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Evaluation of FKB238 and Avastin in Patients With Advanced/Recurrent Non-squamous Non-small Cell Lung Cancer (AVANA)

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ClinicalTrials.gov Identifier: NCT02810457
Recruitment Status : Active, not recruiting
First Posted : June 23, 2016
Results First Posted : March 19, 2020
Last Update Posted : March 19, 2020
Sponsor:
Information provided by (Responsible Party):
Centus Biotherapeutics Limited

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Carcinoma, Non-Small-Cell Lung
Interventions Drug: FKB238 (bevacizumab)
Drug: Avastin (bevacizumab)
Drug: Paclitaxel
Drug: Carboplatin
Enrollment 731
Recruitment Details Screening occurred at 146 centers in 24 countries (randomized at 136 centers, 24 countries) in Belarus, Bosnia & Herzegovina, Bulgaria, Croatia, Georgia, Germany, Greece, Hungary, Italy, Japan, South Korea, Peru, Philippines, Poland, Romania, Russia, Serbia, Spain, Taiwan, Thailand, Turkey, Ukraine, US and Vietnam. No screening occurred in Canada.
Pre-assignment Details Of a total of 1023 patients who signed informed consent and were screened, 292 patients were not randomized. Of the 731 randomized patients, 2 patients were randomized in error and never received any study treatment, and 1 patient was randomized but withdrew consent prior to receiving any study treatment.
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

Area under the curve (AUC) = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Period Title: Overall Study
Started 364 [1] 367 [2]
Completed [3] 37 38
Not Completed 327 329
Reason Not Completed
Randomised but no treatment received             2             1
Objective PD assessed by RECIST v1.1             191             199
Adverse Event             37             43
Patient decision             31             35
Patient lost to follow-up             2             2
Death             39             28
Ongoing at data cutoff and discontinued             3             2
Clinical progression             15             16
Investigator decision             3             2
Patient ineligibility             3             0
Miscalculated PD             1             0
Physician Decision             0             1
[1]
362 patients received study treatment
[2]
366 patients received study treatment
[3]
Patients still in the study at DCO
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin Total
Hide Arm/Group Description

