Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma

The combination of lenalidomide with bortezomib has not been studied in patients with MCL,
but feasibility and tolerability has been demonstrated in patients with multiple myeloma.
Thus, almost every 2-drug combination of rituximab, lenalidomide, and bortezomib has been
tested, or is being tested. We hypothesize that all three drugs are important in MCL, and
therefore propose to combine all 3 agents (rituximab, bortezomib, and lenalidomide) in a
schedule that is convenient to lymphoma patients.

Approximately 18 patients may be enrolled in the Phase I portion of the study. Approximately
45 patients are planned for enrollment in Phase II.

Inclusion Criteria:

1. All study participants must be registered into the Mandatory Revllimid Risk
Evaluation and Mitigation Strategies (REMS) Program, and be willing and able to
comply with the requirements of the REMS program.

2. Histology: biopsy-proven mantle cell lymphoma (MCL).

3. Prior therapy: both newly diagnosed patients and relapsed or refractory patients who
have received one prior therapy are eligible. Patients who have previously received
high-dose chemotherapy with peripheral stem cell support are eligible. Newly
diagnosed patients are eligible for the Phase II portion of the study only.

4. Presence of at least one lymph node evaluable or mass measurable for response.

5. Platelets > 75,000/µL and absolute neutrophil count (ANC) > 1,000/µL within 14 days
of study registration (unless the treating physician deems the neutropenia is related
to bone marrow involvement, then an ANC of > 750/mm3 is allowed).

6. Renal fnction assessed by calculated creatinine clearance between ≥ 30 ml/min and
˂60ml/min by the Cockcroft-Gault method within 14 days of study registration:

7. ECOG performance of 0, 1, or 2.

8. Recovery from any previous treatment therapy.

9. Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy
testing required in the Revlimid REMS® program, must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 14 days prior and
again within 24 hours of starting lenalidomide for Cycle 1 (prescriptions must be
filled within 7 days as required by Revlimid REMS Program) and must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also
agree to ongoing pregnancy testing. Men must agree to use a latex condom during
sexual contact with a FCBP even if they have had a successful vasectomy.

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

11. Ability to understand and willingness to voluntarily sign a written informed consent
document before performance of any study-related procedure not part of normal medical
care, with the understanding that consent may be withdrawn by the subject at any time
without prejudice to future medical care.

Exclusion Criteria:

1. Patient has 1.5 x ULN total bilirubin.

2. Peripheral neuropathy ≥ CTCAE grade 2.

3. Pregnant or breastfeeding females. (Lactating females must agree not to breastfeed
while taking lenalidomide.)

4. Thrombolic or embolic events (such as a cerebrovascular accident, including transient
ischemic attacks) within the past 6 months.

5. Pulmonary hemorrhage/bleeding event less than or equal to CTCAE grade 2 within 28
days of the first dose of study drug.

6. Female patients who have a positive serum pregnancy test during the screening period,
or a positive urine pregnancy test on DAY 1 before first dose of study drug, if
applicable.

7. Thrombolic or embolic events (such as a cerebrovascular accident, including transient
ischemic attacks) within the past 6 months.

8. Pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within 28 days of the first dose
of study drug.

9. Any other hemorrhage/bleeding event ≥ CTCAE grade 3 ≤ 28 days of the first dose of
study drug

10. Known brain metastasis. Patients with neurological symptoms must undergo a CT
scan/MRI of the brain to exclude brain metastasis.

11. Central nervous system (CNS) involvement by lymphoma at time of enrollment.

12. Other medical conditions or psychiatric illness that would potentially interfere with
patient participation in this trial.

13. A second malignancy, other than basal cell carcinoma of the skin or in situ carcinoma
of the cervix, unless the tumor was treated with curative intent at least 2 years
previously.

14. Previous evidence of hypersensitivity to bortezomib, boron, mannitol, thalidomide,
(and development of erythema nodosum if characterized by a desquamating rash), or
rituximab (true anaphylaxis, not a rituximab-infusion reaction).

15. Known human immunodeficiency virus (HIV) infection or chronic hepatitis A, B, or C.
Patients who are HIV positive or who are positive for chronic hepatitis A, B, or C
will be excluded due to increased risk for bone marrow suppression and other
toxicities.

16. Active, clinically serious infection > CTCAE grade 2. Patients may be eligible upon
resolution of the infection.

17. Evidence or history of bleeding diathesis or coagulopathy.

18. Major surgery, open biopsy, or significant traumatic injury within 28 days of the
first dose of study drug.

19. Use of any other standard chemotherapy, radiation therapy, or experimental drug for
the treatment of MCL within 28 days of starting treatment.

20. Any condition that impairs a patient's ability to swallow whole pills. Impairment of
gastrointestinal function (GI) or GI disease that may significantly alter the
absorption of lenalidomide (e.g., ulcerative disease, uncontrolled nausea, vomiting,
diarrhea, malabsorption syndrome, or small bowel resection).

21. Patients with grade 3/4 cardiac problems, as defined by the New York Heart
Association (NYHA) criteria or any of the following:

- History of uncontrolled or symptomatic angina

- History of arrhythmias requiring medications, or clinically significant, with
the exception of asymptomatic atrial fibrillation requiring anticoagulation

- Myocardial infarction < 6 months from study entry

- Uncontrolled or symptomatic congestive heart failure

- Ejection fraction below the institutional normal limit

- Electrocardiographic evidence of acute ischemia or active conduction system

- Any other cardiac condition that, in the opinion of the treatment physician,
would make this protocol unreasonably hazardous for the patient

21. Uncontrolled hypertension (systolic blood pressure [BP] > 180 or diastolic BP > 100mm
Hg) or uncontrolled cardiac arrhythmias.

22. Any prior use of lenalidomide.