Lenalidomide and Rituximab in the Treatment of Relapsed Mantle Cell Lymphoma (MCL) and Diffuse Large B-Cell Lymphoma

Rituximab is a type of drug known as a monoclonal antibody. It is designed to act against the
cluster of differentiation antigen 20 (CD20) antigen that is found on the surface of both
normal B lymphocytes or on the malignant lymphoma cells. When rituximab attacks the CD20
antigen, it can kill the lymphoma cells. lenalidomide is known as an immunomodulatory drug.
It is thought to work by helping the immune system fight disease.

If you are found to be eligible, you will receive lenalidomide plus rituximab. This study
will be done in 2 phases. In the Phase I portion of this study, 6 dose levels of lenalidomide
will be studied. The same level of rituximab will be given to all participants. Between 3-6
participants will be treated at each dose level. Those enrolled first on this study will
receive the lowest dose of lenalidomide plus rituximab. After treatment, each dose level of
lenalidomide will be evaluated to check for any intolerable side effects. The dose of
lenalidomide that you will receive will depend on the time that you enter this study and the
side effects of those participants that entered the study before you. Once a dose has been
assigned to you, it will not increase, but it could decrease or remain the same for a while
if you have intolerable side effects. Once the highest tolerable dose of lenalidomide has
been found, additional participants will receive that dose during the Phase II portion of
this study.

You should swallow lenalidomide capsules whole by mouth every day at the same time, with a
glass of water on either a full or an empty stomach. Do not break, chew or open the capsules.
This will continue for 21 days, followed by a 7-day rest period. Each 28-day period is called
a cycle of therapy.

If you miss a dose of lenalidomide, take it as soon as you remember on the same day. If you
miss taking your dose for the entire day, take your regular dose the next scheduled day (do
NOT take double your regular dose to make up for the missed dose).

During Cycle 1 only, you will also take rituximab by vein once a week for 4 weeks (total of 4
doses). The first rituximab infusion (by vein) usually takes 6 to 8 hours. Later infusions
are generally shorter, taking about 4 hours to complete. For participants who have a large
mass or who have lymphoma cells in their blood, the rituximab dose may be split into a 2-day
infusion. Vital signs (temperature, blood pressure, respiration, and heart rate) will be
monitored just before, during, and after the infusions. There will be an observation period
of about 1 hour after the end of each rituximab infusion, after which you will be allowed to
go home.

You will be given a diary to record when you take all of the study medications and any
problems or illnesses you experience. You should also write down in the diary any other
medications you take while you are on this study.

After you begin your treatment on the study drug, you will have check-up visits weekly for
the first cycle, every 2 weeks for Cycles 2 and 3 of therapy, and then once a month for the
rest of the study. If your doctor feels it is necessary, the check-up visits may take place
more often. At the end of each 28-day treatment cycle, you will have a visit with the study
doctor to see if it is safe for you to continue on this study and make sure the cancer has
not gotten worse. If at the end of the each cycle, your doctor believes that you are eligible
to continue (based on the degree and type of side effects you are having and the response of
the cancer to the study drug), you will receive enough study drug for another 28-day
treatment cycle.

At these visits you will have a complete physical exam, including measurement of vital signs.
You will be asked questions about how you have felt since your last visit. All medications
you have taken since your last visit will be reviewed by the study doctor. You should bring
the empty pill packages and any unused medication along with the diary you were given earlier
to each visit. You will have a blood sample collected (around 8 tablespoons) for routine
blood tests to check on the status of the disease.

If you are eligible to continue on this study, a new 28-day supply of lenalidomide capsules
will be given to you at this visit. Other tests may be done at these visits to check on the
status of the disease. You may have a sample of bone marrow collected and/or have either
x-rays or CT scans, positron emission tomography (PET) scan (if needed), and gastrointestinal
endoscopy (for patients with known or suspected site of disease) to evaluate your response to
therapy. These tests may not be done at every check-up visit. They will be done when your
doctor feels they are necessary. You may have unscheduled visits at any time during this
study if your doctor feels it is necessary for your care.

You may continue to receive treatment as long as the cancer does not get worse and you do not
experience any intolerable side effects. If, at any time during treatment, the disease gets
worse or you experience any intolerable side effects, you will be taken off this study, and
your doctor will discuss other treatment options with you. The number of weeks you are on the
study drug depends on how well you are tolerating the study drug and how well the lymphoma
responds to the study drugs.

After your participation in this study ends, and if you have completed cycle 1 or more, you
will have an end-of-study visit. At this visit you will have a complete physical exam,
including measurement of vital signs and weight. You will have an ECG and you will be asked
questions about how you have felt since your last visit. All medications you have taken since
your last visit will be reviewed by the study doctor. You will have a blood sample collected
(around 3 tablespoons) for routine blood tests to check on the status of the disease. You
will have bone marrow collected for tests and have either x-rays or CT scans of your body to
check on the status of the disease. You should return all empty drug packaging as well as any
unused lenalidomide capsules at this visit.

