Adenocarcinoma of Lung
Conditions
Brief summary
To demonstrate that CT-P16 is similar to EU-Approved Avastin in terms of efficacy as determined by objective response rate (ORR) during the Induction Study Period
Interventions
DRUGCT-P16
15mg/kg IV of CT-P16 every 3 weeks up to 6 cycles in the induction study period and every 3 weeks until PD occurs in the maintenance study period.
DRUGAvastin
15mg/kg IV of Avastin every 3 weeks up to 6 cycles in the induction study period and every 3 weeks until PD occurs in the maintenance study period.
Sponsors
Celltrion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* diagnosed as recurrent disease or stage IV * has at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumor (RECIST) Version 1.1
Exclusion criteria
* has predominantly squamous cell histology non-small cell lung cancer * had surgery for metastatic non-squamous non-small cell lung cancer (nsNSCLC)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) During the Induction Study Period From Central Review | Induction Study Period (around 18 weeks) | The ORR was defined as the proportion of patients with a confirmed Best Overall Response (BOR) of CR or PR (the 'responder'). All other patients except responders were considered as non-responders, including patients without post-baseline tumor assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression From Central Review | Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months. | Time to progression was defined as time from randomization to determined PD/recurrence. |
| Progression Free Survival From Central Review | Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months. | Progression-free survival was defined as time from randomization to determined PD/recurrence or death from any cause, whichever occurs first. |
| Response Duration From Central Review | Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months. | Response duration was defined as time between initial response (CR or PR) that is confirmed by the subsequent assessment after study treatment administration and PD/recurrence or death from any cause, whichever occurs first. |
| Trough Serum Concentrations During the Induction Study Period | Induction Study Period. Pharmacokinetic samples were collected on Day 1 of each cycle in Induction Study Period. | Pharmacokinetic samples were collected on Day 1 of each cycle (prior to the beginning of the study drug administration) in the Induction Study Period. |
| Patients With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) at Anytime During the Whole Study Period | Immunogenicity was assessed Day 1 of Cycle 1 (predose), every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, EOT visit, and at the first visit of Follow-up period. | Immunogenicity was assessed on Day 1 of Cycle 1 (pre-dose), every 2 cycles during the Induction Study Period, and every 3 cycles during the Maintenance Study Period and End of Treatment (EOT) visit. In the Follow-Up Period, immunogenicity was assessed once at the first visit of the Follow-Up Period (ninth week). |
| Overall Survival | Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months. | Overall survival was defined as time from randomization to death from any cause. |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CT-P16 Drug: Bevacizumab 15mg/kg IV of CT-P16 will be administered every 3 weeks up to 6 cycles during the Induction Study Period and every 3 weeks until PD or intolerable toxicity during the Maintenance Period.
CT-P16: 15mg/kg IV of CT-P16 every 3 weeks up to 6 cycles in the induction study period and every 3 weeks until PD occurs in the maintenance study period. | 342 |
| Avastin Drug: Bevacizumab 15mg/kg IV of EU-approved Avastin will be administered every 3 weeks up to 6 cycles during the Induction Study Period and every 3 weeks until PD or intolerable toxicity during the Maintenance Period.
Avastin: 15mg/kg IV of Avastin every 3 weeks up to 6 cycles in the induction study period and every 3 weeks until PD occurs in the maintenance study period. | 347 |
| Total | 689 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Induction Study Period | Adverse Event | 21 | 20 |
| Induction Study Period | Death | 23 | 20 |
| Induction Study Period | Lost to Follow-up | 3 | 3 |
| Induction Study Period | Physician Decision | 6 | 3 |
| Induction Study Period | Progressive Disease | 32 | 21 |
| Induction Study Period | Protocol Violation | 1 | 2 |
| Induction Study Period | Withdrawal by Subject | 20 | 15 |
Baseline characteristics
| Characteristic | Avastin | Total | CT-P16 |
|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 9.42 | 61.4 years STANDARD_DEVIATION 9.21 | 61.3 years STANDARD_DEVIATION 9.01 |
| Disease Status Metastatic | 314 Participants | 631 Participants | 317 Participants |
| Disease Status Recurrent | 33 Participants | 58 Participants | 25 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 110 Participants | 215 Participants | 105 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 237 Participants | 474 Participants | 237 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 9 Participants | 18 Participants | 9 Participants |
| Race/Ethnicity, Customized Asian | 55 Participants | 114 Participants | 59 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 18 Participants | 26 Participants | 8 Participants |
| Race/Ethnicity, Customized White or Caucasian | 264 Participants | 528 Participants | 264 Participants |
| Sex: Female, Male Female | 125 Participants | 244 Participants | 119 Participants |
| Sex: Female, Male Male | 222 Participants | 445 Participants | 223 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 24 / 345 | 25 / 344 |
| other Total, other adverse events | 332 / 345 | 320 / 344 |
| serious Total, serious adverse events | 69 / 345 | 73 / 344 |
Outcome results
Primary
Objective Response Rate (ORR) During the Induction Study Period From Central Review
The ORR was defined as the proportion of patients with a confirmed Best Overall Response (BOR) of CR or PR (the 'responder'). All other patients except responders were considered as non-responders, including patients without post-baseline tumor assessment.
