Ofatumumab Bendamustine Combination Compared With Bendamustine Monotherapy in Indolent B-cell NHL Unresponsive to Rituxtherapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Lymphoma, Follicular

Intervention / Treatment
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* Drug: Ofatumumab
* Drug: Bendamustine infusion
* Drug: Ofatumumab and Bendamustine infusions (Arm A)
* Drug: Bendamustine infusion (Arm B)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized open label bendamustine monotherapy vs. ofatumumab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ofatumumab and Bendamustine (Arm A)<br>Up to 8 cycles of bendamustine (90 mg/m2) on Days 1,2 every 21 days with12 doses of ofatumumab (1000 mg, Day 1 q21 days when with bendamustine and q28 days when given as monotherapy) | Drug: Ofatumumab<br>* Ofatumumab was a liquid concentrate solution for infusion presented in glass vials containing 50 mL of solution at a concentration of 20 mg/mL to provide 1000 mg per vial. The ofatumumab infusions were prepared in 1000 mL sterile, pyrogen-free 0.9% NaCl to yield a 1 mg/mL ofatumumab concentration infusion.<br>* Other names: OMB157;Drug: Ofatumumab and Bendamustine infusions (Arm A)<br>* Up to 8 cycles of Bendamustine (90 mg/m2 Days 1 and 2, every 21 days) given in combination with 12 doses of ofatumumab (1000 mg). Ofatumumab will be given on day 1 of each cycle of bendamustine as long as patients in Arm A receive bendamustine. Once patients in Arm A complete bendamustine therapy, the remaining doses of ofatumumab will be given monthly until all 12 doses are completed.<br>|
| Active Comparator: Bendamustine (Arm B)<br>Up to 8 cycles of bendamustine (120 mg/m2) on Days 1,2 every 21 days | Drug: Ofatumumab<br>* Ofatumumab was a liquid concentrate solution for infusion presented in glass vials containing 50 mL of solution at a concentration of 20 mg/mL to provide 1000 mg per vial. The ofatumumab infusions were prepared in 1000 mL sterile, pyrogen-free 0.9% NaCl to yield a 1 mg/mL ofatumumab concentration infusion.<br>* Other names: OMB157;Drug: Bendamustine infusion<br>* Bendamustine 100 mg/vial, injection<br>Drug: Bendamustine infusion (Arm B)<br>* Bendamustine (120 mg/m2 Days 1 and 2, every 21 days, up to 8 cycles).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | PFS is defined as the time interval between randomization until disease progression or death (due to any cause). | From randomization to the date of first documented disease progression or death due to any cause (67.5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) in Participants With Follicular Lymphoma (FL) Per IRC | PFS is defined as the time interval between randomization until disease progression or death (due to any cause). | From randomization to the date of first documented disease progression or death due to any cause (67.5 months) | 
| Overall Response Rate (ORR) in All Participants Per IRC | ORR: Percentage of subjects achieving complete response (CR) or partial response (PR) from the start of randomization until disease progression or the start of new anti-cancer therapy, including the optional ofatumumab for subjects in Arm B based on responses from the IRC assessment of best overall response using the Revised Response Criteria for Malignant Lymphoma (RRCML). Response criteria is CR, PR, standard disease (SD), progressive disease (PD) or not estimable. CR is the complete disappearance of all detectable clinical evidence of disease & disease-related symptoms. PR is at least a 50% decrease from baseline in the sum of the product of the diameters (SPD) of target lesions. SD is failure to attain the criteria needed for a CR, PR or PD. PD is the appearance of any new lesion more than 1.5 cm in any axis or at least a 50% increase from nadir in the SPD of target or non target lesions or at least a 50% increase in the longest diameter(SLD) or any Target or non target lesions. | From randomization until the 217th PFS event occurred, up to about 67.5 months | 
| Overall Response Rate (ORR) in Participants With FL Per IRC | ORR: Percentage of subjects achieving complete response (CR) or partial response (PR) from the start of randomization until disease progression or the start of new anti-cancer therapy, including the optional ofatumumab for subjects in Arm B based on responses from the IRC assessment of best overall response using the Revised Response Criteria for Malignant Lymphoma (RRCML). Response criteria is CR, PR, standard disease (SD), progressive disease (PD) or not estimable. CR is the complete disappearance of all detectable clinical evidence of disease & disease-related symptoms. PR is at least a 50% decrease from baseline in the sum of the product of the diameters (SPD) of target lesions. SD is failure to attain the criteria needed for a CR, PR or PD. PD is the appearance of any new lesion more than 1.5 cm in any axis or at least a 50% increase from nadir in the SPD of target or non target lesions or at least a 50% increase in the longest diameter(SLD) or any Target or non target lesions. | From randomization until the 217th PFS event occurred, up to about 67.5 months | 
| Overall Survival (OS) in All Participants | The interval of time between the date of randomization and the date of death due to any cause. For subjects who are alive, time of death will be censored at the date of last contact. | From randomization up to about 89 months | 
