Zanubrutinib in Combination With R-CHOP (ZaR-CHOP) for Newly Diagnosed Diffuse Large B-Cell Lymphoma
Zanubrutinib in Combination With R-CHOP (ZaR-CHOP) for Newly Diagnosed Diffuse Large B-Cell Lymphoma
This phase Ib trial seeks to find out the best dose and possible side effects and/or benefits
 of zanubrutinib in combination with the R-CHOP in treating patients with newly diagnosed
 diffuse large B-cell lymphoma (DLBCL). Zanubrutinib is designed to block a protein called
 Bruton Tyrosine Kinase in order to stop cancer growth. R-CHOP is the acronym for the
 combination of five drugs: rituximab, cyclophosphamide, doxorubicin, vincristine and
 prednisone. It is the most widely used chemoimmunotherapy regimen for DLBCL and is considered
 the standard-of-care treatment for patients with DLBCL. Three of the drugs in R-CHOP
 (cyclophosphamide, doxorubicin and vincristine) are chemotherapy drugs. Rituximab is a type
 of immunotherapy and prednisone is a type of steroids.
PRIMARY OBJECTIVE:

 I. Determine the safety, toxicity profile and recommended phase 2 dose (RP2D) of zanubrutinib
 in combination with R-CHOP (ZaR-CHOP) for patients with previously untreated diffuse large
 B-cell lymphoma (DLBCL).

 SECONDARY OBJECTIVES:

 I. Determine the objective response rate (ORR) (complete and partial responses),
 progression-free survival (PFS) and overall survival (OS) of ZaR-CHOP in patients treated at
 the RP2D.

 II. Provide descriptive data on treatment exposure to zanubrutinib and R-CHOP including
 treatment discontinuation rate and relative dose intensity.

 OUTLINE: This is a dose de-escalation study of zanubrutinib and fixed-dose R-CHOP regimen
 followed by a dose-expansion study.

 Patients receive zanubrutinib orally (PO) once or twice daily on days 1-21, rituximab
 intravenously (IV) on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on
 day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats
 every 21 days for up to 6 cycles in the absence of disease progression or unacceptable
 toxicity.

 After completion of study treatment, patients are followed every 6 months for 2 years.
Inclusion Criteria:

 -  Patients must have histologically confirmed DLBCL, irrespective of cell-of-origin.
 Patients with previously diagnosed indolent lymphoma (follicular lymphoma and marginal
 zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are
 eligible only if they have not previously been treated for indolent lymphoma except
 for local radiation for early-stage disease

 -  Patients may have received brief treatment with glucocorticoids (up to 250 mg/day
 prednisone or equivalent for a maximum of 10 days) and/or 1 cycle of chemotherapy such
 as R-CHOP (or some component[s] thereof) for the diagnosis of B-cell lymphoma provided
 they had staging computed tomography (CT) and/or positron emission tomography (PET)/CT
 scans prior to glucocorticoids and/or chemotherapy. Treatment must occur within 28
 days prior to enrollment

 -  Age >= 18 years. Because no dosing or adverse event data are currently available on
 the use of zanubrutinib in combination with R-CHOP in patients <18 years of age,
 children are excluded from this study

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2. Performance status
 of 3 will be accepted if the impairment is caused by DLBCL complications and
 improvement is expected once therapy is initiated

 -  Measurable disease (defined as >= 1.5cm in diameter) or at least one PET
 fludeoxyglucose F-18 (FDG) avid area of disease

 -  Patients must have adequate hematologic, hepatic, and renal function as defined below:

 -  Hemoglobin >= 7.0 g/dL

 -  Absolute neutrophil count (ANC) > 1,000/mcL

 -  Platelet count > 75,000/mcL

 -  Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) (unless due to
 Gilbert's disease)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) <
 2.5 x institutional ULN

 -  Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 2.5 x
 institutional ULN

 -  Creatinine clearance > 40 mL/min calculated by Cockcroft-Gault

 -  Adequate cardiac function with a left ventricular ejection fraction (LVEF) >= 50% as
 assessed by echocardiogram or MUGA (Multigated acquisition scan)

 -  The effects of zanubrutinib on the developing human fetus are unknown. For this reason
 and because chemotherapeutic agents used in this study are known to be teratogenic,
 women of child-bearing potential and men must agree to use adequate contraception
 (double barrier method of birth control or abstinence) 2 weeks prior to initiation of
 treatment, for the duration of study participation and for 3 months after completing
 treatment. Should a woman become pregnant or suspect that she is pregnant while she or
 her partner is participating in this study, she should inform the treating physician
 immediately. Men must agree to refrain from sperm donation for at least 90 days after
 the last dose of zanubrutinib

