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

A Phase II Trial of Lenalidomide (Revlimid (TM), CC-5013) (NSC #703813) Plus Rituximab in Previously Untreated Follicular Non-Hodgkin Lymphoma (NHL)

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.

Study Overview

• Status: Completed
• Conditions: Ann Arbor Stage III Grade 1 Follicular Lymphoma; Ann Arbor Stage III Grade 2 Follicular Lymphoma; Ann Arbor Stage IV Grade 1 Follicular Lymphoma; Ann Arbor Stage IV Grade 2 Follicular Lymphoma; Ann Arbor Stage II Grade 3 Contiguous Follicular Lymphoma; Ann Arbor Stage II Grade 3 Non-Contiguous Follicular Lymphoma; Ann Arbor Stage III Grade 3 Follicular Lymphoma; Ann Arbor Stage IV Grade 3 Follicular Lymphoma; Ann Arbor Stage II Grade 1 Contiguous Follicular Lymphoma; Ann Arbor Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Ann Arbor Stage II Grade 2 Contiguous Follicular Lymphoma; Ann Arbor Stage II Grade 2 Non-Contiguous Follicular Lymphoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Rituximab; Drug: Lenalidomide

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Mountain View, California, United States, 94040
      • Palo Alto Medical Foundation-Camino Division
    • Palo Alto, California, United States, 94301
      • Palo Alto Medical Foundation Health Care
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Beebe Medical Center
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
  • Illinois
    • Bloomington, Illinois, United States, 61704
      • Illinois CancerCare-Bloomington
    • Bloomington, Illinois, United States, 61701
      • Saint Joseph Medical Center
    • Canton, Illinois, United States, 61520
      • Illinois CancerCare-Canton
    • Canton, Illinois, United States, 61520
      • Graham Hospital Association
    • Carthage, Illinois, United States, 62321
      • Illinois CancerCare-Carthage
    • Carthage, Illinois, United States, 62321
      • Memorial Hospital
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Decatur, Illinois, United States, 62526
      • Heartland Cancer Research NCORP
    • Eureka, Illinois, United States, 61530
      • Illinois CancerCare-Eureka
    • Eureka, Illinois, United States, 61530
      • Eureka Hospital
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare-Galesburg
    • Havana, Illinois, United States, 62644
      • Mason District Hospital
    • Havana, Illinois, United States, 62644
      • Illinois CancerCare-Havana
    • Kewanee, Illinois, United States, 61443
      • Illinois CancerCare-Kewanee Clinic
    • La Grange, Illinois, United States, 60525
      • AMITA Health Adventist Medical Center
    • Macomb, Illinois, United States, 61455
      • Illinois CancerCare-Macomb
    • Macomb, Illinois, United States, 61455
      • Mcdonough District Hospital
    • Monmouth, Illinois, United States, 61462
      • Illinois CancerCare-Monmouth
    • Monmouth, Illinois, United States, 61462
      • Holy Family Medical Center
    • Normal, Illinois, United States, 61761
      • Carle Cancer Institute Normal
    • Normal, Illinois, United States, 61761
      • Bromenn Regional Medical Center
    • Normal, Illinois, United States, 61761
      • Illinois CancerCare-Community Cancer Center
    • Ottawa, Illinois, United States, 61350
      • Illinois CancerCare-Ottawa Clinic
    • Ottawa, Illinois, United States, 61350
      • Ottawa Regional Hospital and Healthcare Center
    • Pekin, Illinois, United States, 61554
      • Illinois CancerCare-Pekin
    • Pekin, Illinois, United States, 61554
      • OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center
    • Peoria, Illinois, United States, 61636
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Peoria, Illinois, United States, 61614
      • Proctor Hospital
    • Peru, Illinois, United States, 61354
      • Illinois CancerCare-Peru
    • Peru, Illinois, United States, 61354
      • Illinois Valley Hospital
    • Princeton, Illinois, United States, 61356
      • Illinois CancerCare-Princeton
    • Princeton, Illinois, United States, 61356
      • Perry Memorial Hospital
    • Spring Valley, Illinois, United States, 61362
      • Illinois CancerCare-Spring Valley
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology Inc-Parkview
  • Iowa
    • Bettendorf, Iowa, United States, 52722
      • University of Iowa Healthcare Cancer Services Quad Cities
  • Maine
    • Augusta, Maine, United States, 04330
      • Harold Alfond Center for Cancer Care
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • MedStar Franklin Square Medical Center/Weinberg Cancer Institute
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
    • Elkton, Maryland, United States, 21921
      • Christiana Care - Union Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Minneapolis VA Medical Center
  • Missouri
    • Cape Girardeau, Missouri, United States, 63703
      • Southeast Cancer Center
    • Chesterfield, Missouri, United States, 63017
      • Saint Luke's Hospital
    • Columbia, Missouri, United States, 65212
      • University of Missouri - Ellis Fischel
    • Jefferson City, Missouri, United States, 65109
      • Capital Region Southwest Campus
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
    • Saint Louis, Missouri, United States, 63141
      • Center for Cancer Care and Research
    • Saint Louis, Missouri, United States, 63141
      • Comprehensive Cancer Care PC
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • CHI Health Saint Francis
    • North Platte, Nebraska, United States, 69101
      • Great Plains Health Callahan Cancer Center
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • New Hampshire Oncology Hematology PA-Concord
    • Exeter, New Hampshire, United States, 03833
      • Exeter Hospital
    • Laconia, New Hampshire, United States, 03246
      • LRGHealthcare-Lakes Region General Hospital
    • Manchester, New Hampshire, United States, 03103
      • Solinsky Center for Cancer Care
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Hospital University Medical Center
  • New York
    • East Syracuse, New York, United States, 13057
      • Hematology Oncology Associates of Central New York-East Syracuse
    • Glens Falls, New York, United States, 12801
      • Glens Falls Hospital
    • Lake Success, New York, United States, 11042
      • Northwell Health NCORP
    • Lake Success, New York, United States, 11042
      • Northwell Health/Center for Advanced Medicine
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10065
      • NYP/Weill Cornell Medical Center
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Randolph Hospital
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Greensboro, North Carolina, United States, 27403
      • Cone Health Cancer Center
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
    • Kinston, North Carolina, United States, 28501
      • Vidant Oncology-Kinston
    • Reidsville, North Carolina, United States, 27320
      • Annie Penn Memorial Hospital
    • Statesville, North Carolina, United States, 28677
      • Iredell Memorial Hospital
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • South Carolina
    • Florence, South Carolina, United States, 29506
      • McLeod Regional Medical Center
  • Vermont
    • Berlin, Vermont, United States, 05602
      • Central Vermont Medical Center/National Life Cancer Treatment
    • Burlington, Vermont, United States, 05405
      • University of Vermont and State Agricultural College
  • Virginia
    • Danville, Virginia, United States, 24541
      • Danville Regional Medical Center
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (lenalidomide, 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Rituximab; Given IV; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Riabni; Rituximab ABBS; Rituximab ARRX; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar JHL1101; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; Rituximab Biosimilar SIBP-02; rituximab biosimilar TQB2303; Rituximab PVVR; rituximab-abbs; Rituximab-arrx; Rituximab-pvvr; RTXM83; Ruxience; Truxima; Drug: Lenalidomide; Given PO; Other Names: CC-5013; Revlimid; CC5013; CDC 501

