Lenalidomide and Rituximab in Treating Patients With Previously Untreated Stage II, Stage III, or Stage IV Follicular Non-Hodgkin Lymphoma

Phase 2

Completed

Conditions: Ann Arbor Stage II Grade 3 Contiguous Follicular Lymphoma
Ann Arbor Stage III Grade 1 Follicular Lymphoma
Ann Arbor Stage IV Grade 2 Follicular Lymphoma
Ann Arbor Stage IV Grade 3 Follicular Lymphoma
Ann Arbor Stage IV Grade 1 Follicular Lymphoma
Ann Arbor Stage II Grade 2 Contiguous Follicular Lymphoma
Ann Arbor Stage II Grade 2 Non-Contiguous Follicular Lymphoma
Ann Arbor Stage II Grade 3 Non-Contiguous Follicular Lymphoma
Ann Arbor Stage III Grade 3 Follicular Lymphoma
Ann Arbor Stage II Grade 1 Contiguous Follicular Lymphoma

Interventions: Other: Laboratory Biomarker Analysis
Drug: Lenalidomide
Biological: Rituximab

Registration Number: NCT01145495

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies how well lenalidomide and rituximab work in treating patients with previously untreated stage II, stage III, or stage IV follicular non-Hodgkin lymphoma. Biological therapies, such as lenalidomide, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving lenalidomide together with rituximab may kill more cancer cells.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the response rate (overall and complete) to lenalidomide + rituximab in follicular non-Hodgkin lymphoma (NHL) patients who have received no prior systemic therapy.

II. To determine the time to progression after lenalidomide + rituximab in previously untreated patients with cluster of differentiation (CD)20+ follicular NHL.

SECONDARY OBJECTIVES:

I. To determine the toxicity profile of lenalidomide + rituximab therapy in previously untreated patients with CD20+ follicular NHL.

II. To establish whether the therapeutic effects of lenalidomide + rituximab combination are sufficiently promising to warrant evaluation in a subsequent randomized trial (in comparison to rituximab alone).

III. To correlate fragment crystallizable gamma (Fcg) receptor polymorphism profiling with response to lenalidomide + rituximab in previously untreated patients with follicular NHL.

IV. To determine the impact of lenalidomide on immune parameters in patients with previously untreated follicular lymphoma.

V. To determine the impact of lenalidomide on angiogenic parameters in patients with previously untreated follicular lymphoma.

VI. To correlate lymphoma-associated macrophages (LAM) and forkhead box P3 (FOXP3), granzyme B (GzB), CD10, multiple myeloma oncogene 1 (MUM1), and B-cell lymphoma 2 (BCL2) expression with response to rituximab + lenalidomide in previously untreated patients with follicular lymphoma.

VII. Determine whether immune gene signatures previously identified as prognostic factors in follicular lymphoma (FL) can be applied to paraffin-embedded tissues in rituximab treated patients; evaluate micro ribonucleic acid (RNA) signatures associated with these gene signatures and outcome; to validate immunohistochemical markers associated with outcome in FL (CD68 LAMs, FOXP3, CD10, BCL6, FOXP1, MUM1); and investigate whether markers of angiogenesis may be of value in prognosis of FL.

OUTLINE:

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment with lenalidomide repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab intravenously (IV) on days 1, 8, 15, and 22 and on weeks 13, 21, 29, and 37 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 2 years and then every 6 months for up to 8 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 66