Time frame: Induction Study Period (around 18 weeks)
Population: Intent-to-Treat (ITT) population: All randomized patients who were randomly assigned to study drug regardless of whether or not any study treatment dosing was completed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT-P16 | Objective Response Rate (ORR) During the Induction Study Period From Central Review | 42.40 percentage of responders |
| Avastin | Objective Response Rate (ORR) During the Induction Study Period From Central Review | 42.07 percentage of responders |
Comparison: Logistic regression model including treatment groups (CT-P16 and EU-approved Avastin) as a fixed effect and region (EMEA vs. America vs. Asia), sex (female vs. male), disease status at baseline (recurrence vs. metastatic), and ECOG performance score at baseline (0 vs. 1) as covariates was used.95% CI: [-7.02, 7.83]
Comparison: Log-binomial regression model including treatment groups (CT-P16 and EU-approved Avastin) as a fixed effect and region (EMEA vs. America vs. Asia), sex (female vs. male), disease status at baseline (recurrence vs. metastatic), and ECOG performance score at baseline (0 vs. 1) as covariates was used.90% CI: [0.8767, 1.1719]
Secondary
Overall Survival
Overall survival was defined as time from randomization to death from any cause.
Time frame: Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months.
Population: ITT population: All randomized patients who were randomly assigned to study drug regardless of whether or not any study treatment dosing was completed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P16 | Overall Survival | 12 months | 0.66 Proportion of participants |
| CT-P16 | Overall Survival | 24 months | 0.35 Proportion of participants |
| CT-P16 | Overall Survival | 36 months | 0.19 Proportion of participants |
| Avastin | Overall Survival | 12 months | 0.62 Proportion of participants |
| Avastin | Overall Survival | 24 months | 0.34 Proportion of participants |
| Avastin | Overall Survival | 36 months | 0.21 Proportion of participants |
Comparison: Adjusted stratified Cox regression model is used to estimate the hazard ratio and its 95% CI for receiving CT-P16 compared with receiving EU-approved Avastin using region (EMEA vs. America vs. Asia), sex (female vs. male), disease status at baseline (recurrence vs. metastatic), and ECOG performance score at baseline (0 vs. 1) as stratification factors.95% CI: [0.77, 1.19]
Secondary
Patients With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) at Anytime During the Whole Study Period
Immunogenicity was assessed on Day 1 of Cycle 1 (pre-dose), every 2 cycles during the Induction Study Period, and every 3 cycles during the Maintenance Study Period and End of Treatment (EOT) visit. In the Follow-Up Period, immunogenicity was assessed once at the first visit of the Follow-Up Period (ninth week).
Time frame: Immunogenicity was assessed Day 1 of Cycle 1 (predose), every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, EOT visit, and at the first visit of Follow-up period.
Population: Safety Population: all randomly assigned patients who received at least 1 dose (partial or full) of study drug (CT-P16 or Avastin). Patients receiving at least 1 dose of CT-P16 at any time of during the treatment period were analyzed under the CT-P16 treatment group. Three patients who were randomized to Avastin treatment group were analyzed under the CT-P16 treatment group since the patients incorrectly received CT-P16 during the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P16 | Patients With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) at Anytime During the Whole Study Period | Subject with at least 1 positive ADA result after the first infusion | 81 participants |
| CT-P16 | Patients With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) at Anytime During the Whole Study Period | Patients with at least 1 positive NAb result after the first infusion | 12 participants |
| Avastin | Patients With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) at Anytime During the Whole Study Period | Subject with at least 1 positive ADA result after the first infusion | 90 participants |
| Avastin | Patients With Positive Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) at Anytime During the Whole Study Period | Patients with at least 1 positive NAb result after the first infusion | 11 participants |
Secondary
Progression Free Survival From Central Review
Progression-free survival was defined as time from randomization to determined PD/recurrence or death from any cause, whichever occurs first.
Time frame: Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months.