If you completed at least 12 and no more than 24 cycles of treatment with lenalidomide, you
will have follow-up visits every 3 months. If you complete 24 or more cycles of treatment
with lenalidomide, you will have follow-up visits every 6 months. This will continue until
the disease gets worse. At each visit, blood (about 1 teaspoon) will be drawn to test your
thyroid function. The status of your disease will be evaluated and you may have a bone marrow
biopsy and aspirate. You will have a chest x-ray and CT scans of the chest, abdomen, and
pelvis. If needed, you will also have a CT scan of the neck. If needed, you will have a
colonoscopy or endoscopy. You may also have a bone marrow biopsy and aspirate performed.

After the end-of-study visit, you will be contacted by phone every 6 months until March 15,
2015, to check on your health and for information about any other cancer treatments you may
have received.

This is an investigational study. Lenalidomide is FDA approved and commercially available.
Lenalidomide is approved for the treatment of patients with transfusion-dependent anemia due
to Low- or Intermediate-1-risk myelodysplastic syndromes associated with the chromosome 5
abnormality with or without other chromosome abnormalities. Lenalidomide is also approved in
combination with dexamethasone for the treatment of patients with multiple myeloma that have
received at least one prior therapy. Its use in this study, for relapsed mantle cell lymphoma
or large B-cell Non-Hodgkin's lymphoma, is investigational. It is currently being tested in a
variety of cancer conditions. In this case it is considered experimental.

Rituximab is FDA approved and commercially available for the treatment of non-Hodgkin's
lymphomas.

Up to 71 participants with mantle cell lymphoma and 41 participants with diffuse large B-cell
non-Hodgkin's lymphoma, transformed large cell lymphoma, and/or Grade 3 follicular lymphoma
(follicular cleaved large cell lymphoma or follicular non-cleaved large cell lymphoma) will
take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Phase I and Phase II: Confirmed diagnosis of mantle cell lymphoma with CD20 positivity
in tissue biopsy. Patients must have previously treated relapsed and/or refractory
MCL. Or for Phase II: Confirmed diagnosis of previously treated relapsed and/or
refractory diffuse large B-cell lymphoma, transformed large cell lymphoma, and/or
Grade 3 follicular lymphoma (follicular cleaved large cell lymphoma or follicular
non-cleaved large cell lymphoma).

2. Understand and voluntarily sign an Institutional Review Board (IRB) approved informed
consent form.

3. Age equal to or greater than 18 years at the time of signing the informed consent.

4. Patients must have bi-dimensional measurable disease (bone marrow only involvement is
acceptable).

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

6. Serum bilirubin <1.5 mg/dl and serum creatinine < 2.0 mg/dl; platelet count
>75,000/mm^3 and absolute neutrophil count (ANC) > 1,000/mm^3. AST (SGOT) and ALT
(SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic
metastases are present.

7. Disease free of prior malignancies of equal to or greater than 5 years 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, with a life expectancy > 3 years.

8. Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy
test 10-14 days prior to therapy and repeated within 24 hours of starting study drug
and must either commit to continued abstinence from heterosexual intercourse or begin
2 acceptable methods of birth control, one highly effective method and one additional
effective method AT THE SAME TIME, at least 4 weeks before she starts taking
lenalidomide.

9. Continuation from # 8 : (HIGHLY EFFECTIVE METHODS - Intrauterine device (IUD),
hormonal (birth control pills, injections, implants), tubal ligation, partner's
vasectomy. ADDITIONAL EFFECTIVE METHOD-latex condom, diaphragm, cervical cap) while on
study drug.

10. WCBP must agree to have pregnancy tests every week for the first 4 weeks of treatment,
then every 4 weeks if her menstrual cycles are regular or every 2 weeks if her cycles
are irregular, while on study drug, and 4 weeks after the last dose of study drug. Men
must agree not to father a child and agree to use a condom if his partner is of child
bearing potential.

11. Patients may have 1 to 4 lines of prior therapy for MCL (projected median 2 prior
lines of therapy). Patient may or may not have received an anthracycline-based
chemotherapy regimen.

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

13. Past stem cell (autologous or allogenic) transplantation is acceptable.

14. Patients may have prior therapy with rituximab.

Exclusion Criteria:

1. Any serious medical condition including but not limited to, uncontrolled hypertension,
diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive
pulmonary disease (COPD), renal failure, active infection, active hemorrhage,
laboratory abnormality, or psychiatric illness that places the patient at unacceptable
risk and would prevent the subject from signing the informed consent form. Patients
with history of cardiac arrythmias should have cardiac evaluation and clearance.

2. Pregnant or lactating females.

3. Use of any standard/experimental anti-lymphoma drug therapy, including steroids,
within 3 weeks of initiation of the study or use of any experimental non-drug therapy
(e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the
study drug treatment.

4. Known hypersensitivity to thalidomide or rituximab; including the development of
erythema nodosum if characterized by a desquamating rash while taking thalidomide.

5. Prior use of lenalidomide.

6. Known HIV infection. Patients with active hepatitis B infection (not including
patients with prior hepatitis B vaccination; not including patients with 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.

7. All patients with history of central nervous system lymphoma.

8. Patients with peripheral blood involvement with white blood cell count (WBC) > 20,000
are EXCLUDED for the Phase I component of the study.

9. Patients with >/= Grade 3 neuropathy.

10. Patients with active pulmonary embolism or deep vein thrombosis (30 days within
diagnosis).

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