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

• Sponsor: Centus Biotherapeutics Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02810457
• Collaborator: (none)
• Enrollment: 731
• Locations: 147
• Arms: 2
• Actual Duration (Months): 64.6
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this research study is to compare the effectiveness and safety of FKB238 against Avastin® in men and women with advanced/recurrent non squamous non-small cell lung cancer

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: FKB238 (bevacizumab); Drug: Avastin (bevacizumab); Drug: Paclitaxel; Drug: Carboplatin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 731 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised, Parallel, Double Blinded Study to Compare the Efficacy and Safety of FKB238 to Avastin® In 1st Line Treatment for Patients With Advanced/Recurrent Non Squamous NSCLC in Combination of Paclitaxel and Carboplatin
• Actual Study Start Date: Sep 7, 2016
• Actual Primary Completion Date: Jan 24, 2019
• Actual Study Completion Date: Jan 26, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FKB238 / paclitaxel / carboplatin 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 Curve (AUC) = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.	Drug: FKB238 (bevacizumab); Drug: Paclitaxel; Drug: Carboplatin
Active Comparator: Avastin / 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.	Drug: Avastin (bevacizumab); Drug: Paclitaxel; Drug: Carboplatin

Outcome Measures

Primary Outcome Measures

1. 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) [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.]

   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.

Secondary Outcome Measures

1. ORR at Week 19 [From the date of randomization up to Week 19.]

   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.

2. Progression-free Survival (PFS) [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.]

   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.

3. Overall Survival (OS) [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.]

   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.

4. Duration Of Response (DOR) [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.]

   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.

5. Disease Control Rate (DCR) Assessed as the Proportion of Patients With a BOR of Either CR, PR, SD or NED [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.]

   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).

Other Outcome Measures

1. Serum Trough Concentration (Ctrough) [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.]

   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.

2. Proportion of Patients Developing Anti-drug Antibodies (ADAs) [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.]

   The ADA levels were summarized at baseline and post-baseline time points using descriptive statistics.

3. Adverse Events (AEs) [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.]

4. Vital Signs [Up to approximately 30 days after last dose of study treatment.]

5. Hematology [Up to approximately 30 days after last dose of study treatment.]

6. Clinical Chemistry [Up to approximately 30 days after last dose of study treatment.]

7. Urinalysis [Up to approximately 30 days after last dose of study treatment.]

8. Electrocardiogram [Up to approximately 30 days after last dose of study treatment.]

9. Eastern Collaborative Oncology Group Performance Status [Up to approximately 30 days after last dose of study treatment.]

10. Physical Examination [Up to approximately 30 days after last dose of study treatment.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients aged 18 years or older

• Newly diagnosed advanced (stage IV) /recurrent non-squamous NSCLC for which they had not received any systemic anti-cancer therapy for metastatic disease

• Histologically or cytologically confirmed diagnosis of predominantly non-squamous NSCLC

• Existence of at least 1 measurable lesion by RECIST v1.1

• Adequate hematological, renal and liver function

• Eastern Collaborative Oncology Group Performance Status (ECOG PS) 0 or 1

• Life expectancy longer than 6 months

Exclusion Criteria:

• Small cell lung cancer (SCLC) or combination SCLC and NSCLC. Squamous-cell tumors and mixed adenosquamous carcinomas of predominantly squamous nature

• Any unresolved toxicities from prior systemic therapy

• Known sensitizing epidermal growth factor receptor (EGFR) mutations or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation positive mutations

• Previous dosing with vascular endothelial growth factor (VEGF) inhibitor

• Known hypersensitivity to any excipients of the Investigational Products (IPs) and combination chemotherapy

• Use of prohibited concomitant medication

• Known Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV) infection

• Fertile men or women of childbearing potential not using adequate contraception.

