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Ofatumumab and Bendamustine Followed by Maintenance Ofatumumab for Rituximab Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (B-NHL)

NCT01294579

Description:

The purpose of this phase II open label study was is to evaluate the safety and efficacy of ofatumumab and bendamustine followed by maintenance ofatumumab in subjects with indolent B-NHL who had relapsed after Rituximab treatment. A maximum of 53 subjects at least 18 years old with Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, or follicular lymphoma; Grades 1, 2 and 3a, would have been enrolled (34 in Stage 1 and 19 in Stage 2). Subjects should have had Rituximab-sensitive disease, defined as a Partial Remission (PR) or Complete Remission (CR) to the last rituximab-containing therapy lasting at least 6 months following completion of therapy or subjects should have relapsed or have had disease progression following response to prior rituximab-based therapy a Eastern Cooperative Oncology Group (ECOG) Performance status of 0 1 or 2. During the induction phase, ofatumumab 1000 mg IV on day 1 of each cycle (cycles 1-6) were followed by Bendamustine 90 mg/m2 IV on days 1, 2 of each cycle (cycles 1-6).During the maintenance phase, subjects with a PR or CR after the induction phase received ofatumumab 1000 mg IV every 2 months for 2 years.

Related Conditions:
  • Non-Hodgkin Lymphoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ofatumumab and Bendamustine Followed by Maintenance Ofatumumab for Rituximab Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (B-NHL)
  • Official Title: A Phase II Open-Label Study of Ofatumumab and Bendamustine Followed by Maintenance Ofatumumab for Indolent B-cell Non-Hodgkin's Lymphoma (B-NHL) Which Has Relapsed After Rituximab or a Rituximab Containing Therapy

Clinical Trial IDs

  • ORG STUDY ID: 114612
  • NCT ID: NCT01294579

Conditions

  • Lymphoma, Non-Hodgkin

Interventions

DrugSynonymsArms
Ofatumumabofatumumab and bendamustine
Bendamustineofatumumab and bendamustine

Purpose

The purpose of this phase II open label study was is to evaluate the safety and efficacy of ofatumumab and bendamustine followed by maintenance ofatumumab in subjects with indolent B-NHL who had relapsed after Rituximab treatment. A maximum of 53 subjects at least 18 years old with Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, or follicular lymphoma; Grades 1, 2 and 3a, would have been enrolled (34 in Stage 1 and 19 in Stage 2). Subjects should have had Rituximab-sensitive disease, defined as a Partial Remission (PR) or Complete Remission (CR) to the last rituximab-containing therapy lasting at least 6 months following completion of therapy or subjects should have relapsed or have had disease progression following response to prior rituximab-based therapy a Eastern Cooperative Oncology Group (ECOG) Performance status of 0 1 or 2. During the induction phase, ofatumumab 1000 mg IV on day 1 of each cycle (cycles 1-6) were followed by Bendamustine 90 mg/m2 IV on days 1, 2 of each cycle (cycles 1-6).During the maintenance phase, subjects with a PR or CR after the induction phase received ofatumumab 1000 mg IV every 2 months for 2 years.

Trial Arms

NameTypeDescriptionInterventions
ofatumumab and bendamustineExperimental1000 mg intravenous (IV) on day 1 of each cycle (cycles 1-6) for induction phase and 1000 mg IV every 2 months for 2 years. Bendamustine 90 mg/m2 was given on day 1 (after the ofatumumab infusion) and day 2 of each cycle (cycles 1-6)
  • Ofatumumab
  • Bendamustine

Eligibility Criteria

        Inclusion Criteria:

          -  Signed written informed consent

          -  Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, and follicular lymphoma;
             Grades 1, 2 and 3a, defined according to World Health organization (WHO) guidelines.
             [Tefferi, 2008]

          -  Tumor was verified to be CD20+ (based on local evaluation), from a current or previous
             tissue biopsy. Tissue biopsy should be repeated if no report or specimen is available,
             CD20 staining was not previously performed, or there is clinical suspicion that the
             indolent lymphoma has transformed to aggressive lymphoma/higher malignancy grade.

          -  Rituximab-sensitive disease, defined as a Partial Remission (PR) or Complete Remission
             (CR) to the last rituximab-containing therapy lasting at least 6 months following
             completion of therapy. Last rituximab-containing therapy is defined as the last
             therapy regimen containing at least one full dose of rituximab.

