Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma

Phase I/II Study Evaluating Rituximab, Lenalidomide, and Bortezomib in the First-Line or Second-Line Treatment of Patients With Mantle Cell Lymphoma

This is a Phase I/II multicenter, open-label, dose-escalation study of rituximab, bortezomib, and lenalidomide in the first-line or second-line treatment of patients with Mantle Cell Lymphoma (MCL).

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 Revlimid 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.
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 function assessed by calculated creatinine clearance between ≥ 30 ml/min and ˂60ml/min by the Cockcroft-Gault method within 14 days of study registration
7. Total bilirubin ≤ 1.5x upper limit of normal (ULN), aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGOT) ≤ 3 x ULN
8. Eastern Cooperative Oncology Group (ECOG) performance of 0, 1, or 2.
9. Recovery from any previous treatment therapy.
10. 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.
11. 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.
12. 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. Relapsed or refractory patients who have received more than one prior therapy.

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

5. 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.

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

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

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

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

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

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

12. 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.

13. 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).

14. 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.

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

16. Evidence or history of bleeding diathesis or coagulopathy.

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

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

19. 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).

20. 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
    • Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.

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

22. Any prior use of lenalidomide.