Single Agent Ofatumumab Vs. Single Agent Rituximab in Indolent B-Cell Non Hodgkin Lymphoma Relapsed After Rituximab-Containing Therapy
Condition: Non-Hodgkin's Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell
Intervention: Ofatumumab; Rituximab; Ofatumumab; Rituximab
Intervention description: liquid concentrate for solution for infusion in glass vials containing 50 mL of solution at a concentration of 20mg/ml to provide 1000 mg per vial.; sourced locally from commercial stock; Four weekly doses of single agent ofatumumab (1000 mg), followed by ofatumumab (1000 mg) every two months for four additional doses.; Four weekly doses of single agent rituximab (375 mg/m2), followed by rituximab (375 mg/m2) every two months for four additional doses.
Intervention MeSH terms: Rituximab; Ofatumumab; Antibodies, Monoclonal
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)
Enrollment: 438.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Randomized trial; Ofatumumab; Rituximab; Indolent B-Cell Non Hodgkin Lymphoma

Summary:

      This was a multi-center, parallel, active comparator controlled, open-label, randomized (1:1)
      phase III study of single agent ofatumumab compared to single agent rituximab in subjects
      with rituximab-sensitive indolent B-cell non hodgkin lymphoma that has relapsed at least 6
      months after completing treatment with single agent rituximab or a rituximab-containing
      regimen. Subjects must have attained a Complete Response or Partial Response to their last
      prior rituximab containing therapy lasting at least six months beyond the end of rituximab
      therapy. Subjects were to receive four weekly doses of single agent ofatumumab (1000 mg) or
      rituximab (375 mg/m2), followed by ofatumumab (1000 mg) or rituximab (375 mg/m2) every 2
      months for four additional doses. Therefore, subjects were to receive a total of eight doses
      of anti-CD20 antibody over 9 months. Subjects were evaluated for response after completion of
      the first four doses of therapy, after six doses of therapy, and after completion of study
      therapy. Subjects were to be followed until the end of the designated follow-up period (total
      study duration of 200 weeks) or until they meet the withdrawal criteria.

      The primary objective of the study OMB157D 2303 was to demonstrate the efficacy of Arzerra
      based on the primary endpoint (Progression-free survival (PFS) as assessed by the IRC) in
      patients with Indolent B-cell Non-Hodgkin's Lymphoma Relapsed After Rituximab-Containing
      Regimen.

      The Independent Data Monitoring Committee (IDMC) met on November 22, 2015 and recommended the
      termination of the study due to futility (cut-off date = 12Jun2015). The IDMC reviewed
      analyses results for progression free survival (PFS), overall response rate (ORR), and
      overall survival (OS). Novartis accepted this recommendation and the study was closed.

      Final analysis was performed (cut-off date =19 Dec 2016). As the study was stopped for
      futility, the primary objective was not met and some secondary endpoints, supportive of
      primary objective (Duration of Response (DOR), time to next therapy, and pharmacokinetics)
      were removed as secondary end points.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Indolent NHL subtypes defined according to World Health Organization guidelines:

               1. Follicular lymphoma Grades 1, 2, 3 A

               2. Small lymphocytic lymphoma (SLL)

               3. Marginal zone lymphoma

               4. Lymphoplasmacytic lymphoma

          2. Rituximab-sensitive iNHL, defined as a partial or complete response to their last
             prior treatment with rituximab or a rituximab-containing regimen lasting at least 6
             months following completion of rituximab treatment.

          3. Relapse or disease progression following response to prior rituximab-based therapy, as
             defined by 2007 RRCML criteria, which requires therapy.

          4. Radiographically measurable disease, defined as: 2 or more clearly demarcated
             lesions/nodes with a long axis >1.5 cm and short axis ≥1.0cm. OR 1 clearly demarcated
             lesion/node with a long axis >2.0 cm and short axis ≥1.0cm.

          5. ECOG Performance Status of 0, 1, or 2.

          6. Age ≥18 years.

          7. Life expectancy of at least 6 months in the opinion of the investigator.

          8. The patient or their legally acceptable representative must be capable of giving
             written informed consent prior to performing any study-specific tests or procedures.

          9. All prior treatment related non-hematologic toxicities (with the exception of
             alopecia) must have resolved to CTCAE (Version 4.0) ≤ Grade 2 at the time of
             randomization.

