Smart Start: Study of Rituximab, Lenalidomide, and Ibrutinib Combined With Chemotherapy For Patients With High Risk Diffuse Large B-Cell Lymphoma

Study Drug Administration:

Each study cycle will be 21 days.

If you are found to be eligible to take part in this study, you will receive up to 2 cycles
of rituximab, ibrutinib, and lenalidomide. In each of these cycles, you will receive
rituximab by vein over about 4-6 hours on Day 1. You will take ibrutinib (up to four [4]
capsules) by mouth 1 time every day. You will take lenalidomide by mouth 1 time every day on
Days 1-10 of each cycle. You should take the capsules at about the same time each day, with
about 1 cup (8 ounces) of water. You should swallow the capsules whole; do not open, break,
or chew them.

At the end of each cycle, you should bring your pill bottle(s) to the clinic so the study
staff can count the number of pills, if any, that are leftover.

After the first 2 cycles, you will begin to receive either EPOCH or R-CHOP. The doctor will
decide which of these standard treatments you will receive, based on what he/she thinks is in
your best interest.

If you receive EPOCH, in these cycles, you will continue to receive rituximab, ibrutinib, and
lenalidomide as described above, as well as:

- Etoposide by vein over 24 hours on Days 1-4 of each cycle.

- Prednisone by mouth 1 time each day on Days 1-5 of each cycle.

- Oncovin (vincristine) by vein over 24 hours on Days 1-4 of each cycle.

- Cyclophosphamide by vein over about 1 hour on Day 5 of each cycle.

- Hydrodaunorubicin (doxorubicin) by vein over 24 hours on Days 1-4 of each cycle.

If you receive R-CHOP, in these cycles, you will continue to receive rituximab, ibrutinib,
and lenalidomide as described above, as well as:

- Cyclophosphamide by vein over about 1 hour on Day 1 of each cycle.

- Doxorubicin by vein over about 1 hour on Day 1 of each cycle.

- Vincristine by vein over about 1 hour on Day 1 of each cycle.

- Prednisone by mouth on Days 1-5 of each cycle.

Study Visits:

Within 3 days before the beginning of each cycle:

- You will have a physical exam.

- Blood (about 3-4 tablespoons) and urine will be collected for routine tests. If you can
become pregnant, part of this sample will be used for a pregnancy test.

Before Cycles 2 and 3, blood (about 2-3 tablespoons) will be drawn to test for a fungal
infection.

At the end of Cycles 2 and 4, you will have an FDG-PET/CT scan to check the status of the
disease. This may be performed earlier if the doctor thinks it is in your best interest.

During Cycles 3-8, blood (about 1 tablespoon) will be drawn 2 times every week for routine
tests.

Length of Treatment:

You may receive the study drugs for up to a total of 8 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 the study will be over after the follow-up visits.

End-of-Treatment Visit:

Within 3-4 weeks after you start the last cycle, you will have an End-of-Treatment visit. The
following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 3-4 tablespoons) will be drawn for routine tests.

- You will have an FDG-PET/CT scan to check the status of the disease.

- If the doctor thinks it is needed, you will have a bone marrow biopsy to check the
status of the disease.

Follow-Up:

Every 3 months for 1 year after the End-of-Treatment visit, and then every 4 months for 1
year after that:

- You will have a physical exam.

- Blood (about 3-4 tablespoons) will be drawn for routine tests.

- You will have a CT scan or an FDG-PET/CT scan to check the status of the disease.

Inclusion Criteria:

1. Histopathologically confirmed diagnosis of previously untreated DLBCL of the non-GCB
DLBCL subtype.

2. No prior treatment except a prior limited-field radiotherapy, a short course of
glucocorticoids 1 of cycle 1, and/or cyclophosphamide for an urgent lymphoma related problem at
diagnosis (e.g. epidural cord compression, superior vena cava syndrome).

3. Patient or durable power of attorney (DPA) for healthcare must be able to understand
and voluntarily sign an IRB-approved informed consent form.

