Clinical trial NCT01077518: Ofatumumab Bendamustine Combination Compared With Bendamustine Monotherapy in Indolent B-cell NHL Unresponsive to Rituxtherapy
Official title: Randomized Open Label of Ofatumumab and Bendamustine Combination Compared With Bendamustine Monotherapy in Indolent B-cell Non-Hodgkin's Lymphoma Unresponsive to Rituximab or a Rituximab-Containing Regimen During or Within Six Months of Treatment
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Lymphoma, Follicular
Keywords: Refractory
Safety
Efficacy
Rituximab refractory
Oncology
Ofatumumab
Bendamustine
Indolent B-cell Non- Hodgkin's Lymphoma Unresponsive
Rituximab
Rituximab-Containing Regimen
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-03-01
Enrollment: 346
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized open label bendamustine monotherapy vs. ofatumumab
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the safety and efficacy of ofatumumab and bendamustine combination therapy in patients with indolent B-cell NHL that did not respond to rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab treatment.

Detailed description: Ofatumumab is an anti-CD20 monoclonal antibody shown to have monotherapy activity in patients with follicular lymphoma that has relapsed following rituximab-containing therapy. Bendamustine was approved by FDA for the treatment of in patients with indolent B-cell Non-Hodgkin's Lymphoma (NHL) that did not respond to rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab treatment.

Biologics have demonstrated enhanced efficacy when added to chemotherapeutic combinations in the frontline treatment for indolent NHL. The combination of ofatumumab and bendamustine may provide additional clinical benefit and efficacy to those who no longer respond to rituximab or rituximab-containing regimens.

The objective of this study is to determine the effect of ofatumumab and bendamustine combination therapy in patients with indolent B-cell NHL that did not respond to rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab treatment.

Eligibility criteria: Inclusion Criteria:

* Indolent lymphoma including Grades 1-3a follicular, small lymphocytic, lymphoplasmacytic, and marginal zone lymphoma; Stages III-IV, or bulky disease, Stage II. Tumor verified CD20+ and CT imaging done at screening verifying disease
* Indolent B-cell NHL that remains stable or unresponsive during or within 6 months of treatment with rituximab or a rituximab-containing regimen
* Indolent lymphoma including grades 1-3a follicular, small lymphocytic, lymphoplasmacytic, and marginal zone lymphoma; stages III-IV, or bulky disease stage II (i.e. as any single mass \> 5 cm in any direction)
* ECOG Performance Status of 0, 1, or 2
* Life expectancy of at least 6 months
* 18 years or older
* Signed, written informed consent

Exclusion Criteria:

* Grade 3b follicular lymphoma or evidence that the indolent lymphoma has transformed to aggressive lymphoma
* Previous allogeneic stem cell transplant
* Previous autologous stem cell transplant, fludarabine therapy, or radioimmunotherapy in the past 12 months
* Previous external beam radiation therapy to the pelvis. Previous external beam radiation therapy for bony disease to the cranium, mediastinum, and axilla, or to two or to more than 3 vertebral bodies
* High dose steroids greater to or equal to 60 mg prednisone/day (or equivalent) within 3 months of randomization. No more than 10 mg prednisone (or equivalent) daily at the time of randomization
* Prior bendamustine treatment within 1 year of randomization not resulting in a CR or PR for at least 6 months
* Treatment with anti-CD20 monoclonal antibody within 3 months of randomization
* Known CNS involvement of indolent lymphoma
* Other past or current malignancy. Subjects free of malignancy for at least 5 years or have history of definitively treated non-melanoma skin cancer, or successfully treated in situ carcinoma, are eligible
* Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
* Clinically significant cardiac disease
* History of significant cerebrovascular disease or event with significant symptoms
* Positive serology for Hepatitis B
* Current active liver or biliary disease (except Gibber's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease)
* Known HIV positive
* Abnormal/inadequate blood values, liver and kidney function
* Current participation in other clinical study
* Inability to comply with the protocol activities
* Lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception

Primary outcomes:
measure: Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC)
timeFrame: From randomization to the date of first documented disease progression or death due to any cause (67.5 months)
Secondary outcomes:
measure: Progression-free Survival (PFS) in Participants With Follicular Lymphoma (FL) Per IRC
timeFrame: From randomization to the date of first documented disease progression or death due to any cause (67.5 months)
measure: Overall Response Rate (ORR) in All Participants Per IRC
timeFrame: From randomization until the 217th PFS event occurred, up to about 67.5 months
measure: Overall Response Rate (ORR) in Participants With FL Per IRC
timeFrame: From randomization until the 217th PFS event occurred, up to about 67.5 months
measure: Overall Survival (OS) in All Participants
timeFrame: From randomization up to about 89 months
measure: Overall Survival (OS) in Participants With FL
timeFrame: From randomization up to about 89 months
measure: Time to Response in All Participants Per IRC
timeFrame: From randomization to up to 67.5 months
measure: Time to Response in Participants With FL Per IRC
timeFrame: From randomization to up to 67.5 months
measure: Duration of Response in All Participants Per IRC
timeFrame: time from the initial response (CR/PR) (Day 84) to first documented sign of disease progression or death due to any cause up to 67.5 months
measure: Duration of Response in Participants With FL Per IRC
timeFrame: time from the initial response (CR/PR) (Day 84) to first documented sign of disease progression or death due to any cause up to 67.5 months
measure: Time to Progression in All Participants Per IRC
timeFrame: From randomization to the date of first documented disease progression, whichever occurred first, reported betwen day of first participant randomized up to about 67.5 months
measure: Time to Progression in Participants With FL Per IRC
timeFrame: From randomization to the date of first documented disease progression, whichever occurred first, reported betwen day of first participant randomized up to about 67.5 months
measure: Time to Next Therapy in All Participants Per IRC
timeFrame: from randomization date to the date of receiving the next line treatment or death, up to 67.5 months
measure: Time to Next Therapy in Participants With FL Per IRC
timeFrame: from randomization date to the date of receiving the next line treatment or death, up to 67.5 months
measure: PRO - Change From Baseline in Health Related Quality of Life (HRQL) Measures in All Participants: The FACT-Lym
timeFrame: administered at the screening visit and C5D1 (month 5), C11D1 (month 11), D252, 12m post-D252, withdrawal (24m post-D252) up to 67.5 months; Cycle = 21 days
measure: PRO - Change From Baseline in Health Related Quality of Life (HRQL) Measures in Participants With FL: The FACT-Lym
timeFrame: administered at the screeing visit and C5D1 (month 5), C11D1 (month 11), D252, 12m post-D252, withdrawal (24m post-D252) up to 67.5 months; Cycle = 21 days
measure: PRO - Change From Baseline in HRQL Measures in All Participants: The EQ-5D
timeFrame: administered at screening and C5D1 (month 5), C11D1 (month 11), D252, 12m post-D252, withdrawal (24m post-D252) up to 67.5 months; Cycle = 21 days
measure: PRO - Change From Baseline in HRQL Measures in Participants With FL: The EQ-5D
timeFrame: administered at screening and C5D1 (month 5), C11D1 (month 11), D252, 12m post-D252, withdrawal (24m post-D252) up to 67.5 months; Cycle = 21 days
measure: PRO - Change in Health Treatment in HRQL Measures in All Participants: The Health Change Questionnaire (HCQ)
timeFrame: administered at screening and C5D1 (month 5), C11D1 (month 11), D252, 12m post-D252, withdrawal (24m post-D252) up to 67.5 months; Cycle = 21 days
measure: PRO - Change in Health Treatment in HRQL Measures in Participants With FL: The Health Change Questionnaire (HCQ)
timeFrame: administered at screening and C5D1 (month 5), C11D1 (month 11), D252, 12m post-D252, withdrawal (24m post-D252) up to 67.5 months; Cycle = 21 days
measure: Reduction in Tumor Size
timeFrame: baseline, post-baseline (up to 55 months)
measure: Summary of Change in Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: administered at screening and C5D1 (month 5), C11D1 (month 11), D252, 12m post-D252, withdrawal (24m post-D252) up to 67.5 months; Cycle = 21 days
measure: Summary of Number of Participants With Human Anti-Human Antibodies (HAHA)
timeFrame: From randomization up to about 67.5 months
measure: Overall Response Rate (ORR) to Optional Ofatumumab Monotherapy in Subjects Who Progressed During or Following Single-agent Bendamustine
timeFrame: From randomization until the 217th PFS event occurred, up to about 67.8 months
measure: Quantitative Assessments of Immunoglobulins A, G and M (IgA, IgG, IgM)
timeFrame: Screening, C1D1, 1M post D252, 6M post D252, 12M post D252 up to 67.5 months; Cycle = 21 days
measure: Plasma Ofatumumab Concentrations
timeFrame: C1D1, C7D1, C12D1, C1D1, C12D1, 12M post-D252, withdrawal up to 12 months follow up
measure: B-cell Monitoring (CD19+, CD20+)
timeFrame: C5D1 (month 5), 1M post-D252, 9M post-D252, up to 67.5 months; Cycle = 21 days
measure: Human Anti-chimeric Antibodies (HACA) Over Time
timeFrame: At Baseline and Cycle 1 day 1
Other outcomes:
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country: Puerto Rico
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city: San Juan
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city: Chelyabinsk
country: Russian Federation
facility: Novartis Investigative Site
city: Kaluga
country: Russian Federation
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Novosibirsk
country: Russian Federation
facility: Novartis Investigative Site
city: Penza
country: Russian Federation
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city: St'Petersburg
country: Russian Federation
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
city: Uxbridge
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Rummel MJ, Janssens A, MacDonald D, Keating MM, Zaucha JM, Davis J, Lasher J, Babanrao Pisal C, Izquierdo M, Friedberg JW. A phase 3, randomized study of ofatumumab combined with bendamustine in rituximab-refractory iNHL (COMPLEMENT A + B study). Br J Haematol. 2021 Jun;193(6):1123-1133. doi: 10.1111/bjh.17420. Epub 2021 May 10.