         10. One or more of the following indications for treatment:

               1. Cytopenias

               2. One or more of the following lymphoma-related symptoms:

                    -  Night sweats without signs of infection

                    -  Unintentional weight loss (10% within the previous 6 months)

                    -  Recurrent, unexplained fever of greater than 100.5F (38C) without signs of
                       infection

                    -  Fatigue which interferes with the patient's quality of life

               3. Progressive or massive lymphadenopathy OR

               4. Progressive or massive organomegaly French subjects: In France, a subject will be
                  eligible for inclusion in this study only if either affiliated to or a
                  beneficiary of a social security category.

        Exclusion Criteria:

          1. Previous treatment with ofatumumab.

          2. Previous anti-CD20 radioimmunotherapy (RIT) or non-rituximab anti-CD20 therapy (such
             as obinutuzumab) within 6 months prior to randomization. Patients who have received
             previous anti-CD20 RIT or non-rituximab anti-CD20 therapy (such as obinutuzumab) must
             have attained a partial or complete response lasting at least 6 months, and must have
             recovered from any hematologic or other toxicity.

          3. Previous autologous stem cell transplantation within 6 months prior to randomization.

          4. Previous allogeneic stem cell transplantation.

          5. Previous anti-lymphoma monoclonal antibody therapy (excluding anti-CD20 therapy and
             anti-CD20 RIT), chemotherapy, glucocorticoid, or other systemic therapy for lymphoma
             within 3 months prior to randomization.

          6. Current or previous participation in the treatment phase of another interventional
             clinical study within 4 weeks prior to randomization. Patients may continue in the
             follow-up phase of another interventional clinical study, but may not have undergone
             any treatment on the other study within 4 weeks prior to randomization.

          7. Current or previous other malignancy within 2 years prior to randomization. Subjects
             who have been free of malignancy for at least 2 years, or have a history of completely
             resected non-melanoma skin cancer or successfully treated carcinoma in situ, are
             eligible.

          8. Chronic or current active infectious disease requiring systemic antibiotics,
             antifungal, or antiviral treatment such as, but not limited to, chronic renal
             infection, chronic chest infection with bronchiectasis, tuberculosis, active Hepatitis
             C, and known HIV disease. All HIV-positive patients are excluded from this study,
             regardless of whether they have an Acquired Immunodeficiency Syndrome (AIDS) defining
             disease and/or are on antiviral therapy. Prophylactic antiviral and/or antibacterial
             antibiotics to prevent recurrence of previous infections are permitted.

          9. Clinically significant cardiac disease as judged by the investigator including
             unstable angina, acute myocardial infarction within 6 months prior to randomization,
             uncontrolled congestive heart failure, and uncontrolled arrhythmia. Subjects with
             congestive heart disease or arrhythmias such as atrial fibrillation whose cardiac
             disease is well controlled on a stable medical regimen are eligible.

         10. Other significant concurrent, uncontrolled medical conditions including, but not
             limited to, renal, hepatic, autoimmune, hematological, gastrointestinal, endocrine,
             pulmonary, neurological, cerebral or psychiatric disease which, in the investigator's
             opinion, will impact study participation.

         11. Screening laboratory values:

               1. Neutrophils < 1.5 x 10^9/L (unless due to iNHL involvement of the bone marrow)

               2. Platelets < 50 x 10^9/L (unless due to iNHL involvement of the bone marrow)

               3. ALT or AST > 3 x ULN

               4. Alkaline phosphatase > 1.5 x ULN (unless due to lymphoma or a non-malignant,
                  non-hepatic cause such as Paget's disease)

               5. Total bilirubin > 1.5 x ULN (unless due to lymphoma or isolated, predominantly
                  indirect hyperbilirubinemia due to Gilbert's syndrome)

         12. Known or suspected inability to fully comply with study protocol

         13. Because the effects of ofatumumab on fetuses and nursing infants are not known, the
             following are ineligible for study entry:

               1. Lactating women.

               2. Women with a positive pregnancy test at study entry.

               3. Men with partners of childbearing potential and women of childbearing potential
                  who are not willing to use adequate contraception from study entry through one
                  year following last treatment dose. (Adequate contraception is defined as
                  abstinence, oral hormonal birth control, hormonal birth control injections,
                  implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive
                  patches, intrauterine device, and male partner sterilization if male partner is
                  the sole partner for a female subject. The double barrier method can be used in
                  regions where considered acceptable and adequate, defined as condom or occlusive
                  cap plus spermicidal agent).

         14. Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones).

         15. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In
             addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB
             DNA test will be performed and if positive the subject will be excluded.