Other inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site 7814 - Compassionate Care Research Group	Fountain Valley	California	United States	92708
2	Research Site 7811 - Innovative Clinical Research Institute	Whittier	California	United States	90603
3	Research Site 7803 - 21st Century Oncology	Jacksonville	Florida	United States	32204
4	Research Site 7812 - Joliet Oncology-Hematology Associates, Ltd.	Joliet	Illinois	United States	60435
5	Research Site 7810 - Edward H. Kaplan, MD and Associates	Skokie	Illinois	United States	60076
6	Research Site 7813 - Trinity Cancer Care Center	Minot	North Dakota	United States	58701
7	Research Site 7805 - Hematology & Oncology Associates, Inc.	Canton	Ohio	United States	44708
8	Research Site 7801 - Gabrail Cancer Center	Canton	Ohio	United States	44718
9	Research Site 7804 - Tri-County Hematology & Oncology Associates, Inc.	Massillon	Ohio	United States	44646
10	Research Site 7809 - Millennium Oncology	Houston	Texas	United States	77090
11	Research Site 7806 - Vista Oncology Inc. PS	Olympia	Washington	United States	98502
12	Research Site 8507	Brest	Brestskaya Voblasts	Belarus	224027
13	Research Site 8505	Grodno	Hrodzenskaya Voblasts	Belarus	230017
14	Research Site 8502	Mogilev	Mahilyowskaya Voblasts	Belarus	212018
15	Research Site 8501	Lesnoy	Minskaya Voblasts	Belarus	223040
16	Research Site 8504	Minsk	Minskaya Voblasts	Belarus	220013
17	Research Site 8506	Vitebsk	Vitsyebskaya Voblasts	Belarus	210603
18	Research Site 8605	Tuzla	Tuzlanski Kanton	Bosnia and Herzegovina	75000
19	Research Site 8606	Banja Luka		Bosnia and Herzegovina	78000
20	Research Site 8602	Mostar		Bosnia and Herzegovina	88000
21	Research Site 8601	Sarajevo		Bosnia and Herzegovina	71000
22	Research Site 8603	Sarajevo		Bosnia and Herzegovina	71000
23	Research Site 8604	Zenica		Bosnia and Herzegovina	72000
24	Research Site 0905	Sofia	Dobrich	Bulgaria	9300
25	Research Site 0904	Varna		Bulgaria	9010
26	Research Site 1802	Zagreb	Grad Zagreb	Croatia	10 000
27	Research Site 1803	Zagreb	Grad Zagreb	Croatia	10 000
28	Research Site 1801	Osijek	Osjecko-baranjska Županija	Croatia	31 000
29	Research Site 2504	Bat'umi	Ajaria	Georgia	6010
30	Research Site 2507	Kutaisi	Imereti	Georgia	4600
31	Research Site 2503	Tbilisi		Georgia	0112
32	Research Site 2505	Tbilisi		Georgia	0159
33	Research Site 2508	Tbilisi		Georgia	0186
34	Research Site 2605	Würselen	Nordrhein-Westfalen	Germany	52146
35	Research Site 2603	Kiel	Schleswig-Holstein	Germany	24105
36	Research Site 2604	Hamburg		Germany	22081
37	Research Site 3004	Athens		Greece	11527
38	Research Site 3003	Thessaloniki		Greece	56403
39	Research Site 3005	Thessaloníki		Greece	57010
40	Research Site 3303	Gyula	Békés	Hungary	5700
41	Research Site 3302	Deszk	Csongrád	Hungary	6772
42	Research Site 3301	Mátraháza	Heves	Hungary	3233
43	Research Site 3305	Budapest		Hungary	1121
44	Research Site 3304	Budapest		Hungary
45	Research Site 3306	Zalaegerszeg		Hungary	8900
46	Research Site 4107	Catania		Italy	95126