 -  Women of childbearing potential must have a negative serum (beta-human chorionic
 gonadotropin [beta-hCG]) or urine pregnancy test at screening. Women who are pregnant
 or breastfeeding are ineligible for this study

 -  Patients must have the ability to understand and the willingness to sign a written
 informed consent document and Health Insurance Portability and Accountability Act
 (HIPAA) consent document. Voluntary written consent must be given before performance
 of any study-related procedure not part of standard medical care, with the
 understanding that consent may be withdrawn by the patient at any time without
 prejudice to future medical care

 -  International Prognostic Index must be documented:

 -  ECOG performance status >= 2 (1 point)

 -  Age >= 60 (1 point)

 -  >= 2 extranodal sites (1 point)

 -  Lactate dehydrogenase measurement (LDH) > upper limit of normal (1 point)

 -  Ann Arbor Stage III or IV (1 point)

 -  Is there evidence of transformation from indolent lymphoma?

 Exclusion Criteria:

 -  Major surgery within 4 weeks before Day 1, Cycle 1 of treatment

 -  Prior anthracycline use >= 150 mg/m^2

 -  Known central nervous system (CNS) involvement. Patients at high risk for secondary
 CNS involvement but without neurologic symptoms suspected to be due to lymphoma are
 allowed to be enrolled and receive intrathecal chemotherapy with methotrexate,
 cytarabine, and/or glucocorticoids. CNS prophylaxis with IV methotrexate is NOT
 permitted in this study. Patients who are enrolled and subsequently identified to have
 pathologic confirmation of CNS involvement by lymphoma may be continued on the study
 at the discretion of the principal investigator

 -  Active systemic bacterial, fungal or viral infection except for localized fungal
 infections of skin or nails. Patients with resolving infections such as urinary tract,
 respiratory, or skin infections may be enrolled if clinically improving. NOTE:
 patients may be receiving prophylactic antiviral or antibacterial therapies at the
 investigator's discretion

 -  Evidence of current uncontrolled or symptomatic cardiovascular conditions, including,
 uncontrolled cardiac arrhythmias, history of or symptomatic congestive heart failure
 (New York Heart Association [NYHA] Class III or greater), unstable angina, or
 myocardial infarction within the past 6 months. Poorly controlled or clinically
 significant atherosclerotic vascular disease including angioplasty, cardiac or
 vascular stenting within 6 months of enrollment

 -  History of cerebrovascular accident or transient ischemic attack within the 6 months
 before Day 1, Cycle 1 of treatment

 -  Any prior history of intracranial hemorrhage

 -  Known bleeding diatheses or platelet dysfunction disorders

 -  Known gastrointestinal (GI) disease or gastrointestinal procedure that will
 significantly interfere with the oral absorption or tolerance of zanubrutinib
 including the inability to swallow pills/capsules

 -  Any serious medical or psychiatric illness that could, in the investigator's opinion,
 potentially interfere with the completion of treatment according to this protocol

 -  Known allergy to any of the study medications, their analogues, or excipients in the
 various formulations of any agent

 -  Evidence of prior malignancy except for: adequately treated non-melanoma skin cancer,
 adequately treated in situ carcinoma, low-grade prostate carcinoma (Gleason grade =<
 6) managed with observation that has been stable for at least 6 months, or any
 malignancy treated with curative intent and continuously disease-free for at least 3
 years

 -  Participation in other interventional clinical trials, including those with other
 investigational agents not included in this trial, within 21 days of Day 1, Cycle 1 of
 this trial. Also excluded are patients who are receiving any other investigational
 agents outside of a clinical trial

 -  Known history of human immunodeficiency virus (HIV), active hepatitis C infection (HCV
 ribonucleic acid [RNA] polymerase chain reaction [PCR]-positive) and/or active
 hepatitis B infections (HBV deoxyribonucleic acid [DNA] PCR-positive). If hepatitis B
 virus core (HBc) antibody is positive, the patient must be evaluated for the presence
 of HBV DNA by PCR. If HCV antibody is positive, the patient must be evaluated for the
 presence of HCV RNA by PCR. Patients with positive HBc antibody and negative HBV DNA
 by PCR are eligible. Patients with positive HCV antibody and negative HCV RNA by PCR
 are eligible

 -  Pregnant or breastfeeding women are excluded from this study. Because there is an
 unknown, but potential risk for adverse events in nursing infants secondary to
 treatment of the mother with zanubrutinib, breastfeeding should be discontinued if the
 mother is treated with zanubrutinib. These potential risks may also apply to other
 agents used in this study