          -  Relapse or disease progression following response to prior rituximab-based therapy,
             that requiried treatment by 2007 Revised Response Criteria for Malignant Lymphoma
             (RRCML) guidelines.

          -  CT imaging in screening (based on local evaluation) showing 2 or more clearly
             demarcated lesions with a largest diameter > 1.5 cm, or 1 clearly demarcated lesion
             with a largest diameter > 2.0 cm.

          -  ECOG Performance Status of 0, 1, or 2.

          -  Age ≥ 18 years.

          -  Life expectancy of at least 6 months in the opinion of the investigator.

          -  Women of childbearing potential must have had a negative serum pregnancy test within
             14 days of first dose of study treatment and agree to use effective contraception
             during the study and for one year following the last dose of study drug.

          -  Men with a female partner of childbearing potential must have had either had a prior
             vasectomy or agree to use effective contraception from 2 weeks prior to administration
             of the first dose of study treatment until one year after the last dose of study
             treatment.

          -  Must not have been on any prohibited medications.

          -  Subjects who had received prior bendamustine were eligible if they had achieved a
             response (CR/PR) which lasted > 6 months after the end of bendamustine containing
             treatment.

        Exclusion Criteria:

          -  Lactating women

          -  CLL, Grade 3b follicular lymphoma or evidence that the indolent lymphoma had
             transformed to aggressive lymphoma. Subjects suspicious for transformation should have
             undergone a biopsy to exclude the possibility of transformation. Subjects with a
             previous diagnosis of small lymphocytic leukemia (SLL) and a screening monoclonal
             B-lymphocyte count of ≥ 5000/µl are defined by 2008 International Workshop on Chronic
             Lymphocytic Leukemia (IWCLL) criteria to have CLL; such patients were NOT eligible for
             this study.

          -  Rituximab-refractory disease, defined as failure to have responded to or progression
             within 6 months of completing rituximab or rituximab-containing combination therapy.

          -  Previous treatment with ofatumumab.

          -  Previous radioimmunotherapy (RIT) within 6 months of study entry. Subjects who have
             received RIT must have attained a PR or CR lasting at least 6 months, and must have
             recovered from any hematologic or other toxicity.

          -  Previous allogeneic stem cell transplantation at any time OR autologous stem cell
             transplantation within 6 months of study entry.

          -  Prior use of monoclonal antibody (other than anti CD20) within 3 months prior to
             randomization. Chemotherapy or other systemic lymphoma therapy within 4 weeks of study
             entry.

          -  Received treatment with an investigational agent within 4 weeks of study entry, or was
             actively participating in another interventional clinical study.

          -  Known Central Nervous System (CNS) involvement by lymphoma.

          -  Current or previous other malignancy within 2 years of study entry. Exception:
             Subjects who have been disease-free for 2 years or more, or subjects with a history of
             completely resected non-melanoma skin cancer or successfully treated in situ carcinoma
             are eligible.

          -  Chronic or currently active infectious disease requiring systemic antibiotics,
             antifungal, or antiviral treatment including, but not limited to: chronic renal
             infection, chronic chest infection with bronchiectasis, tuberculosis, active Hepatitis
             C, and known HIV disease. All Human Immunodeficient virus (HIV)-positive subjects are
             excluded from this study, regardless of whether they have an Acquired Immunodeficiency
             Syndrome (AIDS) defining disease and/or are on antiviral therapy.

          -  Clinically significant cardiac disease including unstable angina, acute myocardial
             infarction within 6 months of study entry, uncontrolled congestive heart failure, and
             uncontrolled arrhythmia. Subjects with congestive heart disease or arrhythmia such as
             atrial fibrillation whose cardiac disease is well controlled on a stable medical
             regimen are eligible.

          -  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.

          -  Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B
             surface antigen (HBsAg). In addition, if negative for HBsAg but (Hepatitis B core
             antibody (HBcAb) positive (regardless of Hepatitis B surface antibody [HBsAb] status),
             a HB DNA test had to have been performed and if positive the subject will be excluded.
             If HBV DNA is negative, subject may be included but must have undergone HBV DNA
             monitoring. Prophylactic antiviral therapy may have been initiated at the discretion
             of the investigator.

          -  Current active liver or biliary disease. Exception: Subjects with Gilbert's syndrome
             or asymptomatic gallstones, liver metastases related to indolent NHL or otherwise
             stable chronic liver disease per investigator assessment, are eligible.