47	Research Site 4106	Piacenza		Italy	29100
48	Research Site 4301	Fukuyama-shi	Hiroshima	Japan
49	Research Site 4304	Kumamoto-shi	Kumamoto	Japan
50	Research Site 4303	Sasebo-shi	Nagasaki	Japan
51	Research Site 6005	Busan	Busan Gwang'yeogsi	Korea, Republic of	49241
52	Research Site 6004	Suwon-si	Gyeonggido	Korea, Republic of	16247
53	Research Site 6002	Seoul	Seoul Teugbyeolsi	Korea, Republic of	06973
54	Research Site 6003	Ulsan	Ulsan Gwang'yeogsi	Korea, Republic of	44033
55	Research Site 5402	Arequipa		Peru	054
56	Research Site 5404	Arequipa		Peru	054
57	Research Site 5401	Lima		Peru	27
58	Research Site 5405	Lima		Peru	41
59	Research Site 5505	Cebu City	Cebu	Philippines	6000
60	Research Site 5504	Makati City	National Capital Region	Philippines	1229
61	Research Site 5501	Manila	National Capital Region	Philippines	1000
62	Research Site 5502	Manila	National Capital Region	Philippines	1000
63	Research Site 5506	Manila	National Capital Region	Philippines	1000
64	Research Site 5503	Quezon		Philippines	1112
65	Research Site 5705	Toruniak	Kujawsko-pomorskie	Poland	87-100
66	Research Site 5708	Lodz	Lódzkie	Poland	93-513
67	Research Site 5701	Krakow	Malopolskie	Poland	31-826
68	Research Site 5702	Elblag	Warminsko-mazurskie	Poland	82-300
69	Research Site 5706	Olsztyn	Warminsko-mazurskie	Poland	10-357
70	Research Site 5711	Brzozów		Poland	36-200
71	Research Site 5703	Nowy Sacz		Poland	33-300
72	Research Site 6105	Cluj-Napoca	Cluj	Romania	400058
73	Research Site 6106	Cluj-Napoca	Cluj	Romania	400352
74	Research Site 6108	Floreşti	Cluj	Romania	407280
75	Research Site 6101	Baia Mare		Romania	430031
76	Research Site 6102	Constanta		Romania	900591
77	Research Site 6103	Craiova		Romania	200385
78	Research Site 6107	Iasi		Romania	700106
79	Research Site 6209	Arkhangelsk	Arkhangel'skaya Oblast'	Russian Federation	163045
80	Research Site 6220	Ufa	Bashkortostan, Respublika	Russian Federation	450054
81	Research Site 6221	Belgorod	Belgorodskaya Oblast'	Russian Federation	308010
82	Research Site 6211	Chelyabinsk	Chelyabinskaya Oblast'	Russian Federation	454087
83	Research Site 6217	Kuzmolovskiy	Leningradskaya Oblast'	Russian Federation	188663
84	Research Site 6219	Saransk	Mordoviya, Respublika	Russian Federation	430032
85	Research Site 6225	Moscow	Moskva	Russian Federation	105229
86	Research Site 6203	Moscow	Moskva	Russian Federation	143423
87	Research Site 6230	Novgorod	Nizhegorodskaya Oblast'	Russian Federation	603109
88	Research Site 6214	Novosibirsk	Novosibirskaya Oblast'	Russian Federation	630007
89	Research Site 6213	Novosibirsk	Novosibirskaya Oblast'	Russian Federation	630047
90	Research Site 6215	Omsk	Omskaya Oblast'	Russian Federation	644013
91	Research Site 6224	Omsk	Omskaya Oblast'	Russian Federation	644013
92	Research Site 6208	Orenburg	Orenburgskaya Oblast'	Russian Federation	460021
93	Research Site 6223	Rostov-on-Don	Rostovskaya Oblast'	Russian Federation	344037
94	Research Site 6205	Ryazan'	Ryazanskaya Oblast'	Russian Federation	390011
