Follicular Lymphoma
Conditions
Keywords
Follicular Lymphoma, Biosimilar, GP13-301, rituximab, Antibodies, CD20
Brief summary
The purpose of this study is to demonstrate comparability of the ORR in patients with previously untreated, advanced stage FL who receive GP2013-treatment to patients who receive MabThera-treatment.
Interventions
BIOLOGICALGP2013
Type: Biological/Vaccine
BIOLOGICALrituximab
Type: Biological/Vaccine
Sponsors
Novartis Pharmaceuticals
Sandoz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
A subset of patients is switched from GP2013 to MabThera or continued with MabThera during the maintenance phase, for these patients the treatment is finished as an open labeled parallel arm study. The original treatment assignment is kept blinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient with previously untreated advanced stage, CD20-positive FL * Patient with ECOG performance status 0, 1 or 2.
Exclusion criteria
* Patient with Grade 3b (aggressive) FL or any histology other than FL grade 1, 2 or 3a * Patient who has previously received any prior therapy for lymphoma * Patient with evidence of any uncontrolled, active infection (viral, bacterial or fungal). * Patient with any malignancy within 5 years prior to date of randomization, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 24 weeks | ORR is defined as the proportion of patients whose best overall disease response was either CR or PR during the combination treatment period based on blinded independent central radiology review. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Partial Response (PR) Rate During the Combination Treatment Period | 24 weeks | — |
| To Evaluate the Progression Free Survival (PFS) With up to 3 Years of Follow-up Post Randomization | 3 years | Number of participants with progression free survival events |
| To Evaluate the Overall Survival (OS) With up to 3 Years of Follow-up Post Randomization, as Assessed by the Number of Deaths | 3 years | OS was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, OS was censored at the date of last contact including survival follow-up. |
| To Evaluate the Complete Response (CR) Rate During the Combination Treatment Period | 24 weeks | — |
| To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Max) | day 63 | C max For descriptive purposes only, no hypothesis testing |
| To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Trough) | day 63 | C through For descriptive purposes only, no hypothesis testing |
| To Evaluate a PD Marker (Peripheral CD19+ B-cell Counts) Following the Treatment With GP2013 + Chemotherapy Amd MabThera- Chemotherapy | 21 days | AUEC (0-21d) For descriptive purposes only, no hypothesis testing |
| To Evaluate the Incidence of Immunogenicity (ADA Formation) Against GP2013 and MabThera (Rituximab) | 24 weeks, 3 years | number of participants with confirmed positive ADA |
Countries
Argentina, Australia, Austria, Brazil, Bulgaria, Colombia, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Japan, Malaysia, Netherlands, Peru, Poland, Portugal, Romania, Russia, South Africa, Spain, Ukraine, United Kingdom
Participant flow
Recruitment details
A total of 629 patients were randomized at 159 centers in 26 countries, 314 patients to GP2013 (312 patients treated) and 315 to MabThera. Of those 314 patients in the GP2013 group, 2 patients were randomized by error and discontinued before any treatment with GP2013. The number of patients in both treatment groups remained similar.
