A Safety and Efficacy Study of BCD-021 With Paclitaxel and Carboplatin Compared to Avastin With Paclitaxel and Carboplatin in Non-Small Cell Lung Cancer

• Sponsor: Biocad (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01763645
• Collaborator: (none)
• Enrollment: 138
• Locations: 44
• Arms: 2
• Actual Duration (Months): 25
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

BCD-021-02 is a double-blind randomized clinical trial comparing efficacy of BCD-021 (INN:

bevacizumab) and paclitaxel + carboplatin to Avastin and paclitaxel + carboplatin in inoperable or advanced non-squamous NSCLC patients with pharmacokinetics substudy. The purpose of the study is to demonstrate the non-inferiority of efficacy and safety of BCD-021 compared to Avastin. Also study includes pharmacokinetics assessment.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer	Drug: Bevacizumab; Drug: Paclitaxel; Drug: Carboplatin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 138 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: International Multicenter Randomized Double Blind Phase III Trial Comparing Safety and Efficacy of BCD-021 (CJSC BIOCAD, Russia) and Paclitaxel + Carboplatin to Avastin® (F. Hoffmann-La Roche Ltd, Switzerland) and Paclitaxel + Carboplatin in Inoperable or Advanced Non-squamous Non-small-cell Lung Cancer (NSCLC) Patients
• Actual Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BCD-021 (CISC BIOCAD) BCD-021 is a product code for bevacizumab biosimilar manufactured by CJSC BIOCAD, Russia. In this arm patients will receive 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 will be administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel will be administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	Drug: Bevacizumab; Patients will receive 6 courses of bevacizumab in combination with carboplatin and paclitaxel. Bevacizumab will be administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each cycle).; Other Names: Avastin BCD-021 ; Drug: Paclitaxel; Paclitaxel will be administered at a dose of 175 mg/m2 as 3 hour intravenous infusion on Day 1 of each 3-week course (6 courses totally); Other Names: Taxacad ; Drug: Carboplatin; Carboplatin will be administered (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel on Day 1 of each 3-week course (6 courses totally).
Active Comparator: Avastin (F. Hoffmann-La Roche Ltd) In this arm patients will receive 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin will be administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel will be administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	Drug: Bevacizumab; Patients will receive 6 courses of bevacizumab in combination with carboplatin and paclitaxel. Bevacizumab will be administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each cycle).; Other Names: Avastin BCD-021 ; Drug: Paclitaxel; Paclitaxel will be administered at a dose of 175 mg/m2 as 3 hour intravenous infusion on Day 1 of each 3-week course (6 courses totally); Other Names: Taxacad ; Drug: Carboplatin; Carboplatin will be administered (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel on Day 1 of each 3-week course (6 courses totally).

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [Day 127]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

2. Area Under the Curve After the First Test Drug Administration [up to Day 22, after the first bevacizumab administration (time points for blood samples: 0 h 1.5 h, 3 h, 4.5 h, 6 h, 24 h, 96 h, 168 h, 336 h and 504 h)]

   primary outcome measure for pharmacokinetics (PK) substudy

Secondary Outcome Measures

1. Complete Response Rate [Day 127]

   secondary outcome measure for efficacy evaluation

2. Partial Response Rate [Day 127]

   secondary outcome measure for efficacy evaluation

3. Stabilization Rate [Day 127]

   secondary outcome measure for efficacy evaluation

4. Progression Rate [Day 127]

   secondary outcome measure for efficacy evaluation

5. Occurrence of Anti-bevacizumab Antibodies [Day 1 (before the drug administration), Day 15, 64 and 127]

   Secondary outcome measure for immunogenicity assessment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent;

• Newly diagnosed histologically or cytologically confirmed NSCLC excluding squamous NSCLC (mixed cancer types should be classified according to the prevalent cell type);

• IIIb or IV stage of NSCLC (TNM classification version 6);

• Age ≥ 18 years and age ≤ 75 years (both inclusive);

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2, (not declining within 2 weeks prior to the first dose of investigational product);

• Life expectancy - 12 weeks or more from the moment of randomization;

• Presence of at least 1 measurable tumour with a size not less than 1 cm (revealed with CT slice thickness not more than 5 mm), as defined by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria (specifically, no ascites, pleural, or pericardial effusions, osteoblastic bone metastases, or carcinomatous lymphangitis of the lung as only lesion;

• Patients should be able to follow the Protocol procedures (according to Investigator's assessment);

• Patients must implement reliable contraceptive measures during all the study treatment, starting 4 weeks prior to the administration of the first dose of investigational product until 6 months after the last dose of investigational product. This requirement does not apply to participants who have undergone surgical sterilization, or patients who are postmenopausal (documented) for the past 2 years. Reliable contraceptive measures include two methods of contraception, including one barrier method

Exclusion Criteria:

• Squamous NSCLC;

• Proven coagulopathy, clinically significant hemorrhage in the past including nasal hemorrhage;

• absolute neutrophil count <1500/mm3;