95	Research Site 6234	Samara	Samarskaya Oblast'	Russian Federation	443031
96	Research Site 6235	Saint Petersburg	Sankt-Peterburg	Russian Federation	195271
97	Research Site 6212	Saint Petersburg	Sankt-Peterburg	Russian Federation	197022
98	Research Site 6216	Saint Petersburg	Sankt-Peterburg	Russian Federation	197342
99	Research Site 6201	Saint Petersburg	Sankt-Peterburg	Russian Federation	198255
100	Research Site 6202	Sankt Petersburg	Sankt-Peterburg	Russian Federation	197758
101	Research Site 6210	Sankt Petersburg	Sankt-Peterburg	Russian Federation	197758
102	Research Site 6229	Izhevsk	Udmurtskaya Respublika	Russian Federation	426009
103	Research Site 6228	Kursk		Russian Federation	305035
104	Research Site 6207	Magnitogorsk		Russian Federation	455001
105	Research Site 6222	Saint Petersburg		Russian Federation	198255
106	Research Site 6401	Sremska Kamenica	Vojvodina	Serbia	21204
107	Research Site 6402	Belgrade		Serbia	11000
108	Research Site 6403	Belgrade		Serbia	11000
109	Research Site 6404	Belgrade		Serbia	11000
110	Research Site 6405	Belgrade		Serbia	11070
111	Research Site 6406	Kragujevac	Šumadijski Okrug	Serbia	34000
112	Research Site 7004	A Coruna	A Coruña	Spain	15009
113	Research Site 7002	Castellón De La Plana	Castellon	Spain	12002
114	Research Site 7005	Cordoba	Córdoba	Spain	14004
115	Research Site 7009	Jaen	Jaén	Spain	23007
116	Research Site 7001	Burgos		Spain	9006
117	Research Site 7007	Madrid		Spain	28040
118	Research Site 7008	Murcia		Spain	30008
119	Research Site 7003	Murcia		Spain	30120
120	Research Site 7402	New Taipei City	Taipei	Taiwan	231
121	Research Site 7404	Douliu	Yunlin	Taiwan	64041
122	Research Site 7403	Changhua		Taiwan	500
123	Research Site 7401	Taipei		Taiwan	10449
124	Research Site 7506	Bangkok	Krung Thep Maha Nakhon	Thailand	10330
125	Research Site 7501	Hat Yai	Songkhla	Thailand	90110
126	Research Site 7504	Bangkok		Thailand
127	Research Site 7507	Chiang Mai		Thailand	50200
128	Research Site 7505	Chiang Rai		Thailand	57000
129	Research Site 7503	Khon Kaen		Thailand	40000
130	Research Site 7502	Udon Thani		Thailand	41330
131	Research Site 7607	Ankara		Turkey	06590
132	Research Site 7605	İzmir		Turkey	35100
133	Research Site 7601	Izmir		Turkey	35110
134	Research Site 7606	Malatya		Turkey	44100
135	Research Site 7702	Chernivtsi	Chernivets'ka Oblast'	Ukraine	58013
136	Research Site 7705	Kharkiv	Kharkivs'ka Oblast'	Ukraine	61070
137	Research Site 7706	Odesa	Odes'ka Oblast'	Ukraine	65055
138	Research Site 7713	Lutsk	Volyns'ka Oblast'	Ukraine	63000
139	Research Site 7707	Uzhgorod	Zakarpats'ka Oblast'	Ukraine	88000
140	Research Site 7709	Dnipropetrovs'k		Ukraine	49102
141	Research Site 7701	Ivano-Frankivs'k		Ukraine	76018
142	Research Site 7708	Kryvyi Rih		Ukraine	50048
143	Research Site 7704	Kyiv		Ukraine	03115
144	Research Site 7710	Sumy		Ukraine	40022
145	Research Site 8401	Hanoi	Ha Noi, Thu Do	Vietnam	10000
146	Research Site 8402	Hanoi	Ha Noi, Thu Do	Vietnam	10000
147	Research Site 8405	Hanoi	Ha Noi, Thu Do	Vietnam	10000

