Study of Ibrutinib in Combination With Rituximab and Lenalidomide in Previously Untreated Subjects With Follicular Lymphoma and Marginal Zone Lymphoma

Study Drug Administration:

Each study cycle is 28 days.

You will take lenalidomide by mouth on Days 1-21 of Cycle 1. After Cycle 1, your dose of
lenalidomide will increase and you will take it by mouth on Days 1-21 of Cycles 2-12. You
should return all empty or leftover lenalidomide capsules/bottles to the study staff. Do not
share the study drug with anyone.

You will receive rituximab by vein over about 4-6 hours on Days 1, 8, 15, and 22 of Cycle 1
and then on Day 1 of Cycles 2-12.

You will also receive ibrutinib by mouth 1 time every day of Cycles 1-12. You should take
your dose ibrutinib with a cup (about 8 ounces) of water.

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn for routine tests.

- Blood (about 2-3 teaspoons) will be drawn before your dose of rituximab for biomarker
testing . Biomarkers are found in the blood/tissue and may be related to your reaction
to the study drugs.

On Days 8, 15, and 22 of Cycle 1:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn for routine tests. If you can become pregnant,
this blood draw will also include a pregnancy test.

- Blood (about 2-3 teaspoons) will be drawn for biomarker testing on Day 15 only.

On Day 1 of Cycles 2 and beyond:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn for routine tests. If you can become pregnant,
this blood draw will also include a pregnancy test.

- During Cycles 4 and 7 only, you will have an MRI or PET/CT scan.

- During Cycles 2 and 7 only, blood (about 2-3 teaspoons) will be drawn for biomarker
testing.

Women who can become pregnant and have irregular menstrual periods will have the blood
pregnancy test (about 1 teaspoon) repeated on Day 15 of every cycle.

Length of Treatment:

You may receive the study drugs for up to 12 cycles. You will no longer be able to take the
study drugs if the disease gets worse, if intolerable side effects occur, or if you are
unable to follow study directions.

Your participation on this study will be over after the follow-up visits.

End-of-Treatment Visits:

About 4 weeks after your last dose of study drugs:

- You will have a physical exam.

- Blood (about 4-6 teaspoons) will be drawn for routine tests and biomarker testing.

- You will have an MRI or PET/CT scan.

You will also be asked about any side effects you may have had and if you have been
hospitalized.

If you can become pregnant, you will have a pregnancy test when you are taken off
lenalidomide. The test will be repeated either 28 days after your last dose (if you have
regular or no menstrual cycles), or 14 and 28 days after your last dose (if you have
irregular menstrual cycles).

Follow Up Visits:

After the End-of-Treatment visit, you will have follow-up visits every 12 weeks (± 2 weeks)
for the first year and then every 24 weeks (± 4 weeks) after that. Follow-up will stop when 3
years have passed since the last study participant enrolled received their last dose of study
drug.

If you completed 12 cycles of study treatment, at each follow-up visit:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn for routine tests.

- You will have an MRI or PET/CT scan.

If you stopped study treatment early because the disease got worse or came back, you will be
called and asked about any new therapies you have started, any symptoms you may be having,
and about your overall health. Each call should take about 5-10 minutes.

Inclusion Criteria:

1. Histologically confirmed CD20+ follicular lymphoma, grade 1, 2, or 3a or marginal zone
lymphoma.

2. Have had no prior systemic treatment for lymphoma

3. Bi-dimensionally measurable disease, with at least one mass lesion >/=2 cm in longest
diameter by CT, PET/CT, and/or MRI.

4. In the opinion of the investigator would benefit from systemic therapy

5. Stage II, III, or IV disease

6. Must be >/=18 years of age

7. Eastern Cooperative Oncology Group (ECOG) performance status
8. Adequate hematologic function within 28 days prior to signing informed consent,
including: a. Absolute neutrophil count (ANC) >/=1,000/mm^3, independent of growth
factor support b. Platelet counts >/=100,000/mm^3 or >/=50,000/mm^3 if bone marrow
involvement with lymphoma, independent of transfusion support in either situation

