Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

Inclusion Criteria:

• Known HIV infection and histologically confirmed B-cell non-Hodgkin lymphoma or B-celllymphoproliferative disease as follows, as defined by the World Health Organizationclassification:

• Active B-cell non-Hodgkin lymphoma (cluster of differentiation [CD]20 positive ornegative), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), or multiple myeloma that has relapsed, progressed, or been refractory toat least one regimen

• Note: Patients with CLL, SLL, or mantle cell lymphoma (MCL) may only be enrolledin Stratum C

• At least 14 days between ibrutinib initiation and last cancer therapy; any number ofprior cancer therapies is permitted; patients otherwise fit for blood or marrowtransplantation (BMT) should receive second-line chemotherapy before consideringenrollment

• Serologic documentation of HIV infection at any time prior to study entry, asevidenced by positive enzyme-linked immunosorbent assay (ELISA), positive Westernblot, or any other federally approved licensed HIV test; alternatively, thisdocumentation may include a record that another physician has documented that theparticipant has HIV infection based on prior ELISA and Western blot, or other approveddiagnostic tests

• Participants must be on a stable antiretroviral regimen per current InternationalAcquired Immunodeficiency Syndrome (AIDS) Society guidelines as follows, with nointention of changing the regimen within 8 weeks after ibrutinib initiation:

• Choice of regimen: The specific antiretroviral agents are at physiciandiscretion, and the use of investigational agents currently available on anexpanded-access basis is allowed; use of experimental antiretroviral agents orthose containing zidovudine (including Combivir and Trizivir) is prohibited

• Patients with mantle cell lymphoma, CLL, or SLL must be on non-cytochrome P450,family 3, subfamily A, polypeptide 4 (CYPA3A4) modulating antiretroviral agents (Stratum C) to be eligible for this study

• Patients may be switched to non-conflicting regimens in order to participate

• Stability of regimen: With the exception of patients on zidovudine-based ART, anychanges in antiretroviral regimen must be made at least 4 weeks prior toibrutinib initiation; patients taking zidovudine-based ART must change to anon-zidovudine-based regimen at least 2 weeks prior to ibrutinib initiation;changes to ART therapy during the study may be made if medically necessary (e.g.toxicity, treatment failure)

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 (Karnofsky >= 60%)

• Life expectancy >= 2 months

• Absolute CD4+ lymphocyte count: >= 75 cells/uL

• Absolute neutrophil count >= 750 cells/uL

• Platelets >= 50,000 cells/uL, or >= 30,000/uL if bone marrow is involved by malignancy

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) andalanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 xinstitutional upper limit of normal (ULN), or =< 5.0 x ULN if attributable tomalignancy

• Total bilirubin =< 2.0 x ULN, unless elevated bilirubin is attributable to Gilbert'ssyndrome or to HIV medications (e.g., indinavir, tenofovir, atazanavir)

• Creatinine clearance (CrCl) >= 40 mL/min (modified Cockcroft-Gault)

• All subjects must be screened for hepatitis B and C infection; subjects must eitherhave no history of hepatitis B or C, or must meet the following criteria in order to eeligible:

• Hepatitis B: Subjects infected with hepatitis B must receive anti-hepatitis Btherapy; per Infectious Diseases Society of America (IDSA) and AmericanAssociation for the Study of Liver Diseases (AASLD) guidelines, subjects thatshow no immunity, defined by the lack of hepatitis B surface antibody, and showevidence of chronic infection (i.e. hepatitis B surface antigen positive [HBsAg+], hepatitis B core antibody positive [HB core AB +], hepatitis B surfaceantibody negative [HBsAB-]) must be on anti-hepatitis B therapy throughout thestudy in order to be eligible; the exact hepatitis B therapy is at the discretionof the infection disease specialist or investigator; all patients diagnosed withhepatitis B must also meet the liver function test criteria listed above and haveno evidence of cirrhosis; however, all patients who present with acute hepatitisB, or who show normal transaminases but are HBsAg+ and immunoglobulin M positive (IgM+) for hepatitis B core antigen, are ineligible

• Hepatitis C: Subjects, who are hepatitis C antibody positive, with or without apositive hepatitis C ribonucleic acid (RNA) level, must meet the liver functiontest criteria listed above and have no evidence of cirrhosis; patients diagnosedwith hepatitis C less than 6 months before enrollment will be considered to haveacute hepatitis C and will be ineligible unless the hepatitis C viral load isundetectable

• Must in the opinion of the investigator be capable of complying with this protocol

• Patients may not begin protocol therapy within 7 days of major surgery or within 3days of minor surgery

• Willingness of sexually active subjects to use adequate contraception; both men andwomen of child-bearing potential treated or enrolled on this study must agree to useadequate contraception (hormonal or barrier method of birth control; abstinence)before study entry, for the duration of study participation, and 4 months aftercompletion of ibrutinib; men who only have sex with other men do not need to usecontraception specifically for this study; (should a woman become pregnant or suspectshe is pregnant while she or her partner is participating in this study, she shouldinform her treating physician immediately)

• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Prior exposure to ibrutinib

• Receipt of any investigational agents within 14 days before the first dose ofibrutinib

• Failure to recover to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 2 from clinically significant toxicities due to prior cancertherapies or to any investigational agents

• Active central nervous system involvement by malignancy; central nervous systemdisease that has been treated into remission is permitted; a chart note of theclinician's impression of lack of central nervous system (CNS) involvement isacceptable

• Patients who require concomitant treatment with CYP3A4/5 strong inhibitors or inducersOTHER than antiretroviral therapies for HIV

• As part of the enrollment/informed consent procedures, the patient will becounseled on the risk of interactions with other agents, and what to do if newmedications need to be prescribed or if the patient is considering a newover-the-counter product

• A prednisone equivalent of < 20 mg daily is permitted in patients requiringchronic use; larger doses must be discontinued >= 7 days prior to ibrutinibinitiation and are prohibited during study treatment

• Anticoagulation with warfarin or equivalent vitamin K antagonists within 28 days priorto starting ibrutinib and throughout the study

• Significant or uncontrolled intercurrent condition including, but not limited to:

• Infection other than HIV, hepatitis B, or hepatitis C that is symptomatic orrequires systemic treatment

• Opportunistic infection within 60 days prior to enrollment

• Currently active clinically significant cardiovascular disease such asuncontrolled arrhythmia, congestive heart failure, any class 3 or 4 cardiacdisease as defined by the New York Heart Association Functional Classification,or history of myocardial infection within 6 months prior to enrollment

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment

• History of class B or class C cirrhosis, per the modified Child-Pughclassification

• Psychiatric illness that would limit compliance

• Inability to swallow capsules whole, or disease significantly affectinggastrointestinal function and/or inhibiting small intestine absorption, such asmalabsorption syndrome, small bowel resection, or poorly controlled inflammatory boweldisease affecting the small intestine

• History of prior malignancy, with the exception of the following:

• Malignancy treated with curative intent and with no evidence of active diseasepresent for more than 3 years prior to screening and felt to be at low risk forrecurrence by treating physician

• Adequately treated non-melanomatous skin cancer or lentigo maligna melanomawithout current evidence of disease

• Adequately treated cervical carcinoma in situ without current evidence of disease

• Skin-limited Kaposi sarcoma that has not required systemic treatment within 6months prior to study enrollment

• History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to ibrutinib

• Pregnancy or breastfeeding; a pregnancy test must be performed within 7 days prior toibrutinib initiation in women of childbearing potential; pregnant women are excluded;breastfeeding must be discontinued