Inclusion Criteria

Previously untreated, histologically confirmed follicular lymphoma, World Health Organization (WHO) classification grade 1, 2, or 3a (> 15 centroblasts per high power field with centrocytes present) that is stage III, IV, or bulky (i.e., single mass >= 7 cm in any uni-dimensional measurement) stage II
- Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies; fine needle aspirates are not acceptable for diagnosis
- Failure to submit pathology specimens within 60 days of patient registration will be considered a major protocol violation
Institutional flow cytometry or immunohistochemistry must confirm CD20 antigen expression
Low or intermediate risk by Follicular Lymphoma International Prognostic Index (FLIPI): 0-2 risk factors
No prior systemic therapy for NHL, including chemotherapy or immunotherapy (e.g., monoclonal antibody-based therapy); patients may have received involved-field radiation therapy
No corticosteroids within two weeks prior to study entry, except for maintenance therapy for a non-malignant disease
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass > 1 cm is acceptable
- Lesions that are considered non-measurable include the following:
  - Bone lesions (lesions if present should be noted)
  - Ascites
  - Pleural/pericardial effusion
  - Lymphangitis cutis/pulmonis
  - Bone marrow (involvement by NHL should be noted)
No known central nervous system (CNS) involvement by lymphoma
Patients with human immunodeficiency virus (HIV) infection are eligible, provided they meet the following
- No evidence of coinfection with hepatitis B or C
- CD4+ cell count >= 400/mm^3
- No evidence of resistant strains of HIV
- If not on anti-HIV therapy, HIV viral load < 10,000 copies HIV RNA/mL
- If on anti-HIV therapy, HIV viral load < 50 copies HIV RNA/mL
- No history of acquired immune deficiency syndrome (AIDS)-defining conditions
No evidence of active hepatitis B or C infection (i.e., no positive serology for anti-hepatitis B core [HBc] or anti-hepatitis C virus [HCV] antibodies); hepatitis B virus (HBV) seropositive patients (hepatitis B surface antigen positive [HBsAg +]) are eligible if they are closely monitored for evidence of active HBV infection by HBV deoxyribonucleic acid (DNA) testing and receive suppressive therapy with lamivudine or other HBV suppressive therapy until 6 months after the last rituximab dose
Patients with a history of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome are not eligible
Patients with uncontrolled seizures are not eligible
Patients with an autoimmune disorder requires active immunosuppression are not eligible
Non-pregnant and non-nursing; females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to registration; further, they 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 starting 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; a FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
No known human anti-chimeric antibody (HACA) positivity
Absolute neutrophil count (ANC) >= 1,000/microliter
Platelet count >= 75,000/microliter
Creatinine clearance >= 30 mL/min unless attributable to NHL; to be calculated by method of Cockcroft-Gault, using actual weight; maximum creatinine clearance (CrCl) 125 mL/min
Total bilirubin =< 2 times upper limit of normal (ULN) unless attributable to NHL or Gilbert disease

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (lenalidomide, rituximab)	Lenalidomide	Patients receive lenalidomide PO QD on days 1-21. Treatment with lenalidomide repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, 15, and 22 and in weeks 13, 21, 29, and 37 in the absence of disease progression or unacceptable toxicity.
Treatment (lenalidomide, rituximab)	Laboratory Biomarker Analysis	Patients receive lenalidomide PO QD on days 1-21. Treatment with lenalidomide repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, 15, and 22 and in weeks 13, 21, 29, and 37 in the absence of disease progression or unacceptable toxicity.
Treatment (lenalidomide, rituximab)	Rituximab	Patients receive lenalidomide PO QD on days 1-21. Treatment with lenalidomide repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, 15, and 22 and in weeks 13, 21, 29, and 37 in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Achieved a Complete Response	At 12 months	Response is assessed by investigator according to International Working Group (IWG) criteria. Complete response requires disappearance of all evidence of disease.

Secondary Outcome Measures

Name	Time	Method
Best Response	Up to 5 years	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Disease Progression	Up to 5 years	Kaplan-Meier method will be used. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Toxicity of Study Treatment, Assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0	Up to 5 years	Data will be summarized using frequency tables.