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Total of all reporting groups
Overall Number of Baseline Participants 364 367 731
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 364 participants 367 participants 731 participants
Adults (18-64 years)
238
  65.4%
224
  61.0%
462
  63.2%
From 65-84 years
126
  34.6%
143
  39.0%
269
  36.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 364 participants 367 participants 731 participants
Female
119
  32.7%
129
  35.1%
248
  33.9%
Male
245
  67.3%
238
  64.9%
483
  66.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 364 participants 367 participants 731 participants
White
316
  86.8%
320
  87.2%
636
  87.0%
Black and African American
1
   0.3%
0
   0.0%
1
   0.1%
Asian, other than Japanese
37
  10.2%
37
  10.1%
74
  10.1%
Japanese
2
   0.5%
3
   0.8%
5
   0.7%
American Indian or Alaska Native
1
   0.3%
4
   1.1%
5
   0.7%
Other
7
   1.9%
3
   0.8%
10
   1.4%
1.Primary Outcome
Title Overall Response Rate (ORR) Assessed as the Proportion of Patients With a Best Overall Response (BOR) of Either Complete Response (CR) or Partial Response (PR)
Hide Description The primary variable in this study was ORR, defined as the proportion of patients with a BOR of CR or PR (by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)). A BOR was defined as the best response (in the order of CR, PR, stable disease (SD), no evidence of disease (NED), progressive disease (PD), and not evaluable (NE)) among all post-baseline disease assessments that occurred until progression, or last evaluable assessment in the absence of progression prior to the initiation of subsequent anti-cancer therapy, irrespective of whether or not patients discontinued the study treatment. The 95% Pearson-Clopper confidence interval (CI) of ORR for each treatment arm was provided. Per RECIST v1.1 for target lesions and assessed by computed tomography (CT) or, if contraindicated, magnetic resonance imaging (MRI): CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions. Overall Response=CR+PR.
Time Frame Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.
Hide Outcome Measure Data
Hide Analysis Population Description
In order to meet the Food and Drug Administration (FDA) requirement, the primary efficacy analysis of ORR was performed using the Intent-to-Treat (ITT) population (patients included in each treatment arm as randomized), and the blinded independent central review (BICR) radiological assessments.
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 364 367
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
51.6
(46.38 to 56.89)
53.7
(48.43 to 58.87)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments A 90% CI for the ORR ratio between FKB238 and Avastin was estimated and compared to the margin (0.73 to 1.38), which was deemed to represent a clinically acceptable difference with respect to ORR. If the 90% CI was within the equivalence margin (0.73 to 1.38), an equivalence between FKB238 and Avastin, with respect to the ORR, was confirmed.
Method of Estimation Estimation Parameter Ratio in ORR
Estimated Value 0.96
Confidence Interval (2-Sided) 90%
0.86 to 1.08
Estimation Comments [Not Specified]
2.Secondary Outcome
Title ORR at Week 19
Hide Description ORR (by RECIST v1.1) at Week 19 was defined as the proportion of patients with a BOR of CR or PR assessed at Week 19. Only tumor assessments performed up until 19 weeks (i.e. Week 18 assessment + 7 day assessment window) from randomization were considered in this analysis. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions. Overall Response=CR+PR.
Time Frame From the date of randomization up to Week 19.
Hide Outcome Measure Data
Hide Analysis Population Description
In order to meet the FDA requirement, the secondary efficacy analysis of ORR was performed using the ITT population (patients included in each treatment arm as randomized), and the BICR radiological assessments.
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 364 367
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
47.8
(42.57 to 53.07)
51.0
(45.71 to 56.18)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
Comments Comparison between groups: Risk ratio in ORR at Week 19 by BICR.
Type of Statistical Test Other
Comments Ratio in ORR analysis of FKB238 versus Avastin.
Method of Estimation Estimation Parameter Ratio in ORR
Estimated Value 0.94
Confidence Interval (2-Sided) 90%
0.83 to 1.06