• Platelets <100 000/mm3;

• Hemoglobin < 90 g/L;

• Creatinine level ≥1.5 mg/dL;

• Bilirubin level ≥1.5 × upper limit of normal (ULN);

• Aspartate-aminotransferase(AST) and alanine-aminotransferase (ALT) levels ≥2.5 × ULN (≥5 × ULN for patients with liver metastases);

• Alkaline phosphatase level ≥5 × ULN;

• Current therapeutic anticoagulation treatment, aspirin (more than 325 mg/day), nonsteroidal anti-inflammatory drugs, antiplatelet agents or protracted treatment with these drugs less than 1 month before entering the study;

• Uncontrolled hypertension comprising all cases of arterial hypertension when no decrease in blood pressure could be achieved despite treatment with a combination of 3 antihypertensive drugs including one diuretic and non-medical correction methods (low salt diet, physical exercise);

• Any previous anticancer therapy (chemotherapy, radiation therapy , surgery etc.) of metastatic NSCLC;

• Radiation or hormone therapy within 21 days prior to randomization;

• Major surgery 28 days before inclusion into the study;

• Previous antiangiogenic therapy;

• Hypersensitivity to taxanes, platinum agents, recombinant murine proteins, contrast agents, premedication agents specified by Protocol (dexamethasone, diphenhydramine, ranitidine) or excipients of investigational products;

• NSCLC metastases in central nervous system excluding metastases non-progressing without glucocorticosteroids within 4 weeks before inclusion into the trial;

• Cardiovascular system pathology (CHF stage III-IV according to New York Heart Association (NYHA) classification);

• Pregnancy or lactation;

• Conditions limiting patient's adherence to Protocol requirements (dementia, neurologic or psychiatric disorders, drug addiction, alcoholism and others);

• Stage II-IV neuropathy according to Common Terminology Criteria for Adverse Events (CTCAE) v.4.0;

• Simultaneous participation in other clinical trials, previous participation in other clinical trials within 30 days before entering into the trial, previous participation in the same trial;

• Any other concomitant cancer revealed within 5 years prior to screening, except curatively treated intraductal carcinoma in situ, curatively treated cervical carcinoma in situ or curatively treated basal cell or squamous cell carcinoma;

• Acute or active chronic infections;

• Hepatitis C virus, hepatitis B virus, HIV, or syphilis infections;

• Obstacles in intravenous administration of study drugs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brest Regional Clinical Dispensary	Brest		Belarus
2	Gomel Regional Clinical Oncology Dispensary	Gomel		Belarus
3	Grodno Regional Clinical Hospital	Grodno		Belarus
4	Vitebsk Regional Clinical Oncology Dispensary	Vitebsk		Belarus
5	HCG Bangalore Institute of Oncology	Bangalore		India	560027
6	M.S.Ramaiah Memorial Hospital	Bangalore		India	560054
7	Narayana Hrudayalaya Hospitals	Bangalore		India	560099
8	Arkhangelsk District Clinical Oncology Dispensary	Arkhangelsk		Russian Federation	163045
9	Non-governmental Healthcare Institution "Railway Clinical hospital on the Chelyabinsk Station of JSC Russian Railways"	Chelyabinsk		Russian Federation	454000
10	State-financed Health Institution "Chelyabinsk Region Clinical Oncology Dispansary"	Chelyabinsk		Russian Federation
11	State Healthcare Facility "Kursk Regional Oncology Dispensary"	Kursk		Russian Federation	305035
12	State Health Institution of Moscow "Moscow City Oncology Hospital #62 of Moscow Board of Health"	Moscow Region		Russian Federation	143423
13	Institution of Russian Academy of Medical Sciences "Russian Cancer Research Center named after N.N. Blokhin"	Moscow		Russian Federation	115478
14	Federal State Institution "Moscow Institute of Cancer Research named after P.A. Hertsen" Ministry of Health of Russian Federation	Moscow		Russian Federation	194044
15	Murmansk Regional Oncology Dispensary	Murmansk		Russian Federation	183047
16	Nizhny Novgorod Region State Budgetary Healthcare Facility "Clinical Diagnostics Center"	Nizhny Novgorod		Russian Federation	603006
17	State Healthcare Facility "Nizhny Novgorod Regional Oncology Dispensary"	Nizhny Novgorod		Russian Federation
18	City Clinical Hospital №1	Novosibirsk		Russian Federation	630047
19	Regional State Health Institution "Orlov Oncology Dispansary"	Orel		Russian Federation	302020
20	State Health Institution "Region Oncology Dispansary"	Penza		Russian Federation	440071
21	Perm Region Oncology Dispensary	Perm		Russian Federation	614066
22	Federal Government Budgetary Institution "Rostov Institute of Cancer Research" of Ministry of Health of Russian Federation	Rostov-on-Don		Russian Federation	314019
23	Saint Petersburg City Clinical Oncology Center	Saint Petersburg		Russian Federation	197022
24	State-financed Health Institution "Samara Region Clinical Oncology Dispansary"	Samara		Russian Federation	443031
25	Oncology Dispensary 2	Sochi		Russian Federation	354057
26	St. Petersburg State Medical University n.a. I. P. Pavlov	St. Petersburg		Russian Federation	197022
27	St. Petersburg Research and Practice Center for Secondary Care in Oncology	St. Petersburg		Russian Federation	197758
28	N.N.Petrov Oncology Research Center	St.Petersburg		Russian Federation	197758
29	Military Medical Academy named after S.M. Kirov	St.Petersburg		Russian Federation
30	Russian scientific center of radiology and surgery technologies	St.Petersburg		Russian Federation
31	State-financed Health Institution "Stavropol Region Clinical Oncology Dispansary"	Stavropol		Russian Federation	355047
32	Volgograd District Oncology Dispensary №1	Volgograd		Russian Federation	400138
33	Volgograd Regional Oncology Dispensary №3	Volgograd		Russian Federation	404130
34	State Health Institution "Voronezh Region Clinical Oncology Dispansary"	Voronezh		Russian Federation	394000
35	Donetsk City Oncology Dispensary	Donetsk		Ukraine
36	Donetsk Regional Antitumor Center	Donetsk		Ukraine
37	Kharkiv Regional Clinical Oncology Center	Kharkiv		Ukraine
38	Kryvyi Rih Oncology Dispensary	Kryvyi Rih		Ukraine
39	Lviv State Regional Cancer Diagnostic and Treatment Center	Lviv		Ukraine
40	City Hospital № 2	Makiivka		Ukraine
41	Poltava Regional Clinical Oncology Dispensary	Poltava		Ukraine
42	Zakarpatskyi Clinical Oncology Dispensary	Uzhhorod		Ukraine
43	Vinnytsia Regional Clinical Oncology Dispensary	Vinnytsia		Ukraine
44	Zaporizhia Regional Clinical Oncology Dispensary	Zaporizhia		Ukraine

