Lymphoma, Follicular
Conditions
Keywords
Advanced Follicular Lymphoma
Brief summary
This study is a Phase 3 prospective, randomised, parallel-group, active controlled, double blind, multicentre, international study with 2 coprimary endpoints designed to demonstrate equivalence in pharmacokinetics (Part 1), as well as noninferiority in efficacy (Part 2), of CT-P10 to Rituxan when coadministered with CVP and to assess efficacy and safety in patients with advanced (stage III-IV) FL. Part 1 and Part 2 of the study will run in parallel.
Interventions
Sponsors
Celltrion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient is male or female older than 18 years. 2. Patient has histologically confirmed FL according to the World Health Organization 2008 classification (Jaffe 2009); grades 1 to 3a based on local laboratory review. 3. Patient has at least 1 measurable tumour mass that has not previously been irradiated, and the mass must be: * greater than 1.5 cm in the longest dimension or * between 1.1 and 1.5 cm in the longest dimension and greater than 1.0 cm in the shortest axis 4. Patient has confirmed CD20+ lymphoma, as assessed by local laboratory review. (Tissue obtained within 6 months before Day 1 of Cycle 1 will be reviewed by a central independent reviewer to detect pathological type.) 5. Patient has Ann Arbor stage III or IV disease.
Exclusion criteria
1. Patient has received rituximab (or a rituximab biosimilar), cyclophosphamide, or vincristine. 2. Patient has allergies or hypersensitivity to murine, chimeric, human or humanised proteins, cyclophosphamide, vincristine, or prednisone. 3. Patient has evidence of histological transformation to high-grade or diffuse large B-cell lymphoma. 4. Patient has known central nervous system involvement. 5. Patient has received previous treatment for NHL: * Previous treatment including chemotherapy, radiotherapy, immunotherapy, and/or surgery (except previous biopsy) * All doses of corticoid therapy for treatment of NHL * Corticoid therapy during the previous 4 weeks from Day 1 of Cycle 1 with prednisone \>20 mg per day for the treatment for any purpose
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration-time Curve at Steady State (AUCtau) | Core Cycle 4 (Week 12) | AUCtau: Area under the plasma drug concentration-time curve within a dosing interval at steady state. PK sampling was done at pre-dose and 1 hour after the end of infusion (EOI) at Core Cycles 1-3 and 5-8. At Core Cycle 4 (i.e. steady state), intensive PK samplings were done as follows: predose, EOI, 1 hour after EOI, 24 hour after EOI, 168 hour after EOI, 336 hour after EOI, 504 hour after EOI. Lastly, one sample at any time of the end of treatment (EOT) 1 visit was obtained. |
| Maximum Serum Concentration at Steady State (Cmax,ss) | Core Cycle 4 (Week 12) | Cmax,ss: Maximum concentration of drug in plasma at steady state on administering a fixed dose at equal dosing intervals. PK sampling was done at pre-dose and 1 hour after the end of infusion (EOI) at Core Cycles 1-3 and 5-8. At Core Cycle 4 (i.e. steady state), intensive PK samplings were done as follows: predose, EOI, 1 hour after EOI, 24 hour after EOI, 168 hour after EOI, 336 hour after EOI, 504 hour after EOI. Lastly, one sample at any time of the end of treatment (EOT) 1 visit was obtained. |
| Overall Response Rate (ORR) According to the 1999 International Working Group (IWG) Criteria | During the Core Study Period (up to 8 cycles; Week 24) | ORR was defined as the proportion of patients with the best response of complete response (CR), unconfirmed complete response (CRu), or partial response (PR) by central review. Per 1999 IWG criteria, the disease status was assessed by using contrasted CT, and CR, CRu, and PR were defined as followings; CR=Disappearance of all clinical/radiographic evidence of disease: regression of lymph nodes to normal size, absence of B-symptoms, bone marrow involvement, and organomegaly, and normal LDH level; CRu=Regression of measurable disease: \>=75% decrease in SPD of target lesions and in each target lesions. no increase in the size of non-target lesions, neither new lesion nor organomegaly measured; PR=Regression of measurable disease: \>=50% decrease in SPD of target lesions and no evidence of disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| B-cell Kinetics (B-cell Depletion and Recovery) | Cycles 1 to 8 during the Core Study Period | B-cell kinetics were demonstrated by median values of B-cell counts (Lower limit of quantification was 20 cells/uL). |
Participant flow
Pre-assignment details
A total of 184 participants were screened for the study. Of those, 44 participants failed screening and 140 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| CT-P10 Patient treated with CT-P10 (375 mg/m2 IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 \[max 2 mg\] IV), and prednisone 40 mg/m2 orally) up to 8 cycles every 3 weeks during the Core Study Period.