Sponsors and Collaborators

• Centus Biotherapeutics Limited

Investigators

• Study Director: Centus Biotherapeutics Limited, Centus Biotherapeutics Limited

Study Documents (Full-Text)

• Study Protocol - May 22, 2018
• Statistical Analysis Plan - May 7, 2019

More Information

Publications

None provided.

• Responsible Party: Centus Biotherapeutics Limited
• ClinicalTrials.gov Identifier: NCT02810457
• Other Study ID Numbers: FKB238-002; 2015-004104-33
• First Posted: Jun 23, 2016
• Last Update Posted: Mar 10, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Centus Biotherapeutics Limited: Cancer; Bevacizumab; Carboplatin; Paclitaxel
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Paclitaxel; Bevacizumab; Carboplatin

Study Results

Participant Flow

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 Detail	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
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	367
COMPLETED	37	38
NOT COMPLETED	327	329

Baseline Characteristics

Arm/Group Title	FKB238 / Paclitaxel / Carboplatin	Avastin / Paclitaxel / Carboplatin	Total
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 Participants	364	367	731
Age, Customized (Count of Participants)
Adults (18-64 years)	238 65.4%	224 61%	462 63.2%
From 65-84 years	126 34.6%	143 39%	269 36.8%
Sex: Female, Male (Count of Participants)
Female	119 32.7%	129 35.1%	248 33.9%
Male	245 67.3%	238 64.9%	483 66.1%
Race/Ethnicity, Customized (Count of Participants)
White	316 86.8%	320 87.2%	636 87%
Black and African American	1 0.3%	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%

Outcome Measures

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)
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.

Outcome Measure Data

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
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
Measure Participants	364	367
Number (95% Confidence Interval) [percentage of participants]	51.6 14.2%	53.7 14.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FKB238 / Paclitaxel / Carboplatin, Avastin / Paclitaxel / Carboplatin
	Comments
	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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio in ORR
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 90%; 0.86 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	ORR at Week 19
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.

Outcome Measure Data

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
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
Measure Participants	364	367
Number (95% Confidence Interval) [percentage of participants]	47.8 13.1%	51.0 13.9%

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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio in ORR
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 90%; 0.83 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Progression-free Survival (PFS)
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.

Outcome Measure Data

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
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
Measure Participants	364	367
Median (95% Confidence Interval) [Months]	7.72	7.62

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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment hazard ratio <1 favors FKB238.

4. Secondary Outcome

Title	Overall Survival (OS)
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.

Outcome Measure Data

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
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
Measure Participants	364	367
Median (95% Confidence Interval) [Months]	14.13	16.95

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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment hazard ratio <1 favors FKB238.

5. Secondary Outcome

Title	Duration Of Response (DOR)
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.

Outcome Measure Data

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
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
Measure Participants	188	197
Median (95% Confidence Interval) [months]	6.47	6.31

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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.23
	Parameter Dispersion	Type: Value:
	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
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.

Outcome Measure Data

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
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
Measure Participants	364	367
Number (95% Confidence Interval) [percentage of participants with response]	87.6 24.1%	87.5 23.8%

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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio >1 favors FKB238.

7. Other Pre-specified Outcome

Title	Serum Trough Concentration (Ctrough)
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.

Outcome Measure Data

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
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
Measure Participants	345	351
Cycle 1, Day 1 end of infusion	255.15 (184.3)	245.11 (206.8)
Cycle 2, Day 1 pre-infusion	42.74 (91.9)	48.48 (77.3)
Cycle 4, Day 1 pre-infusion	77.16 (69.4)	83.26 (85.5)
Cycle 4, Day 1 end of infusion	339.91 (91.3)	373.92 (51.6)
Cycle 6, Day 1 pre-infusion	87.25 (124.5)	108.22 (69.8)

8. Other Pre-specified Outcome

Title	Proportion of Patients Developing Anti-drug Antibodies (ADAs)
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.

Outcome Measure Data

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
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
Measure Participants	305	305
ADA prevalence (ADA positive, baseline or post)	3.0 0.8%	3.0 0.8%
Treatment-emergent ADA positive (ADA incidence)	2.3 0.6%	2.3 0.6%

9. Other Pre-specified Outcome

Title	Adverse Events (AEs)
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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Vital Signs
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Hematology
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Clinical Chemistry
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Urinalysis
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Electrocardiogram
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Eastern Collaborative Oncology Group Performance Status
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Physical Examination
Time Frame	Up to approximately 30 days after last dose of study treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