9. Adequate organ function, including: a. Serum aspartate transaminase (AST) or alanine
transaminase (ALT) < 3 x upper limit of normal (ULN) b. Creatinine clearance >30
ml/min calculated by modified Cockcroft-Gault formula. c. Bilirubin < 1.5 x ULN unless
bilirubin is due to Gilbert's syndrome, documented liver involvement with lymphoma, or
of non-hepatic origin, in which case bilirubin should not exceed 3g/dL. d Prothrombin
time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin
time (PTT) < 1.5 x ULN

10. Must be able to adhere to the study visit schedule and other protocol requirements

11. Women of childbearing potential and men who are sexually active must be practicing a
highly effective method of birth control during and after the study (females of
childbearing potential: must either completely abstain from heterosexual sexual
conduct or must use 2 methods of reliable contraception, 1 highly effective
[intrauterine device, birth control pills, hormonal patches, injections, vaginal
rings, or implants] and at least 1 additional method [condom, diaphragm, cervical cap]
of birth control. Reliable contraceptive methods must be started at least 4 weeks
before lenalidomide.

12. 11. continued : Males who are sexually active must be practicing complete abstinence
or agree to a condom during sexual contact with a pregnant female or female of child
bearing potential. Men must agree to not donate sperm during and after the study. For
females, these restrictions apply at least 4 weeks before study treatment, during the
period of therapy and for 1 month after the last dose of study drug. For males, these
restrictions apply during the period of therapy and for 3 months after the last dose
of study drug.

13. 12). Women of childbearing potential must have a negative serum (beta-human chorionic
gonadotropin [Beta-hCG]) pregnancy test at screening. Women who are pregnant or
breastfeeding are ineligible for this study. a) Females of reproductive potential must
adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.

14. 13). 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, including biomarkers, and are willing to participate in the study.

15. 14). All study participants must be registered into the mandatory Revlimid REMS®
program, and be willing and able to comply with the requirements of the REMS® program.

Exclusion Criteria:

1. Known active central nervous system lymphoma or leptomeningeal disease, except
subjects with a history of central nervous system lymphoma treated and in remission >
6 months.

2. Evidence of diffuse large B-cell transformation

3. Grade 3b FL

4. Any prior history of other malignancy besides FL or marginal zone lymphoma, unless the
patient has been free of disease for >/= 5 years and felt to be at low risk for
recurrence by the treating physician, except: a. Adequately treated non-melanoma skin
cancer or lentigo maligna without evidence of disease; b. Adequately treated cervical
carcinoma in situ without evidence of disease.

5. 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 or lenalidomide capsules, or put the study
outcomes at undue risk, including but not limited to: a. Moderate to severe hepatic
impairment (Child-Pugh classes B and C)

6. Known history of human immunodeficiency virus (HIV), or active Hepatitis C Virus, or
active Hepatitis B Virus infection, or any uncontrolled active systemic infection a.
Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation
prophylaxis unless contraindicated.

7. Prior use of ibrutinib or other BTK inhibitors, rituximab or lenalidomide

8. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,
or chronic administration glucocorticoid equivalent of >10mg/day of prednisone) within
28 days of the first dose of study drug.

9. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any
component of rituximab

10. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g.,
phenprocoumon). If patients have been on warfarin or equivalent vitamin K antagonists
in the past, they will not be eligible if administered within 30 days of the first
dose of study drug.

11. Requires chronic treatment with strong CYP3A inhibitors, for a list of strong CYP3A
inhibitors, see the protocol. If patients have been on a strong CYP3A inhibitor in the
past, they will not be eligible if the CYP3A inhibitor was administered within 7 days
of the first dose of study drug.

12. Requires chronic treatment with strong CYP3A inducers, for a list of strong CYP3A
inducers, see the protocol. If patients have been on a strong CYP3A inducer in the
past, they will not be eligible if the CYP3A inducer was administered within 7 days of
the first dose of study drug.

13. 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.

14. Significant screening electrocardiogram (ECG) abnormalities including left bundle
branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree
block.

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

16. History of stroke or intracranial hemorrhage within 6 months prior to study entry.

17. Vaccinated with live, attenuated vaccines within 4 weeks of study entry

18. Lactating or pregnant subjects

19. Administration of any investigational agent within 28 days of first dose of study
drug.

20. Patients who have undergone major surgery within 7 days or minor surgery within 3 days
of first dose of study drug.