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

 ...
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, 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

 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),
 progression free survival (PFS) and overall survival (OS) of combination therapy of
 acalabrutinib and chemoimmunotherapy will be assessed
-INCLUSION CRITERIA:

 1. 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

 2. 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).

 3. Measurable lymph nodes or masses of at least 1.5 centimeters (cm) on baseline CT or
 MRI

 4. Stage II, III, or IV disease as classified by the Ann Arbor Classification

 5. Age greater than or equal to 18 years

 NOTE: Because no dosing or adverse event data are currently available on the use of
 acalabrutinib in patients <18 years of age, children are excluded.

 6. ECOG performance status less than or equal to 2.

 7. Adequate organ and marrow function as defined below unless dysfunction is felt to be
 secondary to lymphoma involvement as determined by the treating investigator:

 -  absolute neutrophil count* >=1,000/mcL

 -  hemoglobin* >= 8 g/dL (transfusions permitted to meet criteria)

 -  Platelets >= 75,000/mcL (transfusions not permitted)

 -  total bilirubin <= 1.5 X institutional ULN (or <= 3 X institutional ULN for
 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

 -  Serum creatinine <= 2.0 mg/dL

 OR

 -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
 investigator.

 8. 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 (e.g., hormonal or barrier method of birth
 control; abstinence) 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.

 -  Should a woman become pregnant or suspect she is pregnant while she or her
 partner is participating in this study, she should inform her treating physician
 immediately.

 -  WOCBP is defined as any female who has experienced menarche and who has not
 undergone successful surgical sterilization or who is not postmenopausal (i.e.,
 amenorrheic for >12 months without alternative medical cause; post-menopausal
 status in females under 55 years of age should be confirmed with a serum
 folliclestimulating hormone [FSH] level within applicable local laboratory
 reference range for postmenopausal women).

 9. Ability of patient to understand and the willingness to sign a written informed
 consent document.

 10. Any HIV status will be included in this study; status must be confirmed prior to
 enrollment.

 EXCLUSION CRITERIA:

 1. 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

 -  B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
 classical Hodgkin lymphoma

 2. 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.

 3. 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.

 4. Major surgical procedure within 28 days of first dose of study drug. If a subject had
 major surgery, they must have recovered adequately from any toxicity and/or
 complications from the intervention before the first dose of study drug

 5. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
 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

 6. Requires treatment with moderate or strong CYP3A inhibitors or inducers

 7. Presence of concomitant indolent lymphomas such as follicular lymphoma, marginal zone
 lymphomas, or chronic lymphocytic leukemia/small lymphocytic lymphoma that are best
 categorized as composite or transformed lymphomas are excluded

 NOTE: Patients with evidence of small monoclonal B-cell clones isolated to the bone
 marrow or peripheral blood that meet criteria for monoclonal B-cell lymphocytosis are
 not excluded

 8. Known lymphomatous involvement of the CNS

 9. 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

 10. 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.

 11. 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:

 -  Uncontrolled active systemic infection

 -  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)

 -  Suspected or confirmed Progressive Multifocal Leukoencephalopathy (PML)

 -  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
 (HbcsAg) or 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 surface antigen (HbcsAg) or
 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.

 -  Diagnosed or treated for malignancy other than DLBCL, except:

 1. Malignancy treated with curative surgical resection and no evidence of
 active disease for 2 years prior to enrollment

 2. Adequately treated non-melanoma skin cancer without evidence of disease

 3. Adequately treated carcinoma in situ without evidence of disease

 -  History of hemorrhagic stroke or intracranial hemorrhage in preceding 6 months

 -  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.

 -  Uncontrolled autoimmune hemolytic anemia

 -  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.