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of Study Treatment, Assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0	Data will be summarized using frequency tables.	Up to 5 years
Disease Progression	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.	Up to 5 years
Best Response	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.	Up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Peter Martin, Alliance for Clinical Trials in Oncology

Publications and helpful links

General Publications

• Lansigan F, Barak I, Pitcher B, Jung SH, Cheson BD, Czuczman M, Martin P, Hsi E, Schoder H, Smith S, Bartlett NL, Leonard JP, Blum KA. The prognostic significance of PFS24 in follicular lymphoma following firstline immunotherapy: A combined analysis of 3 CALGB trials. Cancer Med. 2019 Jan;8(1):165-173. doi: 10.1002/cam4.1918. Epub 2018 Dec 21.
• Martin P, Jung SH, Pitcher B, Bartlett NL, Blum KA, Shea T, Hsi ED, Ruan J, Smith SE, Leonard JP, Cheson BD. A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol. 2017 Nov 1;28(11):2806-2812. doi: 10.1093/annonc/mdx496.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2010
• Primary Completion (Actual): December 31, 2012
• Study Completion (Actual): January 15, 2022

Study Registration Dates

• First Submitted: June 15, 2010
• First Submitted That Met QC Criteria: June 15, 2010
• First Posted (Estimated): June 16, 2010

Study Record Updates

• Last Update Posted (Actual): June 27, 2023
• Last Update Submitted That Met QC Criteria: June 7, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibodies; Lenalidomide; Immunoglobulins; Rituximab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological
• Other Study ID Numbers: NCI-2011-02047 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); U10CA031946 (U.S. NIH Grant/Contract); CDR0000675161; CALGB 50803 (Other Identifier: Alliance for Clinical Trials in Oncology); CALGB-50803 (Other Identifier: CTEP)