Clinical Trials /

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

NCT02320292

Description:

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.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: LS138D
  • SECONDARY ID: NCI-2014-02476
  • SECONDARY ID: LS138D
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02320292

Conditions

  • 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

Interventions

DrugSynonymsArms
RituximabBI 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, RTXM83Arm A (rituximab)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (rituximab)Active ComparatorPatients receive rituximab IV on days 1, 8, 15, and 22.
  • Rituximab
Arm B (rituximab, yttrium Y-90 ibritumomab tiuxetan)ExperimentalPatients receive rituximab IV on days 1 and 8 and yttrium Y-90 ibritumomab tiuxetan over 10 minutes on day 8.
  • Rituximab

Eligibility 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response (CR) rate at the 6-month disease assessment
Time Frame:6 months
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Time to chemotherapy (TTC)
Time Frame:Time from registration to the date of initiation of chemotherapy for follicular lymphoma, assessed up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

January 2, 2019