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description The event of interest for PFS was defined as the interval from the date of randomization until first documented disease progression or death from any cause, whichever occurs first. Disease progression was based on tumor assessments according to RECIST v1.1 criteria. The items of the overall response CR, PR, SD and NED were taken as progression-free whereas PD denoted disease progression. PFS was summarized using Kaplan-Meier estimates of the quartiles for each treatment arm, and 95% CIs for the medians were calculated. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: PD=at least a 20% increase in the sum of the longest diameter of target lesions, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.
Time Frame Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.
Hide Outcome Measure Data
Hide Analysis Population Description
This assessment was performed using the ITT population (patients included in each treatment arm as randomized) and the BICR radiological assessments.
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 364 367
Median (95% Confidence Interval)
Unit of Measure: Months
7.72
(7.46 to 7.98)
7.62
(6.90 to 7.82)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
Comments Hazard ratio and its 95% CI were calculated using the Cox regression model adjusting for baseline characteristics (randomization stratification factors, Eastern Cooperative Oncology Group (ECOG) performance status at baseline, gender, smoking history and age) with ties handled by the Efron method.
Type of Statistical Test Other
Comments Hazard ratio analysis of FKB238 versus Avastin.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.82 to 1.16
Estimation Comments Treatment hazard ratio <1 favors FKB238.
4.Secondary Outcome
Title Overall Survival (OS)
Hide Description The event of interest was defined as death from any cause. OS was defined as the interval from date of randomization until the date of death due to any cause. OS was summarized using Kaplan-Meier estimates of the quartiles for each treatment arm, and 95% CIs for the medians were calculated.
Time Frame Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.
Hide Outcome Measure Data
Hide Analysis Population Description
This assessment was performed using the ITT population (patients included in each treatment arm as randomized).
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 364 367
Median (95% Confidence Interval)
Unit of Measure: Months
14.13
(12.52 to 16.56)
16.95
(14.65 to 19.02)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
Comments Hazard ratio and its 95% CI were calculated using the Cox regression model adjusting for baseline characteristics (randomization stratification factors, ECOG performance status at baseline, gender, smoking history and age) with ties handled by the Efron method.
Type of Statistical Test Other
Comments Hazard ratio analysis of FKB238 versus Avastin.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.18
Confidence Interval (2-Sided) 95%
0.96 to 1.45
Estimation Comments Treatment hazard ratio <1 favors FKB238.
5.Secondary Outcome
Title Duration Of Response (DOR)
Hide Description DOR was evaluated in this study as a secondary efficacy endpoint. Only the patients defined as responders in the primary analysis of ORR were taken into account for the analysis of DOR. The event of interest was defined as first documented disease progression or death due to any reason, whichever occurred first. DOR was defined as the interval from the first documented response (as defined per RECIST v1.1) until the earlier date of the first documented disease progression or death due to any reason. The date of first documented response was taken as the date of the first tumor assessment with an overall visit response of CR or PR. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions. DOR was calculated in units of months.
Time Frame Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.
Hide Outcome Measure Data
Hide Analysis Population Description
This assessment of DOR was based on patients with events in the ITT population (patients included in each treatment arm as randomized), and the BICR radiological assessments.
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 188 197
Median (95% Confidence Interval)
Unit of Measure: months
6.47
(5.39 to 7.69)
6.31
(4.93 to 7.29)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
Comments Hazard ratio and its 95% CI were calculated using the Cox regression model adjusting for baseline characteristics (randomization stratification factors, ECOG performance status at baseline, gender, smoking history and age) with ties handled by the Efron method.
Type of Statistical Test Other
Comments Hazard ratio analysis of FKB238 versus Avastin.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.74 to 1.23
Estimation Comments Treatment hazard ratio <1 favors FKB238.
