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Rituximab With or Without Yttrium Y-90 Ibritumomab Tiuxetan in Treating Patients With Untreated Follicular Lymphoma

This study is currently recruiting participants.
See Contacts and Locations
Verified December 2016 by Mayo Clinic
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT02320292
First received: December 15, 2014
Last updated: December 20, 2016
Last verified: December 2016
  Purpose
This randomized phase III trial studies rituximab and yttrium Y-90 ibritumomab tiuxetan to see how well they work compared to rituximab alone in treating patients with untreated follicular lymphoma. Monoclonal antibodies, such as rituximab, may find cancer cells and help kill them. Radioactive substances linked to monoclonal antibodies can bind to cancer cells and give off radiation which may help kill cancer cells. It is not yet known whether rituximab works better with or without yttrium Y-90 ibritumomab tiuxetan in treating follicular lymphoma.

Condition Intervention Phase
Stage I Grade 1 Follicular Lymphoma Stage I Grade 2 Follicular Lymphoma Stage II Grade 1 Contiguous Follicular Lymphoma Stage II Grade 1 Non-Contiguous Follicular Lymphoma Stage II Grade 2 Contiguous Follicular Lymphoma Stage II Grade 2 Non-Contiguous Follicular Lymphoma Stage III Grade 1 Follicular Lymphoma Stage III Grade 2 Follicular Lymphoma Stage IV Grade 1 Follicular Lymphoma Stage IV Grade 2 Follicular Lymphoma Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment Biological: Rituximab Radiation: Yttrium Y-90 Ibritumomab Tiuxetan Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Asymptomatic Follicular Lymphoma (AFL) Trial: A Phase III Study of Single-agent Rituximab Immunotherapy Versus Zevalin Radioimmunotherapy for Patients With New, Untreated Follicular Lymphoma Who Are Candidates for Observation

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Complete response (CR) rate at the 6-month disease assessment [ Time Frame: 6 months ]
    Will be compared between the two arms. The percentage of patients in each response category (e.g., CR, partial remission, stable disease, relapse/progressive disease) will also be tabulated by arm. The proportion of patients who have a CR at 6 months will be evaluated and compared between the two treatment regimens using a two-sided alpha=0.05 continuity corrected Cochran-Mantel-Haenszel test with stratification factors.


Secondary Outcome Measures:
  • Incidence of adverse events assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 6 months ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Rates of individual adverse events (grade 3 and higher) will be compared between arms using a Fisher's exact test.

  • Progression-free survival (PFS) [ Time Frame: Time from registration to the earliest date documentation of disease progression or death due to any cause, assessed up to 5 years ]
    The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier within each arm and compared between the arms using a logrank test. The progression-free survival rates at 3 years and 5 years will be estimated in each arm.

  • Time to any therapy (TTNT) [ Time Frame: Time from registration to the date of initiation of any treatment for follicular lymphoma, assessed up to 5 years ]
    The distribution of time to any therapy will be estimated using the method of Kaplan-Meier within each arm and compared between the arms using a log-rank test. The percentage of patients free of any therapy at 3 years and 5 years will be estimated in each arm.

  • Time to chemotherapy (TTC) [ Time Frame: Time from registration to the date of initiation of chemotherapy for follicular lymphoma, assessed up to 5 years ]
    The distribution of time to chemotherapy will be estimated using the method of Kaplan-Meier within each arm and compared between the arms using a log-rank test. The percentage of patients free of chemotherapy at 3 years and 5 years will be estimated in each arm.


Other Outcome Measures:
  • Beta-2 microglobulin (B2m) plus LDH score [ Time Frame: Baseline ]
    Will be categorized at baseline as low risk (both factors =< 150% ULN), intermediate risk (one factor =< 150% IULN and the other factor > 150% ULN), or high risk (both factors > 150% IULN). The prognostic value of B2m plus LDH score in relation to PFS will be evaluated using Kaplan-Meier methods and log-rank statistics. Will be evaluated in each arm independently and may also be compared between the two arms.

  • Change in ALC [ Time Frame: Baseline to 6 months ]
    Both the absolute and relative change will be summarized for each measure. Will be evaluated in each arm independently and may also be compared between the two arms. Values may be investigated with respect to response (CR vs. less than CR) chi-square tests. Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using Kaplan-Meier methods and log-rank statistics (categorical measures). For values collected at more than one time point, changes over time will be evaluated using paired-t-tests.

  • Change in ALC/AMC ratio [ Time Frame: Baseline to 6 months ]
    Both the absolute and relative change will be summarized for each measure. Will be evaluated in each arm independently and may also be compared between the two arms. Values may be investigated with respect to response (CR vs. less than CR) chi-square tests. Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using Kaplan-Meier methods and log-rank statistics (categorical measures). For values collected at more than one time point, changes over time will be evaluated using paired-t-tests.

