Ibrutinib in Treating Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the antitumor efficacy of single agent ibrutinib as measured by the overall
response rate in patients with relapsed/refractory Hodgkin's lymphoma who have relapsed or
not responded to chemotherapy, immunotherapy and/or radiation.

SECONDARY OBJECTIVES:

I. To assess duration of tumor control including duration of response (DOR) II. To assess
progression free survival (PFS). III. To assess the safety and tolerability of 560mg of
ibrutinib in Hodgkin lymphoma (HL) patients.

TERTIARY OBJECTIVES:

I. To assess the mechanism(s) by which ibrutinib may be active in patients with classical
Hodgkin lymphoma (cHL) by the correlation of potential biomarkers with clinical outcomes.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD). Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days then every 9 weeks
for 1 year.

Inclusion Criteria:

- Patients with relapsed or refractory classical HL who have previously received ASCT.
Patients must have received prior ASCT who have failed at least 12 weeks (3 months)
before the first dose of ibrutinib, OR who have failed at least 2 lines of therapy and
are not eligible for ASCT due to:

- Inability to achieve a CR or partial response (PR) prior to transplant

- Age or comorbid conditions

- Inability to collect stem cells

- Adequate hematologic function independent of transfusion and growth factor support for
at least 7 days prior to screening and randomization, with the exception of PEGylated
GCSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to
screening and randomization defined as:

- Absolute neutrophil count >750 cells/mm3 (0.75 x 109/L).

- Platelet count >50,000 cells/mm3 (50 x 109/L).

- Hemoglobin >8.0 g/dL.

- Adequate hepatic and renal function defined as:

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

- Adequate hematologic function independent of transfusion and growth factor support for
at least 7 days prior to screening and randomization, with the exception of PEGylated
GCSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to
screening and randomization defined as:

- Absolute neutrophil count >750 cells/mm3 (0.75 x 109/L).

- Platelet count >50,000 cells/mm3 (50 x 109/L).

- Hemoglobin >8.0 g/dL.

- Adequate hepatic and renal function defined as:

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

- Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-Gault)

- 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.

- Men and women ≥ 18 years of age.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

- Female subjects who are of non-reproductive potential (i.e., post-menopausal by
history -no menses for ≥1 year; 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 90 days after the last dose of study drug

- Sign (or their legally-acceptable representatives must sign) an informed consent
document indicating that they understand the purpose of and procedures required for
the study and are willing to participate in the study.

Exclusion Criteria:

- Prior allogeneic stem cell transplant

- Previous therapy with Bruton's tyrosine kinase (BTK) inhibition

- Known cerebral/meningeal disease

- Nodular lymphocyte predominant Hodgkin's lymphoma subtype

- Concurrent therapy with other systemic anti-neoplastic or investigational agents

- Patients with a known hypersensitivity to any excipient contained in the drug
formulation

- History of other malignancies, except:

- Malignancy treated with curative intent and with no known active disease present
for >= 3 years before the first dose of study drug and felt to be at low risk for
recurrence by treating physician

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease

- Adequately treated carcinoma in situ without evidence of disease

- Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc.,
or chronic administration [> 14 days] of > 20 mg/day of prednisone) within 28 days of
the first dose of study drug

- 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

- Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade =< 1, or to
the levels dictated in the inclusion/exclusion criteria with the exception of alopecia

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

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

- Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus
(HCV) or hepatitis B virus (HBV); 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

- Any uncontrolled active systemic infection

- Major surgery within 4 weeks of first dose of study drug

- 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

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

- 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

- Currently active, clinically significant hepatic impairment Child-Pugh class B or C
according to the Child Pugh classification

- 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)