablastic lymphoma
Intravascular large B-cell lymphoma
Requires treatment with moderate or strong CYP3A inhibitors or inducers
Known lymphomatous involvement of the CNS
Uncontrolled active systemic infection
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
classical Hodgkin lymphoma
Suspected or confirmed Progressive Multifocal Leukoencephalopathy (PML)
Patients who, at the discretion of the investigator, need immediate cytoreductive
chemotherapy such as patients with evidence of spontaneous tumor lysis or impending
organ compromise are not eligible
Diagnosed or treated for malignancy other than DLBCL, except
Current or prior anti-cancer treatment for DLBCL prior to enrollment. Short course of
corticosteroids (<7 days) for acute issues prior to study enrollment are permitted
Adequately treated non-melanoma skin cancer without evidence of disease
Major surgical procedure within 30 days of first dose of study drug. If a subject had
Adequately treated carcinoma in situ without evidence of disease
major surgery, they must have recovered adequately from any toxicity and/or
History of hemorrhagic stroke or intracranial hemorrhage in preceding 6 months
complications from the intervention before the first dose of study drug
Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole
Uncontrolled autoimmune hemolytic anemia
lansoprazole, dexlansoprazole, rabeprazole or pantoprazole). Subjects receiving
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrollment to this study
Pregnant women, or women who intend to become pregnant during the study are excluded
from this study because of potential teratogenic effects associated with
acalabrutinib, R-CHOP, and/or DA-EPOCH-R
The potential for all study treatments to be excreted in breast milk of nursing
mothers is unknown. Because there is an unknown but potential risk for adverse events
in nursing infants secondary to treatment of the mother with acalabrutinib
breastfeeding must be discontinued
Uncontrolled intercurrent illness including, but not limited to the following that may
limit interpretation of results or that could increase risk to the patient at the
discretion of the investigator
Any condition that requires anticoagulation with warfarin or equivalent vitamin K
antagonist
Active bleeding, history of bleeding diathesis (e.g., hemophilia or von
Willebrand disease)
Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody
positive will need to have a negative HCV PCR result before enrollment. Those
with a positive PCR for hepatitis C are excluded
Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen
(HbsAg) positive will be excluded from enrollment. Patients who are hepatitis B
core antibody (HbcAb) positive will need to have a negative HBV PCR result before
enrollment. Those with a positive PCR for hepatitis B are excluded. Those who are
hepatitis B core antibody (HbcAb) positive with a negative PCR for hepatitis B
will be treated with antivirals designed to prevent hepatitis B reactivation
(e.g., entecavir) throughout therapy and for 12 months after therapy and have
monitoring for hepatitis B reactivation with PCR
Malignancy treated with curative surgical resection and no evidence of
active disease for 2 years prior to enrollment
Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months
of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as
defined by the New York Heart Association Functional Classification. Subjects
with controlled atrial fibrillation/flutter during screening are eligible
Inability to swallow oral medications, or disease involve that significantly
limits absorption of oral medication
Known mental or physical illness that would interfere with cooperation with the
requirements of the trial or confound the results or interpretation of the
results of the trial and, in the opinion of the treating investigator, would make
the patient inappropriate for entry into the study
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