Population: ITT population: All randomized patients who were randomly assigned to study drug regardless of whether or not any study treatment dosing was completed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P16 | Progression Free Survival From Central Review | 6 months | 0.73 Proportion of participants |
| CT-P16 | Progression Free Survival From Central Review | 12 months | 0.23 Proportion of participants |
| CT-P16 | Progression Free Survival From Central Review | 24 months | 0.08 Proportion of participants |
| CT-P16 | Progression Free Survival From Central Review | 36 months | 0.06 Proportion of participants |
| Avastin | Progression Free Survival From Central Review | 36 months | 0.04 Proportion of participants |
| Avastin | Progression Free Survival From Central Review | 6 months | 0.71 Proportion of participants |
| Avastin | Progression Free Survival From Central Review | 24 months | 0.09 Proportion of participants |
| Avastin | Progression Free Survival From Central Review | 12 months | 0.28 Proportion of participants |
Comparison: Adjusted stratified Cox regression model is used to estimate the hazard ratio and its 95% CI for receiving CT-P16 compared with receiving EU-approved Avastin using region (EMEA vs. America vs. Asia), sex (female vs. male), disease status at baseline (recurrence vs. metastatic), and ECOG performance score at baseline (0 vs. 1) as stratification factors.95% CI: [0.77, 1.1]
Secondary
Response Duration From Central Review
Response duration was defined as time between initial response (CR or PR) that is confirmed by the subsequent assessment after study treatment administration and PD/recurrence or death from any cause, whichever occurs first.
Time frame: Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months.
Population: Patients who have confirmed BOR of CR or PR from ITT population (All randomized patients who were randomly assigned to study drug regardless of whether or not any study treatment dosing was completed).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P16 | Response Duration From Central Review | 6 months | 0.60 Proportion of participants |
| CT-P16 | Response Duration From Central Review | 12 months | 0.17 Proportion of participants |
| CT-P16 | Response Duration From Central Review | 24 months | 0.09 Proportion of participants |
| CT-P16 | Response Duration From Central Review | 36 months | 0.08 Proportion of participants |
| Avastin | Response Duration From Central Review | 36 months | 0.06 Proportion of participants |
| Avastin | Response Duration From Central Review | 6 months | 0.56 Proportion of participants |
| Avastin | Response Duration From Central Review | 24 months | 0.10 Proportion of participants |
| Avastin | Response Duration From Central Review | 12 months | 0.25 Proportion of participants |
Secondary
Time to Progression From Central Review
Time to progression was defined as time from randomization to determined PD/recurrence.
Time frame: Tumor assessments were assessed every 2 cycles during the Induction Study Period, every 3 cycles during the Maintenance Study Period, and at the EOT visit. The median follow-up time from randomization was 12.86 months.
Population: ITT population: All randomized patients who were randomly assigned to study drug regardless of whether or not any study treatment dosing was completed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P16 | Time to Progression From Central Review | 6 months | 0.83 Proportion of participants |
| CT-P16 | Time to Progression From Central Review | 12 months | 0.29 Proportion of participants |
| CT-P16 | Time to Progression From Central Review | 24 months | 0.11 Proportion of participants |
| CT-P16 | Time to Progression From Central Review | 36 months | 0.10 Proportion of participants |
| Avastin | Time to Progression From Central Review | 36 months | 0.06 Proportion of participants |
| Avastin | Time to Progression From Central Review | 6 months | 0.81 Proportion of participants |
| Avastin | Time to Progression From Central Review | 24 months | 0.11 Proportion of participants |
| Avastin | Time to Progression From Central Review | 12 months | 0.34 Proportion of participants |
Secondary
Trough Serum Concentrations During the Induction Study Period
Pharmacokinetic samples were collected on Day 1 of each cycle (prior to the beginning of the study drug administration) in the Induction Study Period.
Time frame: Induction Study Period. Pharmacokinetic samples were collected on Day 1 of each cycle in Induction Study Period.
Population: Pharmacokinetic (PK) population: all randomly assigned patients who received at least 1 full dose of study drug (CT-P16 or Avastin) and who had at least 1 post-treatment PK result. Patients who received incorrect treatment during the Induction Study Period were excluded from the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CT-P16 | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 1 | 50426.3 μg/L | Standard Deviation 39847.34 |
| CT-P16 | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 2 | 73127.7 μg/L | Standard Deviation 35883.59 |
| CT-P16 | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 3 | 93100.6 μg/L | Standard Deviation 50495.29 |
| CT-P16 | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 4 | 96445.2 μg/L | Standard Deviation 45597.95 |
| CT-P16 | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 5 | 108957.3 μg/L | Standard Deviation 55135.16 |
| CT-P16 | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 6 | 116188.2 μg/L | Standard Deviation 58735.47 |
| Avastin | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 5 | 108512.5 μg/L | Standard Deviation 49823.61 |
| Avastin | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 1 | 52515.7 μg/L | Standard Deviation 32356.13 |
| Avastin | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 4 | 101583.1 μg/L | Standard Deviation 46275.62 |
| Avastin | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 2 | 81533.7 μg/L | Standard Deviation 52567.34 |
| Avastin | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 6 | 114849.6 μg/L | Standard Deviation 56309.7 |
| Avastin | Trough Serum Concentrations During the Induction Study Period | Induction Cycle 3 | 95878.8 μg/L | Standard Deviation 53977.69 |