  • Change in AMC [ Time Frame: Baseline to 6 months ]
    Both the absolute and relative change will be summarized for each measure. Will be evaluated in each arm independently and may also be compared between the two arms. Values may be investigated with respect to response (CR vs. less than CR) chi-square tests. Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using Kaplan-Meier methods and log-rank statistics (categorical measures). For values collected at more than one time point, changes over time will be evaluated using paired-t-tests.

  • Change in quantification of tissue Tregs and tissue monocytes on study tumor biopsies [ Time Frame: Baseline to 6 months ]
    Will be evaluated in each arm independently and may also be compared between the two arms. Values may be investigated with respect to response (CR vs. less than CR) chi-square tests. Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using Kaplan-Meier methods and log-rank statistics (categorical measures). For values collected at more than one time point, changes over time will be evaluated using paired-t-tests.

  • Change in serum cytokines [ Time Frame: Baseline to 6 months ]
    Each cytokine will be evaluated in reference to normal controls and levels will be categorized as normal, elevated, or suppressed. Will be evaluated in each arm independently and may also be compared between the two arms. Values may be investigated with respect to response (CR vs. less than CR) chi-square tests. Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using Kaplan-Meier methods and log-rank statistics (categorical measures). For values collected at more than one time point, changes over time will be evaluated using paired-t-tests.

  • Change in vitamin D [ Time Frame: Baseline to 6 months ]
    Vitamin D level will be categorized as normal (sufficient) vs. abnormal (insufficient). Will be evaluated in each arm independently and may also be compared between the two arms. Values may be investigated with respect to response (CR vs. less than CR) chi-square tests. Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using Kaplan-Meier methods and log-rank statistics (categorical measures). For values collected at more than one time point, changes over time will be evaluated using paired-t-tests.

  • Incidence of exon 2 bcl2 mutations [ Time Frame: Baseline ]
    Will be evaluated in each arm independently and may also be compared between the two arms. Values may be investigated with respect to response (CR vs. less than CR) chi-square tests. Relationship with time to event measures (PFS, TTNT, TTC) will be evaluated using Kaplan-Meier methods and log-rank statistics (categorical measures).

  • Quality of life (QOL) as assessed FACT [ Time Frame: Up to 5 years ]
    Mean FACT will be graphically presented by arm using a mean plot with standard deviation error bars including all available data with patients according to the randomized treatment assignment. Baseline characteristics will be compared between arms within the subject of patients who provide QOL data at one or more time points using t-tests for continuous variables and chi-squared tests for categorical variables.


Estimated Enrollment: 128
Study Start Date: February 2015
Estimated Primary Completion Date: January 2026 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A (rituximab)
Patients receive rituximab IV on days 1, 8, 15, and 22.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Biological: Rituximab
Given IV
Other Names:
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83
Experimental: Arm B (rituximab, yttrium Y-90 ibritumomab tiuxetan)
Patients receive rituximab IV on days 1 and 8 and yttrium Y-90 ibritumomab tiuxetan over 10 minutes on day 8.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Biological: Rituximab
Given IV
Other Names:
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83
Radiation: Yttrium Y-90 Ibritumomab Tiuxetan
Given IV
Other Names:
  • IDEC-Y2B8
  • IDEC-Y2B8 monoclonal antibody
  • Y 90 Ibritumomab Tiuxetan
  • Y 90 Zevalin
  • Yttrium Y 90 Ibritumomab Tiuxetan
  • yttrium Y90 ibritumomab tiuxetan

Detailed Description:

PRIMARY OBJECTIVES:

I. Test the hypothesis that a single dose of Zevalin (yttrium Y-90 ibritumomab tiuxetan) rituximab immunotherapy (RIT) will increase the complete remission (CR) rate over that achieved with standard rituximab in patients with untreated asymptomatic follicular lymphoma (FL).

SECONDARY OBJECTIVES:

I. Test the hypothesis that Zevalin RIT will improve progression-free survival. II. Test the hypothesis that Zevalin RIT will improve time to next (any) therapy and time to next chemotherapy.

TERTIARY OBJECTIVES:

I. Study the incidence of exon 2 B-cell leukemia/lymphoma 2 protein (bcl2) mutations in patients with asymptomatic follicular lymphoma (AFL).

II. Measure regulatory T cells (Tregs) and tissue monocytes in on-study FL tumor tissue.

III. Measure serum cytokines and vitamin D at on study and month 6. IV. Evaluate beta-2 microglobulin plus lactate dehydrogenase (LDH) score as a prognostic factor.

V. Measure absolute lymphocyte count (ALC), absolute monocyte count (AMC), and ALC/AMC ratio at on study and after treatment.

VI. Compare quality of life as measured by the Functional Assessment of Cancer Therapy (FACT)-Lymphoma (Lym) between arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive rituximab intravenously (IV) on days 1, 8, 15, and 22.