6.Secondary Outcome
Title Disease Control Rate (DCR) Assessed as the Proportion of Patients With a BOR of Either CR, PR, SD or NED
Hide Description The DCR was defined as the proportion of patients defined as responders. The number and percentage of responders and non-responders and the 95% Pearson-Clopper CI of DCR for each treatment arm was provided. The odds ratio for treatment (FKB238 arm versus Avastin arm) and the corresponding 95% Wald CI were produced based on a logistic regression analysis of DCR. Per RECIST v1.1 for target lesions and assessed by CT or, if contraindicated, MRI: CR=disappearance of all target lesions; PR=at least 30% decrease from baseline in the sum of diameters of target lesions; SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. DCR=CR+PR+SD (≥ 6 weeks).
Time Frame Until data cut-off, which occurred 12 months after randomization of the last patient enrolled, for a total estimated period of time of up to approximately 30 months.
Hide Outcome Measure Data
Hide Analysis Population Description
This assessment of DCR was based on patients in the ITT population (patients included in each treatment arm as randomized), and the BICR radiological assessments.
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 364 367
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants with response
87.6
(83.81 to 90.84)
87.5
(83.64 to 90.68)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
Comments The DCR was compared between treatment arms using logistic regression adjusting for baseline characteristics (randomization stratification factors, ECOG performance status at baseline, gender, smoking history and age).
Type of Statistical Test Other
Comments Comparison between arms: Odds ratio.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.64 to 1.58
Estimation Comments Odds ratio >1 favors FKB238.
7.Other Pre-specified Outcome
Title Serum Trough Concentration (Ctrough)
Hide Description Ctrough (pre-infusion) and serum maximum concentration (Cmax; at completion of infusion) were compared between treatment arms and time points, and descriptive statistics provided. Ctrough and Cmax concentrations were summarized using the pharmacokinetics (PK) population for each visit at which samples were taken. The pre-dose serum concentrations at Cycles 2, 4, and 6 were considered as Ctrough values and the post-dose serum concentrations at Cycles 1 and 4 were considered as Cmax values. PK data at Cycle 1 Day 1 pre-infusion were not calculable and are therefore not presented in the outcome measure data table. Data are only provided for the time points at which the serum trough concentration was measured.
Time Frame Cycle 1 Day 1 (pre- and post-infusion), Cycle 2 Day 1 (pre), Cycle 4 Day 1 (pre and post), Cycle 6 Day 1 (pre), discontinuation visit, and every 12 weeks (up to 1 year [±14 days] after randomisation) until death, or the patient was lost to follow-up.
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized to treatment who received at least 1 dose of investigational product with no important protocol deviations, and at least 1 serum drug concentration data after investigational product administration (PK population).
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 345 351
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ug/ml
Cycle 1, Day 1 end of infusion Number Analyzed 343 participants 347 participants
255.15
(184.3%)
245.11
(206.8%)
Cycle 2, Day 1 pre-infusion Number Analyzed 325 participants 327 participants
42.74
(91.9%)
48.48
(77.3%)
Cycle 4, Day 1 pre-infusion Number Analyzed 280 participants 284 participants
77.16
(69.4%)
83.26
(85.5%)
Cycle 4, Day 1 end of infusion Number Analyzed 278 participants 283 participants
339.91
(91.3%)
373.92
(51.6%)
Cycle 6, Day 1 pre-infusion Number Analyzed 247 participants 253 participants
87.25
(124.5%)
108.22
(69.8%)
8.Other Pre-specified Outcome
Title Proportion of Patients Developing Anti-drug Antibodies (ADAs)
Hide Description The ADA levels were summarized at baseline and post-baseline time points using descriptive statistics.
Time Frame Pre-dose at Cycles 1, 2, 4 and 6, discontinuation visit, and every 12 weeks (up to 1 year [±14 days] after randomisation) until death, or the patient was lost to follow-up, whichever occurred first.
Hide Outcome Measure Data
Hide Analysis Population Description
Includes all patients randomized to treatment who received at least 1 dose of investigational product with no important protocol deviations, and who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result (ADA evaluable population).
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Hide Arm/Group Description:

Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

Overall Number of Participants Analyzed 305 305
Measure Type: Number
Unit of Measure: percentage of participants
ADA prevalence (ADA positive, baseline or post) 3.0 3.0
Treatment-emergent ADA positive (ADA incidence) 2.3 2.3
9.Other Pre-specified Outcome
Title Adverse Events (AEs)
Hide Description [Not Specified]
Time Frame From the time of signature of informed consent, throughout the treatment period and up to and including the 30-days after the last dose of study treatment, for a total estimated period of time of up to approximately 30 months.
Outcome Measure Data Not Reported
10.Other Pre-specified Outcome
Title Vital Signs
Hide Description [Not Specified]
Time Frame Up to approximately 30 days after last dose of study treatment.
Outcome Measure Data Not Reported
11.Other Pre-specified Outcome
Title Hematology
Hide Description [Not Specified]
Time Frame Up to approximately 30 days after last dose of study treatment.
Outcome Measure Data Not Reported
12.Other Pre-specified Outcome
Title Clinical Chemistry
Hide Description [Not Specified]
Time Frame Up to approximately 30 days after last dose of study treatment.
Outcome Measure Data Not Reported
13.Other Pre-specified Outcome
Title Urinalysis
Hide Description [Not Specified]
Time Frame Up to approximately 30 days after last dose of study treatment.
Outcome Measure Data Not Reported
14.Other Pre-specified Outcome
Title Electrocardiogram
Hide Description [Not Specified]
Time Frame Up to approximately 30 days after last dose of study treatment.
Outcome Measure Data Not Reported
15.Other Pre-specified Outcome
Title Eastern Collaborative Oncology Group Performance Status
Hide Description [Not Specified]
Time Frame Up to approximately 30 days after last dose of study treatment.
Outcome Measure Data Not Reported
16.Other Pre-specified Outcome
Title Physical Examination
Hide Description [Not Specified]
Time Frame Up to approximately 30 days after last dose of study treatment.
Outcome Measure Data Not Reported
Time Frame From the time of signature of informed consent, throughout the treatment period and up to and including the 30-days after the last dose of study treatment, for a total estimated period of time of up to approximately 30 months. All ongoing and any new AEs/serious AEs (SAEs) identified during the 30 days after last dose were followed to resolution unless the event was considered by the investigator to be unlikely to resolve, or if the patient was lost to follow-up.
Adverse Event Reporting Description All safety summaries and analyses were based on the Safety Population. Adverse events (AEs) were coded using the latest Medical Dictionary for Regulatory Activities(MedDRA) version (21.1). AEs were categorized as treatment-emergent AEs. Intensity of AEs was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 grading system.
 