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
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
All Cause Mortality
	FKB238 / Paclitaxel / Carboplatin		Avastin / Paclitaxel / Carboplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	195/362 (53.9%)		177/366 (48.4%)
Serious Adverse Events
	FKB238 / Paclitaxel / Carboplatin		Avastin / Paclitaxel / Carboplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	91/362 (25.1%)		95/366 (26%)
Blood and lymphatic system disorders
Anaemia	5/362 (1.4%)	5	9/366 (2.5%)	10
Febrile neutropenia	7/362 (1.9%)	7	5/366 (1.4%)	5
Neutropenia	7/362 (1.9%)	8	18/366 (4.9%)	19
Pancytopenia	0/362 (0%)	0	2/366 (0.5%)	2
Thrombocytopenia	2/362 (0.6%)	2	2/366 (0.5%)	2
Cardiac disorders
Acute coronary syndrome	3/362 (0.8%)	3	1/366 (0.3%)	1
Acute myocardial infarction	1/362 (0.3%)	1	0/366 (0%)	0
Atrial fibrillation	0/362 (0%)	0	1/366 (0.3%)	1
Cardiac disorder	0/362 (0%)	0	1/366 (0.3%)	1
Cardio-respiratory arrest	2/362 (0.6%)	2	0/366 (0%)	0
Cor pulmonale	1/362 (0.3%)	1	0/366 (0%)	0
Myocardial infarction	1/362 (0.3%)	1	0/366 (0%)	0
Supraventricular tachycardia	1/362 (0.3%)	1	0/366 (0%)	0
Tachyarrhythmia	0/362 (0%)	0	1/366 (0.3%)	1
Endocrine disorders
Adrenal insufficiency	1/362 (0.3%)	1	0/366 (0%)	0
Gastrointestinal disorders
Diarrhoea	1/362 (0.3%)	1	3/366 (0.8%)	3
Diverticulum intestinal haemorrhagic	1/362 (0.3%)	1	0/366 (0%)	0
Dyspepsia	1/362 (0.3%)	1	0/366 (0%)	0
Enterocolitis	0/362 (0%)	0	1/366 (0.3%)	1
Gastric haemorrhage	1/362 (0.3%)	1	0/366 (0%)	0
Gastrointestinal haemorrhage	0/362 (0%)	0	1/366 (0.3%)	1
Haematemesis	1/362 (0.3%)	1	0/366 (0%)	0
Ileal perforation	0/362 (0%)	0	1/366 (0.3%)	1
Rectal haemorrhage	1/362 (0.3%)	1	0/366 (0%)	0
Small intestinal obstruction	0/362 (0%)	0	1/366 (0.3%)	1
Small intestinal perforation	0/362 (0%)	0	1/366 (0.3%)	1
Stomatitis	0/362 (0%)	0	1/366 (0.3%)	1
Upper gastrointestinal haemorrhage	0/362 (0%)	0	1/366 (0.3%)	1
Vomiting	3/362 (0.8%)	3	2/366 (0.5%)	2
General disorders
Asthenia	1/362 (0.3%)	1	0/366 (0%)	0
Death	5/362 (1.4%)	5	3/366 (0.8%)	3
Fatigue	1/362 (0.3%)	1	0/366 (0%)	0
General physical health deterioration	1/362 (0.3%)	1	2/366 (0.5%)	2
Mucosal inflammation	0/362 (0%)	0	1/366 (0.3%)	1
Oedema peripheral	0/362 (0%)	0	1/366 (0.3%)	1
Pyrexia	1/362 (0.3%)	1	0/366 (0%)	0
Sudden death	1/362 (0.3%)	1	0/366 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/362 (0%)	0	1/366 (0.3%)	1
Cholelithiasis	0/362 (0%)	0	2/366 (0.5%)	2
Drug-induced liver injury	1/362 (0.3%)	1	1/366 (0.3%)	1
Immune system disorders
Hypersensitivity	1/362 (0.3%)	1	0/366 (0%)	0
Infections and infestations
Cellulitis	0/362 (0%)	0	2/366 (0.5%)	2
Empyema	1/362 (0.3%)	1	1/366 (0.3%)	1
