Rituximab, Bendamustine Hydrochloride, and Lenalidomide in Treating Patients With Refractory or Relapsed Indolent Non-Hodgkin Lymphoma

This is a pilot/feasibility study of bendamustine, rituximab, and lenalidomide combination
with a goal of assessing maximum tolerated dose, safety and feasibility of this combination.
Patients receive rituximab IV over 5-8 hours on day 1, bendamustine hydrochloride IV over
30-60 minutes on days 1-2, and lenalidomide orally (PO) on days 1-10. Treatment repeats every
28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Ancillary treatment is available per the protocol (eg, supportive care for rituximab
infusions).

OBJECTIVES:

Primary

- To establish the maximum-tolerated dose of lenalidomide in combination with bendamustine
and rituximab chemotherapy

Secondary

- To evaluate the toxicity profile of lenalidomide in combination with bendamustine and
rituximab chemotherapy

- To assess progression-free survival

- To assess the overall and complete response rates of lenalidomide in combination with
bendamustine and rituximab in patients with relapsed/refractory indolent non-Hodgkin
lymphoma (NHL)

Patients may undergo blood sample collection at baseline and periodically during treatment
for correlative studies. Tumor tissue samples may also be collected.Patients are followed up
for up to 5 years post-registration.

Inclusion Criteria:

1. Age ≥ 18 years

2. Histologically confirmed relapsed (recurrent after previous therapy (-ies)) or
refractory (no response to previous therapy (-ies)), CD20 + indolent/low-grade B-cell
non-Hodgkin lymphoma (NHL) expressing CD20 antigen. Criteria for diagnosis can be
found in reference J Clin Oncol 17(4): 1244-53, 1999. The biopsy confirming relapse
can be up to 12 weeks prior to registration as long as there is no intervening
therapy. If patients have been on active treatment within the the last 12 weeks, the
tumor biopsy must be repeated before study enrollment to evaluate for transformation.

- Small lymphocytic lymphoma (SLL) excluding chronic lymphocytic leukemia (CLL)
(patients with peripheral blood lymphocyte count > 5,000)

- Follicular lymphoma, grades 1, 2 (grade 3 excluded)

- Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue
(MALT) type

- Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia

3. Measurable disease (at least 1 lesion of ≥ 1.5 cm in diameter) as detected by computed
tomography (CT) or the CT images of the positron emission tomography (PET)/CT.
Patients with Waldenstrom macroglobulinemia are not required to have measurable
disease by CT or PET/CT if monoclonal protein is detectable by serum protein
electrophoresis and/or IgM level is at least 2 times upper limit of normal

4. ECOG Performance Status (PS) 0, 1 or 2

5. Required laboratory values obtained ≤ 21 days prior to registration:

- ANC ≥ 1,500/mL

- Platelet count ≥ 100,000/mL

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) OR, if total
bilirubin is > 1.5 x ULN, the direct bilirubin must be normal

- SGOT (AST) ≤ 5 x ULN

- Creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula as outlined in the
protocol

6. All study participants must be registered into the mandatory RevAssist® program, and
be willing and able to comply with the requirements of RevAssist®. The Risks of Fetal
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods are
provided in the protocol for more information.

- Females of childbearing potential (FCBP) as defined per the protocol must have:

1. A negative serum or urine pregnancy test with a sensitivity of at least 25
mIU/mL ≤10 - 14 days prior to registration and again ≤ 24 hours prior to
starting cycle 1 of lenalidomide

2. ≥28 days prior to registration, throughout the duration of the study, and
for up to 28 days from the last dose of lenalidomide, FCBP must agree to
either continued abstinence from heterosexual intercourse or must begin TWO
acceptable methods of birth control, one highly effective method and one
additional effective method AT THE SAME TIME

3. Must agree to ongoing pregnancy testing throughout the duration of the study
and for up to 28 days from the last dose of lenalidomide.

- Men must agree to abstinence or to use a latex condom during sexual contact with
a FCBP even if they have had a successful vasectomy.

7. Willing to provide informed written consent.

8. Willing to return to enrolling institution for follow-up.

9. If currently not on anticoagulation medication, willing and able to take low-dose
aspirin (81 mg) daily. NOTE: The dose of aspirin should be a minimum of 81 mg and can
be higher if the patient is on the agent for other reasons. If aspirin is
contraindicated, the patient may be considered for the study after consultation with
the study chair regarding other alternatives including the possible use of warfarin or
low molecular weight heparin. Patients unable to take any prophylaxis are not
eligible.

10. Life expectancy ≥6 months

11. Ability to swallow oral medications

Exclusion Criteria:

1. This study involves an investigational agent whose genotoxic, mutagenic and
teratogenic effects on the developing fetus and newborn are unknown:

- Pregnant women

- Nursing women (lactating females are eligible provided that they agree not to
breast feed while taking lenalidomide)

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

2. Active CNS lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells
that requires therapy

3. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens.

4. Prior AIDS-defining conditions. Note: HIV positive patients without history of AIDS-
defining conditions are eligible

- If HIV positive, CD4 cells < 400/mm^3

- Current treatment with zidovudine (AZT) (which may cause overlapping adverse
events, primarily myelosuppression). Patients receiving anti-retroviral therapy
other than AZT are eligible

5. Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

6. Receiving any other agent which would be considered as a treatment for the lymphoma.

Note: Prior use of rituximab is allowed.

7. Another active malignancy requiring concomitant active therapy such as radiation,
chemotherapy, or immunotherapy. Exceptions to this are as follows:

- Localized non-melanotic skin cancer

- Cancers that are inactive that are being treated with hormonal therapy

- Any cancer that in the judgment of the investigator will not interfere with the
study treatment plan and response assessment and require concomitant anticancer
therapy for the duration of this study

Contact the study chair regarding any questions related to eligibility of patients
with concomitant active malignancy

8. History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use
of ongoing maintenance therapy for life-threatening ventricular arrhythmias

9. History of life threatening (i.e. pulmonary embolism), DVT or recurrent
thrombosis/embolism and are not on or unwilling to receive anticoagulation

- Patients with history of DVT or life threatening or recurrent thrombosis/embolism
(PE) may enter the study but must receive anticoagulation with low molecular
weight (LMW) heparin or therapeutic warfarin during the protocol treatment and
for ≥6 months afterwards. Patients with strong family history of thrombosis
should be considered for thrombophilia work up and/or anticoagulated at the
discretion of treating MD.

- Patients with a prior history (>6 months prior to study entry) of a non-life
threatening, provoked thrombosis (e.g. history of catheter related thrombus or
similar) and without known thrombophilia can participate in the study and receive
standard prophylaxis with ASA (aspirin) or LMW heparin/warfarin at the discretion
of treating MD. Active smokers should be advised on thrombosis risk and smoking
cessation and may participate in the study if prophylaxis with ASA (aspirin) or
LMW heparin/warfarin (at the discretion of treating MD) is given. Patients on
estrogen birth control pills should be advised of the risks.

10. Known myelodysplastic syndrome

11. Receiving erythroid stimulating agents (EPO: Procrit, Aranesp). Note: Use of erythroid
stimulating agents is not allowed during the study treatment.

12. Prior treatment with bendamustine.