Patients having responses during Core Study Period treated with CT-P10 (375 mg/m2 IV) monotherapy up to 12 cycles every 2 months during the Maintenance Study Period. | 70 |
| Rituxan Patient treated with Rituxan (375 mg/m2 IV) in combination with cyclophosphamide (750 mg/m2 IV), vincristine (1.4 mg/m2 \[max 2 mg\] IV), and prednisone 40 mg/m2 orally) up to 8 cycles every 3 weeks during the Core Study Period.
Patients having responses during Core Study Period treated with Rituxan (375 mg/m2 IV) monotherapy up to 12 cycles every 2 months during the Maintenance Study Period. | 70 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Study Period (Part 2) | Adverse Event | 4 | 1 |
| Core Study Period (Part 2) | Death | 1 | 0 |
| Core Study Period (Part 2) | Physician Decision | 0 | 2 |
| Core Study Period (Part 2) | Progressive Disease | 2 | 3 |
| Core Study Period (Part 2) | Withdrawal by Subject | 1 | 2 |
| Maintenance Study Period (Part 2) | Adverse Event | 3 | 3 |
| Maintenance Study Period (Part 2) | Death | 2 | 1 |
| Maintenance Study Period (Part 2) | Progressive Disease | 11 | 13 |
| Maintenance Study Period (Part 2) | Protocol Violation | 0 | 1 |
| Maintenance Study Period (Part 2) | Stable Disease | 0 | 1 |
| Maintenance Study Period (Part 2) | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | CT-P10 | Rituxan | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years | 58.5 years | 57.5 years |
| Sex: Female, Male Female | 40 Participants | 37 Participants | 77 Participants |
| Sex: Female, Male Male | 30 Participants | 33 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 58 / 70 | 57 / 70 |
| serious Total, serious adverse events | 24 / 70 | 13 / 70 |
Outcome results
Primary
Area Under the Serum Concentration-time Curve at Steady State (AUCtau)
AUCtau: Area under the plasma drug concentration-time curve within a dosing interval at steady state. PK sampling was done at pre-dose and 1 hour after the end of infusion (EOI) at Core Cycles 1-3 and 5-8. At Core Cycle 4 (i.e. steady state), intensive PK samplings were done as follows: predose, EOI, 1 hour after EOI, 24 hour after EOI, 168 hour after EOI, 336 hour after EOI, 504 hour after EOI. Lastly, one sample at any time of the end of treatment (EOT) 1 visit was obtained.
Time frame: Core Cycle 4 (Week 12)
Population: Pharmacokinetic Population consisted of all patients who had at least 1 posttreatment PK concentration result after receiving at least 1 dose of study drug (CT-P10 or Rituxan) in Part 1. Patients considered outliers identified by a robust regression model (95% CI) were excluded from the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 | Area Under the Serum Concentration-time Curve at Steady State (AUCtau) | 41002.43 h*ug/mL | Standard Error 1.136 |
| Rituxan | Area Under the Serum Concentration-time Curve at Steady State (AUCtau) | 40099.08 h*ug/mL | Standard Error 1.143 |
Comparison: Equivalence in AUCtau between CT-P10 and Rituxan90% CI: [94.05, 111.17]ANCOVA
Primary
Maximum Serum Concentration at Steady State (Cmax,ss)
Cmax,ss: Maximum concentration of drug in plasma at steady state on administering a fixed dose at equal dosing intervals. PK sampling was done at pre-dose and 1 hour after the end of infusion (EOI) at Core Cycles 1-3 and 5-8. At Core Cycle 4 (i.e. steady state), intensive PK samplings were done as follows: predose, EOI, 1 hour after EOI, 24 hour after EOI, 168 hour after EOI, 336 hour after EOI, 504 hour after EOI. Lastly, one sample at any time of the end of treatment (EOT) 1 visit was obtained.