Liver abscess	0/362 (0%)	0	1/366 (0.3%)	1
Lung infection	2/362 (0.6%)	2	1/366 (0.3%)	1
Peritonitis	1/362 (0.3%)	1	1/366 (0.3%)	1
Pneumonia	10/362 (2.8%)	12	9/366 (2.5%)	10
Pneumonia fungal	0/362 (0%)	0	1/366 (0.3%)	1
Pseudomonal sepsis	1/362 (0.3%)	1	0/366 (0%)	0
Sepsis	0/362 (0%)	0	2/366 (0.5%)	2
Septic shock	0/362 (0%)	0	1/366 (0.3%)	1
Tuberculosis	0/362 (0%)	0	1/366 (0.3%)	1
Injury, poisoning and procedural complications
Femur fracture	0/362 (0%)	0	1/366 (0.3%)	1
Hip fracture	1/362 (0.3%)	1	0/366 (0%)	0
Spinal fracture	0/362 (0%)	0	1/366 (0.3%)	1
Upper limb fracture	1/362 (0.3%)	1	0/366 (0%)	0
Investigations
Neutrophil count decreased	3/362 (0.8%)	4	2/366 (0.5%)	2
Platelet count decreased	1/362 (0.3%)	1	1/366 (0.3%)	1
White blood cell count decreased	2/362 (0.6%)	2	2/366 (0.5%)	2
Metabolism and nutrition disorders
Hypocalcaemia	1/362 (0.3%)	1	0/366 (0%)	0
Hyponatraemia	0/362 (0%)	0	1/366 (0.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/362 (0%)	0	1/366 (0.3%)	1
Pathological fracture	0/362 (0%)	0	2/366 (0.5%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone	1/362 (0.3%)	1	0/366 (0%)	0
Thyroid cancer	0/362 (0%)	0	1/366 (0.3%)	1
Nervous system disorders
Cerebral arteriosclerosis	1/362 (0.3%)	1	0/366 (0%)	0
Cerebral atrophy	0/362 (0%)	0	1/366 (0.3%)	1
Cerebrovascular accident	2/362 (0.6%)	2	3/366 (0.8%)	3
Dizziness	0/362 (0%)	0	1/366 (0.3%)	1
Epilepsy	2/362 (0.6%)	2	0/366 (0%)	0
Facial paresis	1/362 (0.3%)	1	0/366 (0%)	0
Guillain-Barre syndrome	1/362 (0.3%)	1	0/366 (0%)	0
Haemorrhagic stroke	1/362 (0.3%)	1	1/366 (0.3%)	1
Ischaemic stroke	0/362 (0%)	0	1/366 (0.3%)	2
Polyneuropathy	1/362 (0.3%)	1	0/366 (0%)	0
Posterior reversible encephalopathy syndrome	1/362 (0.3%)	1	0/366 (0%)	0
Presyncope	1/362 (0.3%)	1	0/366 (0%)	0
Seizure	1/362 (0.3%)	1	0/366 (0%)	0
Transient ischaemic attack	1/362 (0.3%)	1	1/366 (0.3%)	1
Uraemic encephalopathy	0/362 (0%)	0	1/366 (0.3%)	1
Renal and urinary disorders
Acute kidney injury	1/362 (0.3%)	1	2/366 (0.5%)	2
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/362 (0.3%)	1	0/366 (0%)	0
Acute respiratory failure	2/362 (0.6%)	2	0/366 (0%)	0
Dyspnoea	2/362 (0.6%)	2	3/366 (0.8%)	3
Haemoptysis	2/362 (0.6%)	2	0/366 (0%)	0
Oesophagobronchial fistula	2/362 (0.6%)	2	0/366 (0%)	0
Pleural effusion	1/362 (0.3%)	2	0/366 (0%)	0
Pneumonia aspiration	2/362 (0.6%)	2	0/366 (0%)	0
Pneumothorax	0/362 (0%)	0	4/366 (1.1%)	4
Pulmonary embolism	6/362 (1.7%)	6	5/366 (1.4%)	5
Pulmonary fibrosis	1/362 (0.3%)	1	0/366 (0%)	0
Pulmonary haemorrhage	3/362 (0.8%)	4	1/366 (0.3%)	1
Pulmonary mass	0/362 (0%)	0	1/366 (0.3%)	1
Pulmonary oedema	2/362 (0.6%)	2	0/366 (0%)	0
Respiratory failure	1/362 (0.3%)	1	3/366 (0.8%)	3
Vascular disorders
