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A Pilot/Feasibility Phase I Study of Bendamustine, Rituximab and Lenalidomide in Patients With Refractory/Relapsed Indolent NHL

Phase 1
18 Years
Not Enrolling

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Trial Information

A Pilot/Feasibility Phase I Study of Bendamustine, Rituximab and Lenalidomide in Patients With Refractory/Relapsed Indolent NHL



- To establish the maximum-tolerated dose of lenalidomide in combination with
bendamustine hydrochloride (B) and rituximab (R) chemotherapy.


- To evaluate the toxicity profile of lenalidomide in combination with BR chemotherapy.

- To assess progression-free survival.

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


- To explore changes of immune microenvironment - cytokine profile with therapy and
relation to the outcome.

- To explore biological factors associated with therapy and therapy outcome (the tumor
tissue and blood specimens will be banked for future exploratory studies).

- To assess impact of statin use on response to therapy and patient outcome.

- To store serum for vitamin D assessment and correlate the levels with outcome.

- To record any transformation to aggressive NHL events and perform exploratory studies
of association of tumor-immune microenvironment, histology, and expression of DNA
damaging and repair enzymes with transformation.

OUTLINE: This is a multicenter, dose-escalation study of lenalidomide.

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

Patients may undergo blood sample collection at baseline and periodically during treatment
for correlative studies. Tumor tissue samples may also be collected.

After completion of study treatment, patients are followed up for up to 5 years.

Inclusion Criteria


- Histologically confirmed relapsed (recurrent after previous therapies) or refractory
(no response to previous therapy), indolent/low-grade B-cell non-Hodgkin lymphoma
(NHL) expressing CD20 antigen

- Small lymphocytic lymphoma (SLL) excluding chronic lymphocytic leukemia (CLL)
(patients with peripheral blood lymphocyte count > 5,000/mm³)

- 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

- 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
last 12 weeks, the tumor biopsy must be repeated before study enrollment to evaluate
for transformation

- 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 (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

- No active CNS lymphoma or cerebrospinal fluid involvement with malignant lymphoma
cells that requires therapy

- No known myelodysplastic syndrome


- ECOG performance status 0, 1, or 2

- Life expectancy ≥ 6 months

- ANC ≥ 1,500/mL

- Platelet count ≥ 100,000/mL

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

- SGOT (AST) ≤ 5 times ULN

- Creatinine clearance ≥ 50 mL/min

- All study participants must be registered into the mandatory RevAssist® program, and
be willing and able to comply with the requirements of RevAssist®

- Females of childbearing potential (FCBP) must have:

- 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 course 1 of lenalidomide

- ≥ 28 days prior to registration, throughout the duration of the study, and
for up to 28 days from the last dose of lenalidomide, FBCP 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

- 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

- Willing to return to North Central Cancer Treatment Group (NCCTG) enrolling
institution for follow-up

- Ability to swallow oral medications

- If currently not on anticoagulation medication, willing and able to take low-dose
aspirin (81 mg) daily

- Any of the following not allowed:

- 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

- No co-morbid systemic illnesses or other severe concurrent disease that, 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

- No prior AIDS-defining conditions

- HIV-positive patients without history of AIDS-defining conditions are eligible
if CD4 cells < 400/mm³

- No 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

- No other 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 or require concomitant
anticancer therapy for the duration of this study

- No history of myocardial infarction ≤ 6 months or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

- Patients with a history of life-threatening (i.e., pulmonary embolism), deep vein
thrombosis (DVT), or recurrent thrombosis/embolism who are not on or unwilling to
receive anticoagulation are excluded

- 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 a 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 aspirin or LMW heparin/warfarin at
the discretion of treating MD


- If currently not on anticoagulation medication, willing and able to take low-dose
aspirin (≥ 81 mg) daily

- 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

- HIV-positive patients with no prior AIDS-defining conditions must not be on current
treatment with zidovudine (AZT)

- Patients receiving antiretroviral therapy other than AZT are eligible

- Not receiving any other agent which would be considered as a treatment for the

- Prior use of rituximab is allowed

- Not receiving erythroid-stimulating agents (EPO: Procrit, Aranesp); use of
erythroid-stimulating agents is not allowed during the study treatment

- No prior treatment with bendamustine hydrochloride

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose of lenalidomide in combination with bendamustine hydrochloride and rituximab

Outcome Time Frame:

Up to 28 days

Safety Issue:


Principal Investigator

Grzegorz S. Nowakowski, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

May 2012

Completion Date:

Related Keywords:

  • Lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • Waldenström macroglobulinemia
  • nodal marginal zone B-cell lymphoma
  • splenic marginal zone lymphoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin



Mayo Clinic Rochester, Minnesota  55905
St. Luke's Regional Medical Center Sioux City, Iowa  51104
Siouxland Hematology-Oncology Sioux City, Iowa  51101-1733
Iowa Methodist Medical Center Des Moines, Iowa  50309
Iowa Lutheran Hospital Des Moines, Iowa  50316-2301
Medical Oncology and Hematology Associates Des Moines, Iowa  50309
Mid Dakota Clinic Bismarck, North Dakota  58501
Medical Oncology and Hematology Associates-West Des Moines Clive, Iowa  50325
Iowa Oncology Research Association CCOP Des Moines, Iowa  50309
Mercy Medical Center - Des Moines Des Moines, Iowa  50314
Medical Oncology and Hematology Associates-Des Moines Des Moines, Iowa  50309
Mercy Medical Center-Sioux City Sioux City, Iowa  51104
Saint Alexius Medical Center Bismarck, North Dakota  58501
Methodist West Hospital West Des Moines, Iowa  50266-7700
Sanford Bismarck Medical Center Bismarck, North Dakota  58501
Mercy Cancer Center-West Lakes Clive, Iowa  50325
Mercy Medical Center-West Lakes West Des Moines, Iowa  50266