A Study of Ibrutinib With Rituximab in People With Untreated Marginal Zone Lymphoma
A Study of Ibrutinib With Rituximab in People With Untreated Marginal Zone Lymphoma
The purpose of this study is to see if the combination of rituximab and ibrutinib can help
 people with marginal zone lymphoma who have not received treatment in the past. The study
 will also compare the combination of rituximab and ibrutinib with the combination of
 rituximab and placebo to see which combination works better.
Inclusion Criteria:

 -  Histologically documented marginal zone lymphoma, including splenic, nodal, and
 extranodal sub-types at the enrolling institution.

 -  No prior systemic therapy for MZL with the exception of the following:

 -  Prior antibiotic therapy for H. pylori, C. psittaci, and B. burgdorferi

 -  Prior antiviral therapy for HCV Note: Subjects are eligible if they had prior
 splenectomy or other local surgical treatment or local radiation therapy without
 systemic therapy and now require their first ever systemic therapy.

 -  Men and women ≥18 years of age

 -  Patients with gastric MALT lymphoma must be H. pylori negative or have failed a trial
 of H. pylori eradication

 -  Patients with gastric MALT lymphoma who are H. pylori negative or who have
 relapsed/refractory disease after H. pylori eradication must be ineligible for, have
 refused or failed gastric radiation therapy

 -  Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

 -  ≥1 measurable lesion on computed tomography (CT) scan (>1.5 cm in longest dimension).
 Lesions in anatomical locations (such as extremities or soft tissue lesions) that are
 not well visualized by CT may be measured by magnetic resonance imaging (MRI) instead.
 Patients with splenomegaly without other measurable disease must have splenomegaly of
 >15 cm in the craniocaudal direction

 -  Life expectancy of >3 months, in the opinion of the investigator

 -  Female subjects must be of non-reproductive potential (i.e., post-menopausal by
 history - no menses for ≥2 years; OR history of hysterectomy; OR history of bilateral
 tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing
 potential must have a negative serum pregnancy test upon study entry

 -  Male and female subjects who agree to use highly effective methods of birth control
 (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine
 devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy
 and for 30 days (females) and 90 days (males) after the last dose of study drug

 -  Documented evidence of need for treatment, including, but not limited to, threatened
 end-organ function, bulky disease (>5 cm), symptoms, requirement for transfusion or
 growth factor support, or medically significant need for intervention For subjects
 with presumptive evidence of transformation based on clinical assessment of factors
 such as, but not limited to, increasing lactate dehydrogenase (LDH), rapidly worsening
 disease, or frequent B-symptoms, both a pre-treatment tumor biopsy and bone marrow
 biopsy are required to rule out large cell transformation. For all subjects, results
 of both the tumor biopsy and bone marrow biopsy must be known prior to enrollment and
 randomization.

 Exclusion Criteria:

 -  Medically apparent central nervous system lymphoma or leptomeningeal disease

 -  Patients with a prior or concurrent malignancy whose natural history or treatment does
 not have the potential to interfere with the safety or efficacy assessment of the
 investigational regimen are eligible

 -  History of other malignancies except adequately treated non-melanoma skin cancer,
 curatively treated in-situ cancer, or other solid tumors curatively treated with no
 evidence of disease for ≥2 years

 -  Subject who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
 to first dose of ibrutinib/placebo or subject who requires continuous treatment with a
 strong CYP3A inhibitor

 -  Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc.,
 or chronic administration of >20 mg/day of prednisone) within 28 days of the first
 dose of study drug

 -  Currently active, clinically significant cardiovascular disease such as uncontrolled
 arrhythmias or Class 3 or 4 congestive heart failure as defined by New York Heart
 Association Functional Classification; or a history of unstable angina, acute coronary
 syndrome, or myocardial infarction within 6 months of prior to screening

 -  Recent infection requiring systemic anti-infective treatment that was completed ≤14
 days before the first dose of study drug

 -  Any uncontrolled active systemic infection

 -  Known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia

 -  Hepatitis B (HBV): All subjects must be screened for hepatitis B and C. Subjects with
 a positive polymerase chain reaction for hepatitis B must be on entecavir or
 equivalent therapy as per institutional standard of care. (Hep C patients may be
 enrolled if other parameters precluding hepatic impairment are met. And they are not
 undergoing active therapy for hepatitis C

 -  Human immunodeficiency virus (HIV): NOTE: HIV is a contraindication if the subject has
 an active opportunistic infection (OI) within 12 months and CD4 count is below the
 normal range

 -  Any of the following abnormalities:

 -  Absolute neutrophil count (ANC) <750 cells/mm3 (0.75 x 10^9/L) unless there is
 documented bone marrow involvement

 -  Platelet count <50,000 cells/mm^3 (50 x 10^9/L) independent of transfusion
 support unless there is documented bone marrow involvement

 -  Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≥3.0 x upper
 limit of normal (ULN)

 -  Creatinine >2.0 x ULN or Estimated Glomerular Filtration Rate GFR
 [Cockcroft-Gault]) <30 mL/min

 -  Hemoglobin <8.0 g/dL

 -  Bilirubin >1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
 non-hepatic origin)

 -  PT/INR >1.5 x ULN and PTT (aPTT) >1.5 x ULN

 -  Unable to swallow capsules or disease significantly affecting gastrointestinal
 function such as malabsorption syndrome, resection of the stomach or small bowel, or
 complete bowel obstruction

 -  Major surgery within 4 weeks prior to the first dose of study drug

 -  Any life-threatening illness, medical condition, including uncontrolled diabetes
 mellitus (DM), or organ system dysfunction that, in the opinion of the investigator,
 could compromise the subject's safety or put the study outcomes at undue risk

 -  Lactating or pregnant

 -  Unwilling or unable to participate in all required study evaluations and procedures

 -  Unable to understand the purpose and risks of the study and to provide a signed and
 dated informed consent form (ICF) and authorization to use protected health
 information (in accordance with national and local subject privacy regulations)

 -  Subjects with chronic liver disease with hepatic impairment Child-Pugh class B or C