Arm/Group Title FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
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Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

FKB238 (bevacizumab)

Paclitaxel

Carboplatin

Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Avastin (bevacizumab)

Paclitaxel

Carboplatin

All-Cause Mortality
FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Affected / at Risk (%) Affected / at Risk (%)
Total   195/362 (53.87%)      177/366 (48.36%)    
Hide Serious Adverse Events
FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   91/362 (25.14%)      95/366 (25.96%)    
Blood and lymphatic system disorders     
Anaemia  1  5/362 (1.38%)  5 9/366 (2.46%)  10
Febrile neutropenia  1  7/362 (1.93%)  7 5/366 (1.37%)  5
Neutropenia  1  7/362 (1.93%)  8 18/366 (4.92%)  19
Pancytopenia  1  0/362 (0.00%)  0 2/366 (0.55%)  2
Thrombocytopenia  1  2/362 (0.55%)  2 2/366 (0.55%)  2
Cardiac disorders     
Acute coronary syndrome  1  3/362 (0.83%)  3 1/366 (0.27%)  1
Acute myocardial infarction  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Atrial fibrillation  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Cardiac disorder  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Cardio-respiratory arrest  1  2/362 (0.55%)  2 0/366 (0.00%)  0
Cor pulmonale  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Myocardial infarction  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Supraventricular tachycardia  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Tachyarrhythmia  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Endocrine disorders     
Adrenal insufficiency  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Gastrointestinal disorders     
Diarrhoea  1  1/362 (0.28%)  1 3/366 (0.82%)  3
Diverticulum intestinal haemorrhagic  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Dyspepsia  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Enterocolitis  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Gastric haemorrhage  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Gastrointestinal haemorrhage  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Haematemesis  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Ileal perforation  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Rectal haemorrhage  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Small intestinal obstruction  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Small intestinal perforation  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Stomatitis  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Upper gastrointestinal haemorrhage  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Vomiting  1  3/362 (0.83%)  3 2/366 (0.55%)  2
General disorders     
Asthenia  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Death  1  5/362 (1.38%)  5 3/366 (0.82%)  3
Fatigue  1  1/362 (0.28%)  1 0/366 (0.00%)  0
General physical health deterioration  1  1/362 (0.28%)  1 2/366 (0.55%)  2
Mucosal inflammation  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Oedema peripheral  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Pyrexia  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Sudden death  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Hepatobiliary disorders     
Cholecystitis  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Cholelithiasis  1  0/362 (0.00%)  0 2/366 (0.55%)  2
Drug-induced liver injury  1  1/362 (0.28%)  1 1/366 (0.27%)  1
Immune system disorders     
Hypersensitivity  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Infections and infestations     
Cellulitis  1  0/362 (0.00%)  0 2/366 (0.55%)  2
Empyema  1  1/362 (0.28%)  1 1/366 (0.27%)  1
Liver abscess  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Lung infection  1  2/362 (0.55%)  2 1/366 (0.27%)  1
Peritonitis  1  1/362 (0.28%)  1 1/366 (0.27%)  1
Pneumonia  1  10/362 (2.76%)  12 9/366 (2.46%)  10
Pneumonia fungal  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Pseudomonal sepsis  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Sepsis  1  0/362 (0.00%)  0 2/366 (0.55%)  2
Septic shock  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Tuberculosis  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Injury, poisoning and procedural complications     
Femur fracture  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Hip fracture  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Spinal fracture  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Upper limb fracture  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Investigations     
Neutrophil count decreased  1  3/362 (0.83%)  4 2/366 (0.55%)  2
Platelet count decreased  1  1/362 (0.28%)  1 1/366 (0.27%)  1
White blood cell count decreased  1  2/362 (0.55%)  2 2/366 (0.55%)  2
Metabolism and nutrition disorders     
Hypocalcaemia  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Hyponatraemia  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Musculoskeletal and connective tissue disorders     
Back pain  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Pathological fracture  1  0/362 (0.00%)  0 2/366 (0.55%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Metastases to bone  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Thyroid cancer  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Nervous system disorders     
Cerebral arteriosclerosis  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Cerebral atrophy  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Cerebrovascular accident  1  2/362 (0.55%)  2 3/366 (0.82%)  3
Dizziness  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Epilepsy  1  2/362 (0.55%)  2 0/366 (0.00%)  0