Trial Locations

Locations (91): Memorial Hospital
🇺🇸
Carthage, Illinois, United States
Illinois CancerCare-Havana
🇺🇸
Havana, Illinois, United States
Heartland Cancer Research NCORP
🇺🇸
Decatur, Illinois, United States
University of Missouri - Ellis Fischel
🇺🇸
Columbia, Missouri, United States
Eureka Hospital
🇺🇸
Eureka, Illinois, United States
Illinois CancerCare-Galesburg
🇺🇸
Galesburg, Illinois, United States
Perry Memorial Hospital
🇺🇸
Princeton, Illinois, United States
Mission Hospital
🇺🇸
Asheville, North Carolina, United States
Mcdonough District Hospital
🇺🇸
Macomb, Illinois, United States
Illinois CancerCare-Princeton
🇺🇸
Princeton, Illinois, United States
Fort Wayne Medical Oncology and Hematology Inc-Parkview
🇺🇸
Fort Wayne, Indiana, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Ohio State University Comprehensive Cancer Center
🇺🇸
Columbus, Ohio, United States
Carle Cancer Institute Normal
🇺🇸
Normal, Illinois, United States
Beebe Medical Center
🇺🇸
Lewes, Delaware, United States
Solinsky Center for Cancer Care
🇺🇸
Manchester, New Hampshire, United States
McLeod Regional Medical Center
🇺🇸
Florence, South Carolina, United States
Harold Alfond Center for Cancer Care
🇺🇸
Augusta, Maine, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
Christiana Care Health System-Christiana Hospital
🇺🇸
Newark, Delaware, United States
Central Vermont Medical Center/National Life Cancer Treatment
🇺🇸
Berlin, Vermont, United States
Christiana Care - Union Hospital
🇺🇸
Elkton, Maryland, United States
Saint Luke's Hospital
🇺🇸
Chesterfield, Missouri, United States
Exeter Hospital
🇺🇸
Exeter, New Hampshire, United States
Illinois CancerCare-Spring Valley
🇺🇸
Spring Valley, Illinois, United States
CHI Health Saint Francis
🇺🇸
Grand Island, Nebraska, United States
Minneapolis VA Medical Center
🇺🇸
Minneapolis, Minnesota, United States
Center for Cancer Care and Research
🇺🇸
Saint Louis, Missouri, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Great Plains Health Callahan Cancer Center
🇺🇸
North Platte, Nebraska, United States
Cone Health Cancer Center
🇺🇸
Greensboro, North Carolina, United States
Northwell Health/Center for Advanced Medicine
🇺🇸
Lake Success, New York, United States
Randolph Hospital
🇺🇸
Asheboro, North Carolina, United States
Long Island Jewish Medical Center
🇺🇸
New Hyde Park, New York, United States
New Hampshire Oncology Hematology PA-Concord
🇺🇸
Concord, New Hampshire, United States
LRGHealthcare-Lakes Region General Hospital
🇺🇸
Laconia, New Hampshire, United States
Northwell Health NCORP
🇺🇸
Lake Success, New York, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
Glens Falls Hospital
🇺🇸
Glens Falls, New York, United States
Danville Regional Medical Center
🇺🇸
Danville, Virginia, United States
Vidant Oncology-Kinston
🇺🇸
Kinston, North Carolina, United States
Wayne Memorial Hospital
🇺🇸
Goldsboro, North Carolina, United States
Annie Penn Memorial Hospital
🇺🇸
Reidsville, North Carolina, United States
Capital Region Southwest Campus
🇺🇸
Jefferson City, Missouri, United States
Missouri Baptist Medical Center
🇺🇸
Saint Louis, Missouri, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
Nebraska Methodist Hospital
🇺🇸
Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Graham Hospital Association
🇺🇸
Canton, Illinois, United States
Iredell Memorial Hospital
🇺🇸
Statesville, North Carolina, United States
North Shore University Hospital
🇺🇸
Manhasset, New York, United States
Palo Alto Medical Foundation-Camino Division
🇺🇸
Mountain View, California, United States
Palo Alto Medical Foundation Health Care
🇺🇸
Palo Alto, California, United States
Saint Joseph Medical Center
🇺🇸
Bloomington, Illinois, United States
Illinois CancerCare-Bloomington
🇺🇸
Bloomington, Illinois, United States
Illinois CancerCare-Canton
🇺🇸
Canton, Illinois, United States
Illinois CancerCare-Carthage
🇺🇸
Carthage, Illinois, United States
Illinois CancerCare-Eureka
🇺🇸
Eureka, Illinois, United States
Illinois CancerCare-Kewanee Clinic
🇺🇸
Kewanee, Illinois, United States
Illinois CancerCare-Macomb
🇺🇸
Macomb, Illinois, United States
Mason District Hospital
🇺🇸
Havana, Illinois, United States
AMITA Health Adventist Medical Center
🇺🇸
La Grange, Illinois, United States
Illinois CancerCare-Community Cancer Center
🇺🇸
Normal, Illinois, United States
Holy Family Medical Center
🇺🇸
Monmouth, Illinois, United States
Bromenn Regional Medical Center
🇺🇸
Normal, Illinois, United States
Illinois CancerCare-Monmouth
🇺🇸
Monmouth, Illinois, United States
Illinois CancerCare-Ottawa Clinic
🇺🇸
Ottawa, Illinois, United States
Ottawa Regional Hospital and Healthcare Center
🇺🇸
Ottawa, Illinois, United States
Illinois CancerCare-Pekin
🇺🇸
Pekin, Illinois, United States
OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center
🇺🇸
Pekin, Illinois, United States
Illinois CancerCare-Peoria
🇺🇸
Peoria, Illinois, United States
Proctor Hospital
🇺🇸
Peoria, Illinois, United States
Methodist Medical Center of Illinois
🇺🇸
Peoria, Illinois, United States
Illinois CancerCare-Peru
🇺🇸
Peru, Illinois, United States
Illinois Valley Hospital
🇺🇸
Peru, Illinois, United States
MedStar Franklin Square Medical Center/Weinberg Cancer Institute
🇺🇸
Baltimore, Maryland, United States
Comprehensive Cancer Care PC
🇺🇸
Saint Louis, Missouri, United States
Hematology Oncology Associates of Central New York-East Syracuse
🇺🇸
East Syracuse, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
NYP/Weill Cornell Medical Center
🇺🇸
New York, New York, United States
University of Vermont and State Agricultural College
🇺🇸
Burlington, Vermont, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
OSF Saint Francis Medical Center
🇺🇸
Peoria, Illinois, United States
Cooper Hospital University Medical Center
🇺🇸
Camden, New Jersey, United States
University of Iowa Healthcare Cancer Services Quad Cities
🇺🇸
Bettendorf, Iowa, United States
Southeast Cancer Center
🇺🇸
Cape Girardeau, Missouri, United States