ARM B: Patients receive rituximab IV on days 1 and 8 and yttrium Y-90 ibritumomab tiuxetan over 10 minutes on day 8.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months and then every 12 months for 5 years.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histological confirmation of follicular lymphoma grades I, II diagnosed within 12 months (365 days) prior to registration; NOTE: the day of biopsy should be used as day 1 of diagnosis for this calculation
  • Stage I, II, III, or IV disease; NOTE: stage I disease are eligible only if the disease is not amenable to external beam radiation therapy
  • No indication for chemotherapy; candidate for observation
  • Measurable disease by tumor imaging with at least one lesion >= 1.5 cm in at least one dimension
  • Previously untreated; NOTE: this includes any chemotherapy or immunotherapy or RIT; patients who received corticosteroids for diseases other than lymphoma are eligible as long as prednisone dose is =< 10 mg/day
  • Low tumor burden as defined by Groupe d'Etudes des Lymphomes Folliculaires (GELF) criteria (2):

    • No tumor mass (nodal or extranodal) >= 7 cm in one dimension on computed tomography (CT)
    • Fewer than 3 (2 or less) nodal masses > 3 cm
    • No systemic or B symptoms
    • No splenomegaly greater than 16 cm by CT scan
    • No risk of organ compression - ureteral, orbital, neurological, gastrointestinal
    • No leukemic phase (> 5.0 x 10^9/L circulating FL cells in the blood as detected by complete blood count [CBC] with differential and smear)
    • No cytopenias - absolute neutrophil count (ANC) < 1000 or platelets < 100,000
  • Meet standard criteria for RIT:

    • < 25% marrow involvement with FL
    • No evidence of myelodysplasia
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelet count >= 100,000/mm^3
  • Hemoglobin > 10.0 g/dL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x ULN, the direct bilirubin must be =< ULN
  • Alkaline phosphatase =< 3 x ULN
  • Aspartate transaminase (AST) =< 3 x ULN
  • Creatinine =< 2 x ULN
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Provide informed written consent
  • Willing to travel to a radioimmunotherapy site for Zevalin, if necessary
  • Willing to return to the enrolling institution for follow-up (during the Active Monitoring Phase of the study); Note: during the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
  • Willing to provide blood samples at baseline for correlative research purposes and tissue for central pathology review
  • < 25% bone marrow involvement of cellular marrow with lymphoma as determined by bilateral bone marrow aspirate and biopsy; NOTE: the percent involvement should be estimated by the hematopathologist using all of the biopsy material
  • Has insurance coverage or is willing to pay for protocol therapy (rituximab x 4 or Zevalin x 1)

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception for at least three months after completing study treatment
  • 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
  • Patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent that would be considered as a treatment for the lymphoma
  • Active other malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment and would interfere with follow-up assessments through year 5
  • Presence of central nervous system (CNS) lymphoma
  • Known to have lymphoma related to HIV or acquired immune deficiency syndrome (AIDS)
  • Abnormal renal function (serum creatinine > 2 x ULN)
  • Received prior external beam radiation therapy for another reason to > 25% of active bone marrow
  • Serious non-malignant disease such as active infection or other condition which in the opinion of the investigator would compromise other protocol objectives
  • Major surgery other than diagnostic surgery =< 4 weeks prior to registration
  • Any evidence of myelodysplastic syndrome or marrow chromosomal changes suggesting myelodysplasia (-7, -5 etc)
  • Corticosteroid therapy at the time the patient enters the protocol; NOTE: patients using prednisone or its equivalent for adrenal failure or using =< 10mg of prednisone/day for other benign causes are accepted
  • Follicular grades IIIA or IIIB are not eligible
  • Marrow cellularity =< 15% (as determined on all bone marrow samples)
  • Seropositive for or active viral infection with hepatitis B virus (HBV):

    • Hepatitis B surface antigen (HBsAg) positive
    • HBsAg negative, anti-hepatitis B surface antibody (HBs) positive and/or anti-hepatitis B core antibody (HBc) positive and detectable viral deoxyribonucleic acid (DNA)

Notes:

  • Subjects who are HBsAg negative, anti-HBs positive, and/or anti-HBc positive, but viral DNA negative are eligible
  • Subjects who are seropositive because of HBV vaccination are eligible (HBV surface antibody positive, HBV core antibody negative, and HBV surface antigen negative)

    • Active infection with hepatitis C virus (HCV)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02320292

Locations
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center Recruiting
Iowa City, Iowa, United States, 52242
Contact: George J. Weiner    800-237-1225    george-weiner@uiowa.edu   
Principal Investigator: George J. Weiner         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Thomas E. Witzig         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
Principal Investigator: Thomas Witzig Mayo Clinic
  More Information

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT02320292     History of Changes
Other Study ID Numbers: LS138D
NCI-2014-02476 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
LS138D ( Other Identifier: Mayo Clinic )
P30CA015083 ( US NIH Grant/Contract Award Number )
Study First Received: December 15, 2014
Last Updated: December 20, 2016

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on June 23, 2017