Ofatumumab Bendamustine Combination Compared With Bendamustine Monotherapy in Indolent B-cell NHL Unresponsive to Rituxtherapy (A+B)

• ClinicalTrials.gov Identifier: NCT01077518
• Recruitment Status: Terminated
• First Posted: March 1, 2010
• Results First Posted: March 27, 2020
• Last Update Posted: March 27, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: February 25, 2010
• First Posted Date: March 1, 2010
• Results First Submitted Date: December 24, 2019
• Results First Posted Date: March 27, 2020
• Last Update Posted Date: March 27, 2020
• Actual Study Start Date: August 26, 2010
• Actual Primary Completion Date: January 3, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 25, 2020)

Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC) [ Time Frame: From randomization to the date of first documented disease progression or death due to any cause (67.5 months) ]

PFS is defined as the time interval between randomization until disease progression or death (due to any cause).

• Original Primary Outcome Measures (submitted: February 25, 2010): Progression-free-survival following ofatumumab and bendamustine combination therapy [ Time Frame: 62 months ]

Current Secondary Outcome Measures (submitted: March 25, 2020)

• Progression-free Survival (PFS) in Participants With Follicular Lymphoma (FL) Per IRC [ Time Frame: From randomization to the date of first documented disease progression or death due to any cause (67.5 months) ]
  PFS is defined as the time interval between randomization until disease progression or death (due to any cause).
• Overall Response Rate (ORR) in All Participants Per IRC [ Time Frame: From randomization until the 217th PFS event occurred, up to about 67.5 months ]
  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.
• Overall Response Rate (ORR) in Participants With FL Per IRC [ Time Frame: From randomization until the 217th PFS event occurred, up to about 67.5 months ]
  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.
• Overall Survival (OS) in All Participants [ Time Frame: From randomization up to about 89 months ]
  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.
• Overall Survival (OS) in Participants With FL [ Time Frame: From randomization up to about 89 months ]
  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.
• Time to Response in All Participants Per IRC [ Time Frame: From randomization to up to 67.5 months ]
  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.
• Time to Response in Participants With FL Per IRC [ Time Frame: From randomization to up to 67.5 months ]
  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.
• Duration of Response in All Participants Per IRC [ Time Frame: 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 (in months) from the initial response (CR/PR) to first documented sign of disease progression or death due to any cause.
• Duration of Response in Participants With FL Per IRC [ Time Frame: 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 (in months) from the initial response (CR/PR) to first documented sign of disease progression or death due to any cause.
• Time to Progression in All Participants Per IRC [ Time Frame: 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 from randomization until disease progression
• Time to Progression in Participants With FL Per IRC [ Time Frame: 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 from randomization until disease progression
• Time to Next Therapy in All Participants Per IRC [ Time Frame: from randomization date to the date of receiving the next line treatment or death, up to 67.5 months ]
  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.
• Time to Next Therapy in Participants With FL Per IRC [ Time Frame: from randomization date to the date of receiving the next line treatment or death, up to 67.5 months ]
  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
• PRO - Change From Baseline in Health Related Quality of Life (HRQL) Measures in All Participants: The FACT-Lym [ Time Frame: 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 ]
  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
• PRO - Change From Baseline in Health Related Quality of Life (HRQL) Measures in Participants With FL: The FACT-Lym [ Time Frame: 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 ]
  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
• PRO - Change From Baseline in HRQL Measures in All Participants: The EQ-5D [ Time Frame: 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 ]
  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)
• PRO - Change From Baseline in HRQL Measures in Participants With FL: The EQ-5D [ Time Frame: 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 ]
  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)
• PRO - Change in Health Treatment in HRQL Measures in All Participants: The Health Change Questionnaire (HCQ) [ Time Frame: 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 ]
  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
• PRO - Change in Health Treatment in HRQL Measures in Participants With FL: The Health Change Questionnaire (HCQ) [ Time Frame: 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 ]
  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
• Reduction in Tumor Size [ Time Frame: baseline, post-baseline (up to 55 months) ]
  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.
• Summary of Change in Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: 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 ]
  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
• Summary of Number of Participants With Human Anti-Human Antibodies (HAHA) [ Time Frame: From randomization up to about 67.5 months ]
  A summary by responders and non-responders
• Overall Response Rate (ORR) to Optional Ofatumumab Monotherapy in Subjects Who Progressed During or Following Single-agent Bendamustine [ Time Frame: From randomization until the 217th PFS event occurred, up to about 67.8 months ]
  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.
• Quantitative Assessments of Immunoglobulins A, G and M (IgA, IgG, IgM) [ Time Frame: Screening, C1D1, 1M post D252, 6M post D252, 12M post D252 up to 67.5 months; Cycle = 21 days ]
  at scheduled visits for actual values as well as for change from baseline
• Plasma Ofatumumab Concentrations [ Time Frame: C1D1, C7D1, C12D1, C1D1, C12D1, 12M post-D252, withdrawal up to 12 months follow up ]
  Concentrations of ofatumumab in plasma listed by actual relative time and summarized by nominal time.
• B-cell Monitoring (CD19+, CD20+) [ Time Frame: C5D1 (month 5), 1M post-D252, 9M post-D252, up to 67.5 months; Cycle = 21 days ]
  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.
• Human Anti-chimeric Antibodies (HACA) Over Time [ Time Frame: At Baseline and Cycle 1 day 1 ]
  The number of participants with positive and negative baseline HACA results

Original Secondary Outcome Measures (submitted: February 25, 2010)

• Clinical benefit, changes in patient reported outcome measures, and pharmacokinetics following ofatumumab and bendamustine combination therapy [ Time Frame: 62 months ]
• Overall response rate, overall survival, time to and duration of response following ofatumumab and bendamustine combination therapy [ Time Frame: 62 months ]
• Safety and tolerability of ofatumumab and bendamustine combination therapy [ Time Frame: 62 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

randomized open label bendamustine monotherapy vs. ofatumumab

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Lymphoma, Follicular

Intervention

• Drug: Ofatumumab
  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.
  Other Name: OMB157
• Drug: Bendamustine infusion
  Bendamustine 100 mg/vial, injection
• Drug: Ofatumumab and Bendamustine infusions (Arm A)
  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.
• Drug: Bendamustine infusion (Arm B)
  Bendamustine (120 mg/m2 Days 1 and 2, every 21 days, up to 8 cycles).

Study Arms

• Experimental: Ofatumumab and Bendamustine (Arm A)
  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)
  Interventions:

  • Drug: Ofatumumab
  • Drug: Ofatumumab and Bendamustine infusions (Arm A)
• Active Comparator: Bendamustine (Arm B)
  Up to 8 cycles of bendamustine (120 mg/m2) on Days 1,2 every 21 days
  Interventions:

  • Drug: Ofatumumab
  • Drug: Bendamustine infusion
  • Drug: Bendamustine infusion (Arm B)

• Publications *: 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 25, 2020): 346
• Original Estimated Enrollment (submitted: February 25, 2010): 600
• Actual Study Completion Date: December 26, 2018
• Actual Primary Completion Date: January 3, 2018 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Belgium, Canada, France, Germany, Greece, Hong Kong, Italy, Japan, Poland, Puerto Rico, Russian Federation, Slovakia, Ukraine, United Kingdom, United States
• Removed Location Countries: Brazil

Administrative Information

• NCT Number: NCT01077518
• Other Study ID Numbers: 110918; 2008-004177-17 ( EudraCT Number ); COMB157E2301 ( Other Identifier: Novartis )
• Has Data Monitoring Committee: Yes

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

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Study Director, GSK
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: GlaxoSmithKline
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2020