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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01294579
Recruitment Status : Completed
First Posted : February 11, 2011
Results First Posted : August 9, 2018
Last Update Posted : August 9, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 3, 2011
First Posted Date  ICMJE February 11, 2011
Results First Submitted Date  ICMJE December 15, 2017
Results First Posted Date  ICMJE August 9, 2018
Last Update Posted Date August 9, 2018
Actual Study Start Date  ICMJE May 17, 2011
Actual Primary Completion Date December 20, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 6, 2018)
Complete Remission (CR) Rate of Induction Therapy After Cycle 6 (28 Days) (FAS) [ Time Frame: Baseline up to 24 weeks ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 10, 2011)
Complete Remission (CR) Rate of Induction Therapy [ Time Frame: 157 Weeks ]
Change History Complete list of historical versions of study NCT01294579 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2018)
  • Overall Response Rate (ORR) During Induction Phase After Cycle 6 (FAS) [ Time Frame: Baseline up to 24 weeks ]
    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.
  • 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 ]
    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
  • Percentage of Participants With Progression Free Survival (PFS) up to 30 Months (FAS) [ Time Frame: Baseline up to approximately 30 months ]
    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.
  • Kaplan-Meier Estimates of Progression Free Survival up to 30 Months (FAS) [ Time Frame: Baseline up to approximately 30 months ]
    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.
  • 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 ]
    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.
  • All Deaths by Preferred Term (Safety Set) up to Approximately 30 Months [ Time Frame: Baseline up to approximately 30 months ]
    Deaths were collected and were considered to be an on treatment death up to 60 days post treatment.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 10, 2011)
  • Overall Response Rate (PR +CR) of Induction therapy [ Time Frame: 157 Weeks ]
  • Conversion of PR to CR with Maintenance Ofatumumab [ Time Frame: 260 weeks ]
  • Progression Free Survival (PFS) [ Time Frame: 260 weeks ]
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability of Combination of Ofatumumab and Bendamustine [ Time Frame: 165 Weeks ]
  • 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: 261 Weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ofatumumab and Bendamustine Followed by Maintenance Ofatumumab for Rituximab Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (B-NHL)
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lymphoma, Non-Hodgkin
Intervention  ICMJE
  • Biological: Ofatumumab

    1000 mg intravenous (IV) on day 1 of each cycle (cycles 1-6) for induction phase

    1000 mg IV every 2 months for 2 years

  • Drug: Bendamustine
    90 mg/m2 on day 1 (after the ofatumumab infusion) and day 2 of each cycle (cycles 1-6)
Study Arms  ICMJE Experimental: ofatumumab and bendamustine

1000 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)

Interventions:
  • Biological: Ofatumumab
  • Drug: Bendamustine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 6, 2018)
49
Original Estimated Enrollment  ICMJE
 (submitted: February 10, 2011)
53
Actual Study Completion Date  ICMJE December 20, 2016
Actual Primary Completion Date December 20, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01294579
Other Study ID Numbers  ICMJE 114612
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP