This phase II trial studies how well ibrutinib and brentuximab vedotin work in treating patients with Hodgkin lymphoma that has returned (relapsed) or does not respond to treatment (refractory). Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as brentuximab vedotin, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib together with brentuximab vedotin may be a better treatment for Hodgkin lymphoma.

PRIMARY OBJECTIVE:

I. Evaluate the anti-tumor activity of the two agent combination ibrutinib and brentuximab vedotin, as assessed by complete response (CR) rate.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of the two agent combination through evaluation of toxicities, including type, frequency, severity, attribution, time course and duration.

II. Obtain estimates of overall response rate (ORR), response duration and survival (overall and progression-free).

III. Describe outcomes of patients who ultimately undergo autologous or allogeneic hematopoietic cell transplantation following treatment with ibrutinib/brentuximab vedotin.

EXPLORATORY OBJECTIVE:

I. Collect deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from lymphoma specimens and serial plasma samples for future biomarker evaluation.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-21 and brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Inclusion Criteria:

• Patients must have histologically documented or cytologically confirmed Hodgkin lymphoma with CD30 expression
• Patients must have absolute neutrophil count (ANC) >= 1000/uL; neupogen can be given before and during treatment to achieve target ANC >= 1000/uL
• Patients must have platelets (plt) >= 50,000/uL; platelet transfusion and packed red blood cell transfusion can also be given prior to the start of treatment and during treatment to achieve a target plt >= 50,000/uL provided that patients have not received growth factors for at least 14 days prior to entering trial
• Patients must have hemoglobin >= 8.5 g/dl; platelet transfusion and packed red blood cell transfusion can also be given prior to the start of treatment and during treatment to achieve a target hemoglobin of >= 8.5/ul provided that patients have not received growth factors for at least 14 days prior to entering trial
• Patients must have measurable disease > 1.5 cm evidenced by computed tomography (CT) scan of the neck/chest/abdomen (abd)/pelvis or CT/positron emission tomography (PET) scans
• Patients must be either refractory to or relapsed after 1 line of therapy
• Prior radiation therapy is allowed
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
• Female subject is either post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control (i.e. a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study
• Male subject agrees to use an acceptable method of contraception for the duration of the study
• Over 40 kg; life expectancy of greater than 3 months
• Eastern Cooperative Oncology Group (ECOG) of 0-2
• Total bilirubin within 1.5 x the upper limit of normal institutional limits; patients with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x institutional upper limit of normal (unless demonstrated Hodgkin lymphoma involvement of the liver); estimated creatinine clearance >= 30 ml/min (Cockcroft-Gault) and/or 24 urine analysis as needed
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT) (activated PTT [aPTT]) < 1.5 x ULN
• The effects of brentuximab vedotin and ibrutinib on the developing fetus is unknowm; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
• All subjects must have the ability to understand and the willingness to sign a written informed consent; they are to give voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
• Patient must be either refractory to or relapsed after 1 line of therapy
• Prior hematopoietic transplantation is allowed (autologous and/or allogeneic)
• Prior brentuximab vedotin is allowed provided that patients were not refractory (defined as developing progressive disease while on treatment or progressed within 3 months of finished last dose of brentuximab vedotin)
• Prior ibrutinib for Hodgkin lymphoma is not allowed

Exclusion Criteria:

• Less than or equal to 40 kg
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk
• 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)
• Patients should not have any uncontrolled illness including ongoing or active infection
• Patients may not be receiving any other investigational agents, or concurrent biological therapy, chemotherapy, or radiation therapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib and brentuximab vedotin (BV)
• Patients must not have received prior chemotherapy or radiation for =< 3 weeks before study enrollment, or those who have not recovered from the adverse events due to agents administered more than 3 weeks earlier are excluded
• Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
• Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac pacemaker who have a QTc interval of >= 470 msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
• Patients with active central nervous system (CNS) disease or history of brain metastases are excluded from study
• Patients may be on steroids prior to initiation of treatment, provided that, by cycle 1 day 1, steroids use was tapered down to less than or equal to 20 mg of prednisone
• Pregnant women are excluded from this study because of the potential teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
• Recent infection requiring systemic treatment that was completed =< 14 days before the first dose of study drug
• Known active infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV); testing to be done only if patients suspected of having infections or exposures; subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded; subjects who have an undetectable human immunodeficiency virus (HIV) viral load with CD4 >= 200 and are on highly active antiretroviral therapy (HAART) medication are allowed
• Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification
• STUDY-SPECIFIC EXCLUSIONS:
• Patient has hypersensitivity to brentuximab vedotin
• Refractory to prior brentuximab vedotin (defined as developing progressive disease while on treatment or progressed within 3 month of finished last dose of brentuximab vedotin)
• No active graft-versus-host disease (GVHD) or on immunosuppressive medication for GVHD
• Recent infection requiring intravenous anti-infective treatment that was completed =< 14 days before the first dose of study drug
• Unresolved toxicities from prior anticancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria, with the exception of alopecia
• Baseline grade II peripheral neuropathy
• Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Major surgery within 4 weeks of first dose of study drug
• Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
• Concomitant use of warfarin or other vitamin K antagonists
• Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
• Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

From the time of the first study treatment up to 2 years post treatment, an average of 28 months.