Pre-assignment details
full analysis set participants : GP2013 312 MabThera 315 safety set participants : GP2013 312 MabThera 315 per protocol set participants: GP2013 310 MabThera 312 pharmacokinetic analysis set 1 : GP2013 119 MabThera 120 immunogenicity analysis set: GP2013 275 MabThera 287 pharmacodynamic analysis set : GP2013 24 MabThera 24
Participants by arm
| Arm | Count |
|---|---|
| GP2013 Experimental Type: Biological/Vaccine | 312 |
| Rituximab Comparator Type: Biological/Vaccine | 315 |
| Total | 627 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Combination Treatment | administrative problems | 0 | 1 |
| Combination Treatment | Adverse Event | 7 | 10 |
| Combination Treatment | Death | 5 | 7 |
| Combination Treatment | disease progression | 10 | 9 |
| Combination Treatment | Physician Decision | 5 | 8 |
| Combination Treatment | Protocol Violation | 6 | 2 |
| Combination Treatment | Withdrawal by Subject | 5 | 4 |
| Maintenance Treatment and/or Follow up | administrative problems | 0 | 6 |
| Maintenance Treatment and/or Follow up | Adverse Event | 11 | 7 |
| Maintenance Treatment and/or Follow up | Death | 1 | 2 |
| Maintenance Treatment and/or Follow up | disease progression | 53 | 37 |
| Maintenance Treatment and/or Follow up | Lost to Follow-up | 1 | 2 |
| Maintenance Treatment and/or Follow up | Physician Decision | 5 | 2 |
| Maintenance Treatment and/or Follow up | Protocol Violation | 1 | 1 |
| Maintenance Treatment and/or Follow up | switch to open label | 44 | 39 |
| Maintenance Treatment and/or Follow up | Withdrawal by Subject | 6 | 6 |
| Open Label Phase | Death | 1 | 0 |
| Open Label Phase | disease progression | 0 | 1 |
Baseline characteristics
| Characteristic | GP2013 | Total | Rituximab |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 11.86 | 56.9 years STANDARD_DEVIATION 11.79 | 56.4 years STANDARD_DEVIATION 11.72 |
| Race/Ethnicity, Customized Asian | 71 Participants | 156 Participants | 85 Participants |
| Race/Ethnicity, Customized Black | 6 Participants | 9 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 214 Participants | 421 Participants | 207 Participants |
| Race/Ethnicity, Customized Chinese | 5 Participants | 11 Participants | 6 Participants |
| Race/Ethnicity, Customized Hispanic / Latino | 59 Participants | 127 Participants | 68 Participants |
| Race/Ethnicity, Customized Indian (Indian Subcontinent) | 40 Participants | 94 Participants | 54 Participants |
| Race/Ethnicity, Customized Japanese | 16 Participants | 30 Participants | 14 Participants |
| Race/Ethnicity, Customized Mixed Ethnicity | 8 Participants | 11 Participants | 3 Participants |
| Race/Ethnicity, Customized Native American | 2 Participants | 7 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 19 Participants | 34 Participants | 170 Participants |
| Race/Ethnicity, Customized Unknown / missing | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 181 Participants | 350 Participants | 169 Participants |
| Sex: Female, Male Male | 131 Participants | 277 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 312 | 5 / 315 | 2 / 254 | 2 / 252 |
| other Total, other adverse events | 262 / 312 | 255 / 315 | 141 / 254 | 144 / 252 |
| serious Total, serious adverse events | 71 / 312 | 63 / 315 | 24 / 254 | 21 / 252 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR is defined as the proportion of patients whose best overall disease response was either CR or PR during the combination treatment period based on blinded independent central radiology review.
Time frame: 24 weeks
Population: per protocol set, participants with measure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GP2013 | Overall Response Rate (ORR) | 87.1 percentage |
| Rituximab | Overall Response Rate (ORR) | 87.5 percentage |
95% CI: [-5.94, 5.14]Binomial approximation
Secondary
To Evaluate a PD Marker (Peripheral CD19+ B-cell Counts) Following the Treatment With GP2013 + Chemotherapy Amd MabThera- Chemotherapy
AUEC (0-21d) For descriptive purposes only, no hypothesis testing
Time frame: 21 days
Population: Pharmnacodynamic analysis set, participants with measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GP2013 | To Evaluate a PD Marker (Peripheral CD19+ B-cell Counts) Following the Treatment With GP2013 + Chemotherapy Amd MabThera- Chemotherapy | 1790 %*day | Geometric Coefficient of Variation 23.5 |
| Rituximab | To Evaluate a PD Marker (Peripheral CD19+ B-cell Counts) Following the Treatment With GP2013 + Chemotherapy Amd MabThera- Chemotherapy | 1910 %*day | Geometric Coefficient of Variation 13.3 |
Secondary
To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Max)
C max For descriptive purposes only, no hypothesis testing
Time frame: day 63
Population: pharmacokinetic analysis set 1, participants with measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GP2013 | To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Max) | 333.59 microg/mL | Geometric Coefficient of Variation 41.09 |
