A Study of Ibrutinib Plus Rituximab With Hyper-CVAD Consolidation in Newly Diagnosed Young Patients With Mantle Cell Lymphoma

Study Drug Administration:

This study will have 2 Parts.

If you are found to be eligible for this study, you will begin Part 1 of the study.

At any time you may be given other drugs to help prevent or decrease side effects, such as
nausea and vomiting. You may ask the study staff for information about how the drugs are
given and their risks.

Part 1:

Part 1 will last up to 12 cycles. Each cycle is 28 days.

Every day you will take 4 ibrutinib capsules with about 1 cup (8 ounces) of water. You must
take all 4 capsules at about the same time every day, at least 30 minutes before or at least
2 hours after eating a meal. Do not open the capsules or dissolve them.

If you miss a dose, you can take it up to 6 hours after the time you would have taken it. If
it is later than 6 hours, you should skip the dose and start taking the capsules at the same
time as usual the next day.

You will need to fill out diary cards with information about when you take ibrutinib. You
should bring the diary cards with you to appointments.

On Days 1, 8, 15, and 22 of Cycle 1, you will receive rituximab by vein. The first dose
should take about 6-8 hours. After that, each dose should take about 4 hours.

You will then receive rituximab by vein over 4 hours on Day 1 of Cycles 3-12. You will not
receive the drug in Cycle 2.

For some patients, you may receive the rituximab dose over 2 days. Your doctor will tell you
if this is best for you.

You will be checked every 2 cycles to learn how you may be responding. Based on your
response, you may start Part 2 of the study.

Part 2:

During part 2, depending on your response in Part 1, you will receive 2 alternating
combinations of drugs (the first combination in the first cycle, then the second combination
in the second cycle, and so on) for 2-8 cycles. Each cycle will be 28 days.

First combination:

You will receive the following drugs during the odd-numbered cycles (Cycles 1, 3, 5, and 7)
of Part 2:

- Rituximab by vein over 6 hours on Day 1

- Dexamethasone either by mouth or by vein on Days 1-4

- Cyclophosphamide by vein (over 3 hours each time) 2 times each day on Days 2-4

- Mesna by vein non-stop on Days 2-4

- Doxorubicin by vein over 24 hours on Day 5

- Vincristine by vein over 15-30 minutes on Day 5

To help prevent infections, you will also receive Filgrastim (G-CSF) injections just under
your skin, starting at 24-36 hours after the end of the doxorubicin infusion. You will
continue to receive these injections every day until your white blood cell counts recover.

Second combination:

You will receive the following drugs during the even-numbered cycles (Cycles 2, 4, 6, and 8)
of Part 2:

- Rituximab by vein over 6 hours on Day 1

- Methotrexate by vein over 24 hours on Day 2

- Cytarabine by vein (over 2 hours each time) 2 times each day on Days 3-4

When you receive methotrexate, you will also be given leucovorin by mouth to help prevent
side effects. Blood (about 1 tablespoon) will be drawn 24 and 48 hours after the end of the
methotrexate infusion so that the study doctor can learn when it is best to stop giving you
leucovorin.

You will again receive G-CSF after doxorubicin until your white blood cell counts recover.

Study Visits in Part 1:

On Day 1 of every cycle:

- You will have a physical and neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of
the disease.

- If you can become pregnant, you will have a blood (about 1½ tablespoons) or urine
pregnancy test.

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

- If the study doctor thinks it is needed, you will have a gastrointestinal endoscopy.

- If the study doctor thinks it is needed, you will have a PET/CT scan to check the status
of the disease.

On Days 8, 15, and 22 of Cycle 1, you will have a physical exam.

On Day 1 of every odd-numbered cycle (Cycles 3, 5, 7, and so on), if the study doctor thinks
it is needed, you will have a CT scan to check the status of the disease.

If your CT scan shows that the disease has gotten better, you will have a PET/CT scan at the
end of Part 1.

If the doctor thinks it is needed based on the results of your screening bone marrow biopsy
and/or colonoscopy, these tests will be repeated at the end of Part 1.

Study Visits in Part 2:

On Day 1 of every cycle:

- You will have a physical and neurological exam.

- You will have an EKG. Blood (about 2 tablespoons) will be drawn for routine tests and to
check the status of the disease.

- If you can become pregnant, you will have a blood (about 1½ tablespoons) or urine
pregnancy test.

Up to 3 times a week from Days 8-28 of all Cycles, you will have a blood (about 2 tablespoons
each time) drawn for routine tests.

At the end of Cycles 2, 4, 6, and 8, and then every 3-6 cycles after that, you will have a CT
scan and chest x-ray to check the status of the disease.

Length of Treatment:

You may continue taking the study drugs in Part 1 for up to 12 cycles. You may continue
taking the study drugs in Part 2 for up to 8 cycles. You will no longer be able to take the
drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to
follow study directions.

End-of-Treatment Visit:

After you finish taking the study drugs:

- You will have a physical and neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of
the disease.

- If your doctor thinks it is needed, you will have a PET/CT scan and/or bone marrow
biopsy/aspiration to check the status of the disease.

- If your doctor thinks it is needed, you will have a gastrointestinal endoscopy.