Facial paresis  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Guillain-Barre syndrome  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Haemorrhagic stroke  1  1/362 (0.28%)  1 1/366 (0.27%)  1
Ischaemic stroke  1  0/362 (0.00%)  0 1/366 (0.27%)  2
Polyneuropathy  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Posterior reversible encephalopathy syndrome  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Presyncope  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Seizure  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Transient ischaemic attack  1  1/362 (0.28%)  1 1/366 (0.27%)  1
Uraemic encephalopathy  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Renal and urinary disorders     
Acute kidney injury  1  1/362 (0.28%)  1 2/366 (0.55%)  2
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Acute respiratory failure  1  2/362 (0.55%)  2 0/366 (0.00%)  0
Dyspnoea  1  2/362 (0.55%)  2 3/366 (0.82%)  3
Haemoptysis  1  2/362 (0.55%)  2 0/366 (0.00%)  0
Oesophagobronchial fistula  1  2/362 (0.55%)  2 0/366 (0.00%)  0
Pleural effusion  1  1/362 (0.28%)  2 0/366 (0.00%)  0
Pneumonia aspiration  1  2/362 (0.55%)  2 0/366 (0.00%)  0
Pneumothorax  1  0/362 (0.00%)  0 4/366 (1.09%)  4
Pulmonary embolism  1  6/362 (1.66%)  6 5/366 (1.37%)  5
Pulmonary fibrosis  1  1/362 (0.28%)  1 0/366 (0.00%)  0
Pulmonary haemorrhage  1  3/362 (0.83%)  4 1/366 (0.27%)  1
Pulmonary mass  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Pulmonary oedema  1  2/362 (0.55%)  2 0/366 (0.00%)  0
Respiratory failure  1  1/362 (0.28%)  1 3/366 (0.82%)  3
Vascular disorders     
Deep vein thrombosis  1  0/362 (0.00%)  0 1/366 (0.27%)  1
Hypertension  1  2/362 (0.55%)  2 1/366 (0.27%)  1
Hypertensive crisis  1  0/362 (0.00%)  0 2/366 (0.55%)  2
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
FKB238 / Paclitaxel / Carboplatin Avastin / Paclitaxel / Carboplatin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   341/362 (94.20%)      348/366 (95.08%)    
Blood and lymphatic system disorders     
Anaemia  1  105/362 (29.01%)  135 119/366 (32.51%)  146
Leukopenia  1  43/362 (11.88%)  58 50/366 (13.66%)  89
Neutropenia  1  109/362 (30.11%)  163 145/366 (39.62%)  212
Thrombocytopenia  1  44/362 (12.15%)  78 66/366 (18.03%)  102
Gastrointestinal disorders     
Constipation  1  19/362 (5.25%)  23 21/366 (5.74%)  23
Diarrhoea  1  35/362 (9.67%)  44 35/366 (9.56%)  41
Nausea  1  52/362 (14.36%)  72 45/366 (12.30%)  57
Vomiting  1  24/362 (6.63%)  29 18/366 (4.92%)  24
General disorders     
Asthenia  1  37/362 (10.22%)  45 59/366 (16.12%)  71
Fatigue  1  41/362 (11.33%)  55 45/366 (12.30%)  48
Non-cardiac chest pain  1  18/362 (4.97%)  18 11/366 (3.01%)  15
Pyrexia  1  15/362 (4.14%)  17 21/366 (5.74%)  24
Infections and infestations     
Pneumonia  1  18/362 (4.97%)  20 20/366 (5.46%)  24
Investigations     
Alanine aminotransferase increased  1  38/362 (10.50%)  53 35/366 (9.56%)  45
Aspartate aminotransferase  1  32/362 (8.84%)  43 35/366 (9.56%)  45
Blood alkaline phosphatase increased  1  19/362 (5.25%)  24 27/366 (7.38%)  39
Gamma-glutamyltransferase  1  38/362 (10.50%)  48 31/366 (8.47%)  46
Neutrophil count decreased  1  24/362 (6.63%)  32 25/366 (6.83%)  30
Platelet count decreased  1  30/362 (8.29%)  48 25/366 (6.83%)  38
Weight decreased  1  41/362 (11.33%)  48 56/366 (15.30%)  62
White blood cell count decreased  1  24/362 (6.63%)  36 26/366 (7.10%)  36
Metabolism and nutrition disorders     
Decreased appetite  1  43/362 (11.88%)  56 42/366 (11.48%)  48
Hyperglycaemia  1  14/362 (3.87%)  18 22/366 (6.01%)  29
Musculoskeletal and connective tissue disorders     
Arthralgia  1  32/362 (8.84%)  49 36/366 (9.84%)  48
Back pain  1  22/362 (6.08%)  25 14/366 (3.83%)  14
Myalgia  1  29/362 (8.01%)  61 32/366 (8.74%)  73
Nervous system disorders     
Headache  1  18/362 (4.97%)  21 23/366 (6.28%)  24
Neuropathy peripheral  1  58/362 (16.02%)  63 52/366 (14.21%)  60
Paraesthesia  1  24/362 (6.63%)  26 22/366 (6.01%)  22
Peripheral sensory neuropathy  1  28/362 (7.73%)  28 25/366 (6.83%)  25
Polyneuropathy  1  16/362 (4.42%)  18 23/366 (6.28%)  31
Renal and urinary disorders     
Proteinuria  1  24/362 (6.63%)  31 41/366 (11.20%)  52
Respiratory, thoracic and mediastinal disorders     
Cough  1  17/362 (4.70%)  20 25/366 (6.83%)  26
Dyspnoea  1  17/362 (4.70%)  17 29/366 (7.92%)  29
Epistaxis  1  16/362 (4.42%)  20 23/366 (6.28%)  36
Skin and subcutaneous tissue disorders     
Alopecia  1  154/362 (42.54%)  157 159/366 (43.44%)  162
Vascular disorders     
Hypertension  1  42/362 (11.60%)  47 44/366 (12.02%)  54
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Any publications/presentations made within 2 years of study completion require the Sponsor or CRO's prior written consent. The Sponsor shall be provided with copies of any materials relating to the study that they intend to publish/present at least 30 days in advance of publication, submission or presentation and the Institution shall withhold publication, submission or presentation for 90 days from the date on which the Sponsor receives the material (total time-frame of 120 days).
Results Point of Contact
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Name/Title: Clinical Trial Information
Organization: Centus Biotherapeutics Limited
Phone: +353 1 609 7100
EMail: Clinical-Trial@centusbio.com
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Responsible Party: Centus Biotherapeutics Limited
ClinicalTrials.gov Identifier: NCT02810457    
Other Study ID Numbers: FKB238-002
2015-004104-33 ( EudraCT Number )
First Submitted: June 3, 2016
First Posted: June 23, 2016
Results First Submitted: January 24, 2020
Results First Posted: March 19, 2020
Last Update Posted: March 19, 2020