Deep vein thrombosis	0/362 (0%)	0	1/366 (0.3%)	1
Hypertension	2/362 (0.6%)	2	1/366 (0.3%)	1
Hypertensive crisis	0/362 (0%)	0	2/366 (0.5%)	2
Other (Not Including Serious) Adverse Events
	FKB238 / Paclitaxel / Carboplatin		Avastin / Paclitaxel / Carboplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	341/362 (94.2%)		348/366 (95.1%)
Blood and lymphatic system disorders
Anaemia	105/362 (29%)	135	119/366 (32.5%)	146
Leukopenia	43/362 (11.9%)	58	50/366 (13.7%)	89
Neutropenia	109/362 (30.1%)	163	145/366 (39.6%)	212
Thrombocytopenia	44/362 (12.2%)	78	66/366 (18%)	102
Gastrointestinal disorders
Constipation	19/362 (5.2%)	23	21/366 (5.7%)	23
Diarrhoea	35/362 (9.7%)	44	35/366 (9.6%)	41
Nausea	52/362 (14.4%)	72	45/366 (12.3%)	57
Vomiting	24/362 (6.6%)	29	18/366 (4.9%)	24
General disorders
Asthenia	37/362 (10.2%)	45	59/366 (16.1%)	71
Fatigue	41/362 (11.3%)	55	45/366 (12.3%)	48
Non-cardiac chest pain	18/362 (5%)	18	11/366 (3%)	15
Pyrexia	15/362 (4.1%)	17	21/366 (5.7%)	24
Infections and infestations
Pneumonia	18/362 (5%)	20	20/366 (5.5%)	24
Investigations
Alanine aminotransferase increased	38/362 (10.5%)	53	35/366 (9.6%)	45
Aspartate aminotransferase	32/362 (8.8%)	43	35/366 (9.6%)	45
Blood alkaline phosphatase increased	19/362 (5.2%)	24	27/366 (7.4%)	39
Gamma-glutamyltransferase	38/362 (10.5%)	48	31/366 (8.5%)	46
Neutrophil count decreased	24/362 (6.6%)	32	25/366 (6.8%)	30
Platelet count decreased	30/362 (8.3%)	48	25/366 (6.8%)	38
Weight decreased	41/362 (11.3%)	48	56/366 (15.3%)	62
White blood cell count decreased	24/362 (6.6%)	36	26/366 (7.1%)	36
Metabolism and nutrition disorders
Decreased appetite	43/362 (11.9%)	56	42/366 (11.5%)	48
Hyperglycaemia	14/362 (3.9%)	18	22/366 (6%)	29
Musculoskeletal and connective tissue disorders
Arthralgia	32/362 (8.8%)	49	36/366 (9.8%)	48
Back pain	22/362 (6.1%)	25	14/366 (3.8%)	14
Myalgia	29/362 (8%)	61	32/366 (8.7%)	73
Nervous system disorders
Headache	18/362 (5%)	21	23/366 (6.3%)	24
Neuropathy peripheral	58/362 (16%)	63	52/366 (14.2%)	60
Paraesthesia	24/362 (6.6%)	26	22/366 (6%)	22
Peripheral sensory neuropathy	28/362 (7.7%)	28	25/366 (6.8%)	25
Polyneuropathy	16/362 (4.4%)	18	23/366 (6.3%)	31
Renal and urinary disorders
Proteinuria	24/362 (6.6%)	31	41/366 (11.2%)	52
Respiratory, thoracic and mediastinal disorders
Cough	17/362 (4.7%)	20	25/366 (6.8%)	26
Dyspnoea	17/362 (4.7%)	17	29/366 (7.9%)	29
Epistaxis	16/362 (4.4%)	20	23/366 (6.3%)	36
Skin and subcutaneous tissue disorders
Alopecia	154/362 (42.5%)	157	159/366 (43.4%)	162
Vascular disorders
Hypertension	42/362 (11.6%)	47	44/366 (12%)	54

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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).