| Overall Survival (OS) in Participants With FL | The interval of time between the date of randomization and the date of death due to any cause. For subjects who are alive, time of death will be censored at the date of last contact. | From randomization up to about 89 months | 
| Time to Response in All Participants Per IRC | Time to response = time from randomization to the first response (CR/ PR). If no CR/PR value was present data was to be censored at last adequate assessment. | From randomization to up to 67.5 months | 
| Time to Response in Participants With FL Per IRC | Time to response = time from randomization to the first response (CR/ PR). If no CR/PR value was present data was to be censored at last adequate assessment. | From randomization to up to 67.5 months | 
| Duration of Response in All Participants Per IRC | Time (in months) from the initial response (CR/PR) to first documented sign of disease progression or death due to any cause. | 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 | 
| Duration of Response in Participants With FL Per IRC | Time (in months) from the initial response (CR/PR) to first documented sign of disease progression or death due to any cause. | 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 | 
| Time to Progression in All Participants Per IRC | Time from randomization until disease progression | 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 | 
| Time to Progression in Participants With FL Per IRC | Time from randomization until disease progression | 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 | 
| Time to Next Therapy in All Participants Per IRC | Time to next therapy was defined as the time (in months) from randomization date to the date of receiving the next line treatment, including all therapy types. | from randomization date to the date of receiving the next line treatment or death, up to 67.5 months | 
| Time to Next Therapy in Participants With FL Per IRC | Time to next therapy was defined as the time (in months) from randomization date to the date of receiving the next line treatment, including all therapy types | from randomization date to the date of receiving the next line treatment or death, up to 67.5 months | 
| PRO - Change From Baseline in Health Related Quality of Life (HRQL) Measures in All Participants: The FACT-Lym | The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is intended as a lymphoma specific additional concerns subscale that is designed to supplement the FACT-G. The subscale consists of 15 items. Subjects respond to the items on a five point Likert scale ranging from 0 'Not at all' to 4 'Very much'. Subscale scores are calculated by summing individual items to obtain a score, then multiplying the sum of the item scores by the number of items in the subscale, then dividing by the number of items answered. The Score range is 0 -28 for Physical Well-Being, Social/Family Well-Being, 0 -24 for Functional Well-Being and 0 - 60 for the Lymphoma subscale (LYMS). FACT lymphoma TOI is the sum of Physical, Functional Well-Being & Lymphoma scores. FACT-G Total Score is the sum of Physical, Emotional, Social and Functional Well-Being scores. FACT-Lymph is the sum of Physical, Social, Emotional, Functional and Lymphoma scores. The higher the score, the better the QOL. C =cycle; D=Day | 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 | 
| PRO - Change From Baseline in Health Related Quality of Life (HRQL) Measures in Participants With FL: The FACT-Lym | The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is intended as a lymphoma specific additional concerns subscale that is designed to supplement the FACT-G. The subscale consists of 15 items. Subjects respond to the items on a five point Likert scale ranging from 0 'Not at all' to 4 'Very much'. Subscale scores are calculated by summing individual items to obtain a score, then multiplying the sum of the item scores by the number of items in the subscale, then dividing by the number of items answered. The Score range is 0 -28 for Physical Well-Being, Social/Family Well-Being, 0 -24 for Functional Well-Being and 0 - 60 for the Lymphoma subscale (LYMS). FACT lymphoma TOI is the sum of Physical, Functional Well-Being & Lymphoma scores. FACT-G Total Score is the sum of Physical, Emotional, Social and Functional Well-Being scores. FACT-Lymph is the sum of Physical, Social, Emotional, Functional and Lymphoma scores. The higher the score, the better the QOL. C =cycle; D=Day | 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 | 
| PRO - Change From Baseline in HRQL Measures in All Participants: The EQ-5D | The EuroQoL Five-Dimension (EQ-5D) is a self-administered, generic, indirect utility measure used for health economic analysis.EQ-5D should be answered as one of 3 levels about current condition for 5 dimensions and was calculated total average by giving a weighting on 3 level of answers (EQ-5D levels into 'no problems' (level 1) and 'problems' (level 2 and 3)). Table of scores by each level for EQ-5D items: mobility(level 1=0, level2=0.069,level 3=0.314), self care(level 1=0, level2=0.104,level 3=0.214), usual activities(level 1=0, level2=0.036,level 3=0.094), pain/discomfort (level 1=0, level2=0.,level 3=0.386) and anxiety/depression(level 1=0, level2=0.071,level 3=0.2) *EQ-5D Total = 1 - 0.081 - (the score of the each level) - 0.269 (if at least one of level 3 presents) | 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 | 
