Ibrutinib for Patients With Follicular Lymphoma Without Complete Response to Initial Chemoimmunotherapy

Inclusion Criteria:

- Follicular lymphoma with histology documented by the participating institution (grades
1, 2 or 3a).

°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, a pre-treatment biopsy is required
to rule out large cell transformation

- Completion of a full course of first line immunochemotherapy including rituximab OR
completion of 4 cycles of first line immunochemotherapy including rituximab if
intolerant (e.g. which include, but are not limited to, R-CHOP, R-CVP,
Bendamustine-R).

- Patients must have achieved PR to primary treatment and not be refractory to prior
treatment.

- Residual FDG-PET activity defined as Deauville 4 or 5 on a PET-CT within 3 and 8 weeks
post the last dose of front line therapy.

- Treatment must begin within 90 days of the last dose of immunochemotherapy.

- Men and women ≥ 18 years of age.

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

- ≥ 1 measurable disease site on computed tomography (CT) scan or positron emission
tomography (PET) (1.5 cm in longest dimension). (In select cases, for example
extremity lesions, an MRI may be substituted.)

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

- Female subjects who are 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., implants, injectables, combined oral contraceptives, some intrauterine devices
[IUDs], sexual abstinence, or sterilized partner) and a barrier method (e.g. condoms,
vaginal ring, sponge, etc) during the period of therapy and for 30 days (females) and
90 days (males) after the last dose of study drug.

Exclusion Criteria:

- Medically apparent central nervous system lymphoma or leptomeningeal disease.

- History of any other active malignancies.

- History of any prior cancer curatively treated within the last two years except:

- Any non-melanoma skin cancer

- Any cancer excised, not treated with chemotherapy and with less than a 30% chance
of recurrence within the next 2 years from registration

- History of any organ transplantation.

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

- More than one prior line of any systemic chemoimmunotherapy for follicular lymphoma.

- Chemotherapy ≤ 21 days prior to first administration of study treatment and/or
monoclonal antibody ≥ 3 weeks prior to first administration of study treatment.

- Prior exposure to radio- or toxin-immunoconjugates.

- Concurrent use of warfarin or other vitamin K antagonists.

- Concurrent use of a strong cytochrome P450 (CYP)3A4/5 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.

- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

- Significant screening electrocardiogram (ECG) abnormalities including left bundle
branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or
corrected QT interval (QTc) >/= 470 msec.

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure (new York Heart Association >Class 2), unstable
angina, uncontrolled hypertension, or myocardial infarction within 6 months of
Screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart
Association Functional Classification.

- Any uncontrolled active systemic infection or recent infection requiring intravenous
anti-infective treatment that was complete ≤ 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 4.0), Grade 0 or 1,
or to the levels dictated in the inclusion/exclusion criteria with the exception of
alopecia.

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

- Known history of infection with human immunodeficiency virus (HIV) or history of
active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV),
or any uncontrolled active systemic infection. Hepatitis B surface antigen must be
confirmed negative within on year before enrollment. 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 of the following abnormalities

- Absolute neutrophil count (ANC) <750 cells/mm^3 (0.75 x 10^9/L)

- Platelet count <50,000 cells/mm^3 (50 x 10^9/L) independent of transfusion
support

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

- Creatinine clearance (CrCl) <30mL/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(unless abnormalities are unrelated to
coagulopathy or bleeding disorder).

- 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 planned within 4 weeks of 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.

- Concurrent enrollment in another therapeutic investigational study or have previously
taken ibrutinib.

- 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).

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