4. Age >/=18 years at the time of signing the informed consent.

5. Patients must have bi-dimensional measurable disease, as defined as radiographically
apparent disease with the longest dimension of >/= 1.5cm.

6. Patients with performance status of deemed related to lymphoma and felt potentially reversible by the treating physician)

7. Serum bilirubin <1.5x ULN except in patients with Gilbert's syndrome as defined by >
80% unconjugated bilirubin; AST (SGOT) and ALT (SGPT) hepatic metastases are present; ANC >1000/mm^3 and platelets >100,000/mm^3 unless
deemed related to lymphoma involvement in the bone marrow and felt potentially
reversible by the treating physician.

8. Renal function assessed by calculated creatinine clearance: a. Calculated creatinine
clearance >/=30ml/min by Cockcroft-Gault formula. See section below, Dosing Regimen,
regarding lenalidomide dose adjustment for calculated creatinine clearance >/=30ml/min
and < 60ml/min.

9. Patients must be willing to receive transfusions of blood products.

10. 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.

11. Women of childbearing potential must have a negative serum (Beta-human chorionic
gonadotropin [Beta-hCG]) or urine pregnancy test at screening and must adhere to the
scheduled pregnancy testing as required in the Revlimid REMS® program.

12. Women of childbearing potential and men who are sexually active with a woman of
childbearing potential must be practicing a highly effective method of birth control
during and after the study (12 months for women and 3 months for men), consistent with
local regulations regarding the use of birth control methods for subjects
participating in this clinical study. Men must agree to not donate sperm during and
for up to 3 months after their conclusion of therapy on study.

13. Able to take aspirin (81mg) daily or alternative therapy as prophylactic
anticoagulation.

Exclusion Criteria:

1. 1. Any serious medical condition including but not limited to uncontrolled
hypertension, uncontrolled congestive heart failure within past 6 months prior to
screening (Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the
New York Heart Association Functional Classification), uncontrolled diabetes mellitus,
active/symptomatic coronary artery disease, COPD, LVEF less than 40%, renal failure,
active infection, history of invasive fungal infection, moderate to severe hepatic
disease (Child Pugh Class B or C), active hemorrhage, laboratory abnormality, or
psychiatric illness that, in the investigators opinion places the patient at
unacceptable risk and would prevent the subject from signing the informed consent
form. Patients with history of cardiac arrhythmias should have cardiac evaluation and
clearance.

2. Pregnant or lactating females.

3. Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab,
etoposide, vincristine, doxorubicin, cyclophosphamide, or prednisone.

4. Known HIV infection. Patients with active hepatitis B infection (not including
patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody).
Known hepatitis C infection is allowed as long as there is no active disease and is
cleared by GI consultation.

5. All patients with central nervous system involvement with lymphoma.

6. Diagnosis of prior malignancy within the past 2 years with the exception of
successfully treated basal cell carcinoma, squamous cell carcinoma of the skin,
carcinoma "in situ" of the cervix or breast. History of other malignancies are allowed
if in remission (including prostate cancer patients in remission from radiation
therapy, surgery or brachytherapy), not actively being treated, with a life expectancy
> 3 years.

7. Significant neuropathy (Grades 2 or Grade 1 with pain) within 14 days prior to
enrollment

8. Contraindication to any of the required concomitant drugs or supportive treatments or
intolerance to hydration due to preexisting pulmonary or cardiac impairment including
pleural effusion requiring thoracentesis or ascites requiring paracentesis not due to
lymphoma.

9. Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30
days of study enrollment).

10. Patients with severe bradycardia (heart rate <40 bpm, hypotension, light-headedness,
syncope).

11. Major surgery within 4 weeks of study entry, or wound that is not healed from prior
surgery or trauma.

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

13. Requires anticoagulation with warfarin or equivalent vitamin K antagonists.

14. Requires chronic treatment with strong CYP3A inhibitors

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