| PRO - Change From Baseline in HRQL Measures in Participants With FL: The EQ-5D | The EuroQoL Five-Dimension (EQ-5D) is a self-administered, generic, indirect utility measure used for health economic analysis.EQ-5D should be answered as one of 3 levels about current condition for 5 dimensions and was calculated total average by giving a weighting on 3 level of answers (EQ-5D levels into 'no problems' (level 1) and 'problems' (level 2 and 3)). Table of scores by each level for EQ-5D items: mobility(level 1=0, level2=0.069,level 3=0.314), self care(level 1=0, level2=0.104,level 3=0.214), usual activities(level 1=0, level2=0.036,level 3=0.094), pain/discomfort (level 1=0, level2=0.,level 3=0.386) and anxiety/depression(level 1=0, level2=0.071,level 3=0.2) *EQ-5D Total = 1 - 0.081 - (the score of the each level) - 0.269 (if at least one of level 3 presents) | 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 | 
| PRO - Change in Health Treatment in HRQL Measures in All Participants: The Health Change Questionnaire (HCQ) | The Health Change Questionnaire,(HCQ) used is a nine item scale that asks the patient to rate change in status since beginning treatment on this study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for 'my health is a great deal better' to 9 for 'my health is a great deal worse' since the beginning of the study. Lower scores represent better conditions | 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 | 
| PRO - Change in Health Treatment in HRQL Measures in Participants With FL: The Health Change Questionnaire (HCQ) | The Health Change Questionnaire, (HCQ) used is a nine item scale that asks the patient to rate change in status since beginning treatment on this study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for 'my health is a great deal better' to 9 for 'my health is a great deal worse' since the beginning of the study. Lower scores represent better conditions | 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 | 
| Reduction in Tumor Size | Tumor size was measured by the mean change in the sum of the products of the greatest diameter (SPD) of the largest abnormal nodes from baseline to post-baseline by CT Scan. | baseline, post-baseline (up to 55 months) | 
| Summary of Change in Eastern Cooperative Oncology Group (ECOG) Performance Status | This is the number of participants with change in ECOG status. Change is measured categorically by Improvement, deterioration and No change. Improvement is defined as decrease from baseline by at least one step on the ECOG performance status scale. Deteriorations is defined as increase from baseline by at least one step on the ECOG performance status scale. ECOG status to evaluate daily living: 0: Fully active, able to carry on all pre-disease performance without restriction; 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4: Completely disabled; cannot carry on any self care.Totally confined to bed or chai; 5: Dead | 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 | 
| Summary of Number of Participants With Human Anti-Human Antibodies (HAHA) | A summary by responders and non-responders | From randomization up to about 67.5 months | 
| Overall Response Rate (ORR) to Optional Ofatumumab Monotherapy in Subjects Who Progressed During or Following Single-agent Bendamustine | ORR: Percentage of subjects achieving complete response (CR) or partial response (PR) from the start of randomization until disease progression or the start of new anti-cancer therapy, including the optional ofatumumab for subjects in Arm B based on responses from the IRC assessment of best overall response using the Revised Response Criteria for Malignant Lymphoma (RRCML). Response criteria is CR, PR, standard disease (SD), progressive disease (PD) or not estimable. CR is the complete disappearance of all detectable clinical evidence of disease & disease-related symptoms. PR is at least a 50% decrease from baseline in the sum of the product of the diameters (SPD) of target lesions. SD is failure to attain the criteria needed for a CR, PR or PD. PD is the appearance of any new lesion more than 1.5 cm in any axis or at least a 50% increase from nadir in the SPD of target or non target lesions or at least a 50% increase in the longest diameter(SLD) or any Target or non target lesions. | From randomization until the 217th PFS event occurred, up to about 67.8 months | 
| Quantitative Assessments of Immunoglobulins A, G and M (IgA, IgG, IgM) | at scheduled visits for actual values as well as for change from baseline | Screening, C1D1, 1M post D252, 6M post D252, 12M post D252 up to 67.5 months; Cycle = 21 days | 
| Plasma Ofatumumab Concentrations | Concentrations of ofatumumab in plasma listed by actual relative time and summarized by nominal time. | C1D1, C7D1, C12D1, C1D1, C12D1, 12M post-D252, withdrawal up to 12 months follow up | 
| B-cell Monitoring (CD19+, CD20+) | The percent change of CD5+CD19+ and CD5-CD19+ from baseline was summarized to assess the treatment effect, to monitor the normal B-cell population, and to follow their recovery. | C5D1 (month 5), 1M post-D252, 9M post-D252, up to 67.5 months; Cycle = 21 days | 
| Human Anti-chimeric Antibodies (HACA) Over Time | The number of participants with positive and negative baseline HACA results | At Baseline and Cycle 1 day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory, Safety, Efficacy, Rituximab refractory, Oncology, Ofatumumab, Bendamustine, Indolent B-cell Non- Hodgkin's Lymphoma Unresponsive, Rituximab, Rituximab-Containing Regimen