Ibrutinib in Treating Patients With Relapsed or Refractory Transformed Indolent B-cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. Perform a preliminary assessment of the efficacy of single-agent ibrutinib, based on
overall response rate, in subjects with relapsed or refractory transformed indolent B-cell
non-Hodgkin lymphoma (R/R TIL).

SECONDARY OBJECTIVES:

I. To determine the tolerability of chronic ibrutinib therapy in this patient population.

II. To determine the disease control rate of this regimen.

III. Evaluate the complete response rate, overall survival, and progression-free survival to
single-agent ibrutinib in this patient population.

IV. Determine response rate relative to the underlying B-cell histology.

OUTLINE:

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

After completion of study treatment, patients are followed up every 3 months for up to 5
years.

Inclusion Criteria:

- Patients must have histologically confirmed transformed indolent B-cell non-Hodgkin
lymphoma that is relapsed or refractory to at least one line of therapy

- Patients must have a computed tomography (CT) (preferred) or magnetic resonance
imaging (MRI) scan of the chest, abdomen, and pelvis within 28 days of enrollment

- Patients must have measurable disease defined as lesions greater than 1.5 cm that can
be accurately measured in two dimensions by CT (preferred), or MRI

- Patients must have a positron emission tomography (PET) scan within 56 days of
enrollment

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 2

- Absolute neutrophil count (ANC) >= 1000/mm^3 or >= 750/mm^3 in the setting of marrow
involvement by disease

- Platelets >= 50,000/mm^3 or >= 30,000/mm^3 in the setting of marrow involvement by
disease or splenomegaly due to disease

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit
of normal (ULN)

- Total bilirubin =< 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of
non-hepatic origin

- Creatinine clearance (Clcr) > 25 mL/min

- Patients must be anticipated to complete 2 cycles of therapy in the opinion of the
treating physician

- Women of childbearing potential and men who are sexually active must affirm they are
practicing a highly effective method of birth control during and after the study
consistent with local regulations regarding the use of birth control methods for
subjects participating in clinical trials; men must agree to not donate sperm during
or after the study; for females, these restrictions apply for 1 month after the last
dose of study drug; for males, these restrictions apply for 3 months after the last
dose of the study drug

- 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

- Sign (or their legally-acceptable representatives must sign) an informed consent
document in accordance with institutional and federal guidelines indicating that they
understand the investigational nature of and procedures required for the study,
including biomarkers, and are willing to participate in and comply with the guidelines
of the study

Exclusion Criteria:

- Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or
active hepatitis B virus infection or any uncontrolled active systemic infection

- Major surgery or a wound that has not fully healed within 4 weeks of initiation of
therapy

- Known central nervous system lymphoma

- History of stroke or intracranial hemorrhage within 6 months of screening

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g.,
phenprocoumon)

- Requires chronic treatment with strong cytochrome P450, family 3, subfamily A (CYP3A)
inhibitors

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by
the New York Heart Association Functional Classification

- Vaccinated with live, attenuated vaccines within 4 weeks of initiation of therapy

- Any life-threatening illness, medical condition, or organ system dysfunction which, in
the investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
risk

- Patients with other prior malignancies except for adequately treated basal cell
carcinoma, squamous cell carcinoma of the skin, breast or cervical cancer in situ, or
other cancer from which the patient has been disease-free for 5 years or greater,
unless approved by the protocol sponsor-investigator/lead-sub-investigator

- Patients that previously were treated with ibrutinib for > 7 days

- Previous chemotherapy, immunotherapy, biologically targeted therapy, other
investigational agent, or radiation therapy within 3 weeks of initiation of ibrutinib
therapy or radio-immunotherapy within 12 weeks of initiation of ibrutinib therapy

- Prior allogeneic transplant with graft-versus-host disease (GVHD) requiring
immunosuppressive therapy