          -  Screening laboratory values:

        Neutrophils < 1.5 x 109/L (unless due to NHL involvement of the bone marrow). Platelets <
        100 x 109/L (unless due to NHL involvement of the bone marrow). Serum creatinine ≥2.0
        mg/dL; subjects with serum creatinine ≥2.0 mg/dL were are eligible if the creatinine
        clearance (Cockcroft Gault equation [Cockcroft, 1976]) is ≥40 mL/min.

        Total bilirubin > 1.5 times ULN [upper normal limit] (unless due to liver involvement by
        NHL or Gilbert's disease).

        Transaminases > 3 times ULN (unless due to NHL involvement).

          -  Known or suspected inability to fully comply with study protocol.

          -  Known or suspected hypersensitivity to ofatumumab, bendamustine or mannitol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Remission (CR) Rate of Induction Therapy After Cycle 6 (28 Days) (FAS)
Time Frame:Baseline up to 24 weeks
Safety Issue:
Description:Complete response (CR) included all of the following: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. All target nodes had to have regressed to ≤ 1.5cm in the longest diameter. Non-measureable nodes 1.1 to 1.5cm in the longest diameter and >1cm in the short axis at baseline had to regress to ≤ 1cm in the short axis by visual estimation; enlarged spleen or liver (with nodules) must have returned to normal size and nodules disappeared and if bone marrow was involved, infiltrate had to have cleared on repeat biopsy sample. CR was not valid without imaging data. The corresponding 2-sided 95% exact confidence interval (CI) of the response rate was estimated by the Clopper-Pearson method.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR) During Induction Phase After Cycle 6 (FAS)
Time Frame:Baseline up to 24 weeks
Safety Issue:
Description:The overall response = CR (defined in Primary Outcome) + Partial Response (PR) which required all of the following: > or = to 50% decrease from baseline in target nodules; > or = to 50% decrease in hepatic/splenic nodules and no increase in liver or spleen size; no unequivocal progression in non-target lestions; no new sites of disease.
Measure:Conversion Rate of Partial Response in Induction Phase to Complete Response With Maintenance Ofatumumab (FAS)
Time Frame:Partial response in induction phase up to 24 weeks
Safety Issue:
Description:Rate of conversion from PR in the Induction phase, to CR with maintenance ofatumumab in subjects who have a PR with induction therapy with ofatumumab and bendamustine
Measure:Percentage of Participants With Progression Free Survival (PFS) up to 30 Months (FAS)
Time Frame:Baseline up to approximately 30 months
Safety Issue:
Description:Progression free survival (PFS) is defined as the interval between first treatment and disease progression or death due to any cause. PFS criteria: A previously normal node (≤ 1.5 x ≤ 1.0cm), including nodes that were not previously visible, must increase to >2.0 x ≥ 1.5cm; ≥ 50% increase from nadir in the PPD of any target node. The long axis must increase by at least 5 mm and to >2.0cm.; ≥ 50% increase from nadir in the long axis of any target node. The long axis must increase by at least 5 mm and to >2.0 cm.; ≥ 50% increase from nadir in the SPD of target nodes and at least one node should have a long axis >1.5 cm.
Measure:Kaplan-Meier Estimates of Progression Free Survival up to 30 Months (FAS)
Time Frame:Baseline up to approximately 30 months
Safety Issue:
Description:Progression Free Survival (PFS) is defined as the interval between first treatment and disease progression or death due to any cause. PFS events: progression documented between scheduled visits, death before first PD assessment (or death at baseline or prior to any adequate assessments), death between adequate assessment visits. For the PFS analysis, the survival function was estimated using Kaplan-Meier estimates.
Measure:Pharmacokinetic Profile Which Includes Measuring Blood Levels of Ofatumumab and Bendamustine in Combination and Ofatumumab Alone During Maintenance Treatment and Measuring Blood Levels of Circulating B Cell
Time Frame:up to 30 months
Safety Issue:
Description:Due to recruitment issues, this data analysis was not done per changes in planned analysis. This data was only presented as patient listings. The statistical analysis plan was modified to indicate that Pharmacokinetic/Pharmacodynamic exploratory analyses were not done.
Measure:All Deaths by Preferred Term (Safety Set) up to Approximately 30 Months
Time Frame:Baseline up to approximately 30 months
Safety Issue:
Description:Deaths were collected and were considered to be an on treatment death up to 60 days post treatment.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Non-Hodgkin's Lymphoma
  • Ofatumumab
  • Relapsed
  • Rituximab
  • Bendamustine

Last Updated

August 9, 2018