- If you can become pregnant, you will have a blood (about 1½ tablespoons) or urine
pregnancy test.

Long Term Follow-Up:

After your end-of-treatment visit and if the disease has not gotten worse, you will return
for a clinic visit every 4 months for 2 years, then every 6 months for 2 years, and then
every year after that to see how you are doing. At these visits:

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of
the disease.

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

Inclusion Criteria:

1. Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in
tissue biopsy.

2. Patients with MCL must be symptomatic and need immediate therapy. Symptoms and nature
of MCL include any of the following: a) blastoid variant; b) pleomorphic variant; c) B
symptoms, d) MIPI > 3, e) Ki 67 >/= 30%, f) bulky tumors > 7 cm or in case of >/=2
tumors, each >/=5 cm in diameter, g) disease threatening organ function, h) elevated
LDH, i) PB WBC > 50,000, j) pancytopenia due to bone marrow MCL, k) patient's choice
due to anxiety; l) pain due to lymphoma; m) somatic mutations in the TP53, c-MYC or
NOTCH genes; n) size of spleen >/=20 cm

3. Patients with mantle cell lymphoma with any of the following will be considered
"high-risk" for the purpose of this protocol: • Blastoid or pleomorphic histology •
Ki-67 index larger than 30% • Bulky tumor of larger than 7 cm or in case of multiple
tumors, larger than or equal to 2 cm each in diameter • Somatic mutations in the TP53,
c-MYC or NOTCH genes • Size of spleen >= 20 cm

4. Patient has newly diagnosed disease with no prior therapy.

5. Understand and voluntarily sign an IRB-approved informed consent form.

6. Age
7. Patients should have bi-dimensional measurable disease using the Lugano criteria
(Measureable disease by CT scan defined as at least 1 lesion that measures =/>1.5 cm
in single dimension.) Gastrointestinal or bone marrow or spleen only patients are
allowable.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

9. An absolute neutrophil count (ANC) > 1,000/mm^3 and platelet count >100,000/mm^3
(Patients who have bone marrow infiltration by MCL are eligible if their ANC is >/=
500/mm^3 [growth factor allowed] or their platelet level is equal to or > than
20,000/mm^3. These patients should be discussed with either the principal investigator
(PI) or Co-PI of the study for final approval).

10. Serum bilirubin <1.5 mg/dl and Cr Clearance >/= 30 mL/min, Aspartate transaminase
(AST)/ serum glutamic oxaloacetic transaminase (SGOT) and Alanine transaminase (ALT)/
serum glutamic-pyruvic transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper
limit of normal if hepatic metastases are present. Gilbert's disease is allowed.

11. Cardiac ejection fraction >/= 50% by Echocardiogram (ECHO) or multiple gated
acquisition scan (MUGA).

12. Disease free of prior malignancies with exception of currently treated basal cell,
squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or
other malignancies in remission (including prostate cancer patients in remission from
radiation therapy, surgery or brachytherapy), not actively being treated.

13. Females of childbearing potential (FCBP)* must have a negative serum or urine
pregnancy test (within 30 days of initiation of protocol therapy) and must be willing
to use acceptable methods of birth control. Men must agree to use a latex condom
during sexual contact with a female of childbearing potential even if they have had a
successful vasectomy. *A female of childbearing potential is a sexually mature woman
who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at
any time in the preceding 24 consecutive months).

Exclusion Criteria:

1. Any serious medical condition including but not limited to, uncontrolled hypertension,
uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic
obstructive pulmonary disease (COPD), renal failure, laboratory abnormalities, active
hemorrhage, 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.

2. Pregnant or breast feeding females.

3. Known human immunodeficiency virus (HIV) infection.

4. Patients with active Hepatitis B or C infection (not including patients with prior
Hepatitis B vaccination or positive serum hepatitis B antibody) These patients should
be cleared by GI consultation for Hepatitis B and Infectious Disease consult for
Hepatitis C.

5. All patients with central nervous system lymphoma.

6. Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to
enrollment.

7. 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 unless due
to lymphoma.

8. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel or ulcerative colitis, symptomatic
inflammatory bowel disease, or partial or complete bowel obstruction, or any other
gastrointestinal condition that could interfere with the absorption and metabolism of
ibrutinib.

9. Major surgery within 4 weeks of initiation of therapy. Clearance letter from primary
physician required.

10. Requires anticoagulation with warfarin or equivalent vitamin K antagonist.

11. Requires treatment with strong Cytochrome P4503A (CYP3A) inhibitors

12. Patients with New York Heart Association (NYHA) Class III and IV heart failure,
myocardial infarction in the preceding 6 months, and significant conduction
abnormalities, including but not limited to 2nd degree atrioventricular block (AV
block) type II, 3rd degree block, QT prolongation (QTc > 500 msec), sick sinus
syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 bpm),
hypotension, light headedness and syncope. Patients with persistent and uncontrolled
atrial fibrillation will be excluded. The protocol excludes patients who have recently
had a stent and by recommendation of their cardiologist need to stay on anticoagulants
such as warfarin or equivalent vitamin K antagonist.

13. Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals)
within 14 days prior to initiation of study.