Time frame: Core Cycle 4 (Week 12)
Population: Pharmacokinetic Population consisted of all patients who had at least 1 posttreatment PK concentration result after receiving at least 1 dose of study drug (CT-P10 or Rituxan) in Part 1. Patients considered outliers identified by a robust regression model (95% CI) were excluded from the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 | Maximum Serum Concentration at Steady State (Cmax,ss) | 256.19 ug/mL | Standard Error 1.115 |
| Rituxan | Maximum Serum Concentration at Steady State (Cmax,ss) | 254.49 ug/mL | Standard Error 1.12 |
Comparison: Equivalence in Cmax,ss between CT-P10 and Rituxan90% CI: [93.84, 108]ANCOVA
Primary
Overall Response Rate (ORR) According to the 1999 International Working Group (IWG) Criteria
ORR was defined as the proportion of patients with the best response of complete response (CR), unconfirmed complete response (CRu), or partial response (PR) by central review. Per 1999 IWG criteria, the disease status was assessed by using contrasted CT, and CR, CRu, and PR were defined as followings; CR=Disappearance of all clinical/radiographic evidence of disease: regression of lymph nodes to normal size, absence of B-symptoms, bone marrow involvement, and organomegaly, and normal LDH level; CRu=Regression of measurable disease: \>=75% decrease in SPD of target lesions and in each target lesions. no increase in the size of non-target lesions, neither new lesion nor organomegaly measured; PR=Regression of measurable disease: \>=50% decrease in SPD of target lesions and no evidence of disease progression.
Time frame: During the Core Study Period (up to 8 cycles; Week 24)
Population: Efficacy population consisted of all patients who had at least 1 response evaluation after receiving at least 1 treatment cycle in the Core Study Period without any major protocol deviation that was relevant to the efficacy endpoint in Part 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CT-P10 | Overall Response Rate (ORR) According to the 1999 International Working Group (IWG) Criteria | 64 Participants |
| Rituxan | Overall Response Rate (ORR) According to the 1999 International Working Group (IWG) Criteria | 63 Participants |
Secondary
B-cell Kinetics (B-cell Depletion and Recovery)
B-cell kinetics were demonstrated by median values of B-cell counts (Lower limit of quantification was 20 cells/uL).
Time frame: Cycles 1 to 8 during the Core Study Period
Population: Pharmacodynamic (PD) population consisted of all patients who had at least 1 posttreatment PD result after receiving at least 1 dose of study drug (CT-P10 or Rituxan) without any major protocol deviation that was relevant to the PD endpoint in Part 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 7 (Predose) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 4 (Predose) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 2 (Predose) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 5 (Predose) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 1 (1 hour after the end of infusion) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 6 (Predose) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 3 (Predose) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 8 (Predose) | 20.0 cells/uL |
| CT-P10 | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 1 (Predose) | 92.5 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 8 (Predose) | 20.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 6 (Predose) | 20.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 1 (Predose) | 62.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 1 (1 hour after the end of infusion) | 20.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 2 (Predose) | 20.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 3 (Predose) | 20.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 4 (Predose) | 20.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 5 (Predose) | 20.0 cells/uL |
| Rituxan | B-cell Kinetics (B-cell Depletion and Recovery) | Core Cycle 7 (Predose) | 20.0 cells/uL |