| Rituximab | To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Max) | 331.93 microg/mL | Geometric Coefficient of Variation 35.32 |
Secondary
To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Trough)
C through For descriptive purposes only, no hypothesis testing
Time frame: day 63
Population: pharmacokinetic analysis set 1, participants with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GP2013 | To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Trough) | 66.42 microg/mL | Standard Deviation 47.593 |
| Rituximab | To Evaluate a PK Marker Following the Treatment With GP2013-Chemotherapy and MabThera-Chemotherapy (C Trough) | 82.13 microg/mL | Standard Deviation 61.526 |
Secondary
To Evaluate the Complete Response (CR) Rate During the Combination Treatment Period
Time frame: 24 weeks
Population: per protocol set, participants with measure
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GP2013 | To Evaluate the Complete Response (CR) Rate During the Combination Treatment Period | 46 Participants |
| Rituximab | To Evaluate the Complete Response (CR) Rate During the Combination Treatment Period | 42 Participants |
Secondary
To Evaluate the Incidence of Immunogenicity (ADA Formation) Against GP2013 and MabThera (Rituximab)
number of participants with confirmed positive ADA
Time frame: 24 weeks, 3 years
Population: immunogenicity set, participants with measure
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GP2013 | To Evaluate the Incidence of Immunogenicity (ADA Formation) Against GP2013 and MabThera (Rituximab) | end of treatment combination phase (24 weeks) | 1 Participants |
| GP2013 | To Evaluate the Incidence of Immunogenicity (ADA Formation) Against GP2013 and MabThera (Rituximab) | end of treatment manintenance phase (3 years) | 1 Participants |
| Rituximab | To Evaluate the Incidence of Immunogenicity (ADA Formation) Against GP2013 and MabThera (Rituximab) | end of treatment combination phase (24 weeks) | 2 Participants |
| Rituximab | To Evaluate the Incidence of Immunogenicity (ADA Formation) Against GP2013 and MabThera (Rituximab) | end of treatment manintenance phase (3 years) | 0 Participants |
Secondary
To Evaluate the Overall Survival (OS) With up to 3 Years of Follow-up Post Randomization, as Assessed by the Number of Deaths
OS was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, OS was censored at the date of last contact including survival follow-up.
Time frame: 3 years
Population: per protocol set, participants with measure
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GP2013 | To Evaluate the Overall Survival (OS) With up to 3 Years of Follow-up Post Randomization, as Assessed by the Number of Deaths | 29 Participants |
| Rituximab | To Evaluate the Overall Survival (OS) With up to 3 Years of Follow-up Post Randomization, as Assessed by the Number of Deaths | 31 Participants |
95% CI: [0.55, 1.52]Regression, Cox
Secondary
To Evaluate the Partial Response (PR) Rate During the Combination Treatment Period
Time frame: 24 weeks
Population: per protocol set, participants with measure
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GP2013 | To Evaluate the Partial Response (PR) Rate During the Combination Treatment Period | 225 Participants |
| Rituximab | To Evaluate the Partial Response (PR) Rate During the Combination Treatment Period | 232 Participants |
Secondary
To Evaluate the Progression Free Survival (PFS) With up to 3 Years of Follow-up Post Randomization
Number of participants with progression free survival events
Time frame: 3 years
Population: per protocol set, participants with measure
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GP2013 | To Evaluate the Progression Free Survival (PFS) With up to 3 Years of Follow-up Post Randomization | 97 Participants |
| Rituximab | To Evaluate the Progression Free Survival (PFS) With up to 3 Years of Follow-up Post Randomization | 78 Participants |
95% CI: [0.97, 1.76]Regression, Cox
Post Hoc
All Collected Deaths
On treatment deaths were collected from the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 30 months (treatment duration ranged from 90 to 782 days) Deaths post treatment survival follow up were collected after the on- treatment period, up to 3 years.
Time frame: 30 months, 3 years
Population: clinical data base population - treated patients
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GP2013 | All Collected Deaths | on treatment death | 4 Participants |
| GP2013 | All Collected Deaths | on treatment deaths maintenance | 2 Participants |
| GP2013 | All Collected Deaths | all deaths | 29 Participants |
| Rituximab | All Collected Deaths | on treatment death | 5 Participants |
| Rituximab | All Collected Deaths | on treatment deaths maintenance | 2 Participants |
| Rituximab | All Collected Deaths | all deaths | 31 Participants |