Sponsors and Collaborators

• Biocad

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Biocad
• ClinicalTrials.gov Identifier: NCT01763645
• Other Study ID Numbers: BCD-021-02
• First Posted: Jan 9, 2013
• Last Update Posted: Mar 30, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Biocad: NSCLC; bevacizumab; pharmacokinetics
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Paclitaxel; Bevacizumab; Carboplatin

Study Results

Participant Flow

Pre-assignment Detail	134 of 138 patients received at least one dose of the study drug/comparator. 4 patients discontinued the study without receiving a single dose of the study drug/comparator. 88 patients received all 6 therapy cycles and completed the main study period in accordance with the Protocol. 50 subjects withdrew from the study.

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Period Title: Overall Study
STARTED	69	69
Received at Least 1 Dose of Study Drug	68	66
COMPLETED	43	45
NOT COMPLETED	26	24

Baseline Characteristics

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)	Total
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	Total of all reporting groups
Overall Participants	68	66	134
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.79 (8.88)	58.67 (8.33)	58.23 (8.61)
Sex: Female, Male (Count of Participants)
Female	25 36.8%	24 36.4%	49 36.6%
Male	43 63.2%	42 63.6%	85 63.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	Day 127

Outcome Measure Data

Analysis Population Description

The efficacy analysis included only those patients who received at least one dose of BCD-021 or Avastin®, and in whom it was possible to assess the response to therapy.

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Measure Participants	54	56
Number (95% Confidence Interval) [percentage of participans]	42.59	39.29

2. Primary Outcome

Title	Area Under the Curve After the First Test Drug Administration
Description	primary outcome measure for pharmacokinetics (PK) substudy
Time Frame	up to Day 22, after the first bevacizumab administration (time points for blood samples: 0 h 1.5 h, 3 h, 4.5 h, 6 h, 24 h, 96 h, 168 h, 336 h and 504 h)

Outcome Measure Data

Analysis Population Description

Patients who received one dose of study drug and after 504 hours after injection had missed <= 1 blood sample collection to analyze pharmacokinetics.

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Measure Participants	67	64
Median (Inter-Quartile Range) [(ng/ml)*hour]	66869	58844

3. Secondary Outcome

Title	Complete Response Rate
Description	secondary outcome measure for efficacy evaluation
Time Frame	Day 127

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Measure Participants	54	56
Number (95% Confidence Interval) [percentage of patients]	1.85	1.79

4. Secondary Outcome

Title	Partial Response Rate
Description	secondary outcome measure for efficacy evaluation
Time Frame	Day 127

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Measure Participants	54	56
Number (95% Confidence Interval) [percentage of patients]	40.74	37.50

5. Secondary Outcome

Title	Stabilization Rate
Description	secondary outcome measure for efficacy evaluation
Time Frame	Day 127

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Measure Participants	54	56
Number (95% Confidence Interval) [percentage of patients]	51.85	51.79

6. Secondary Outcome

Title	Progression Rate
Description	secondary outcome measure for efficacy evaluation
Time Frame	Day 127

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Measure Participants	54	56
Number (95% Confidence Interval) [percentage of patients]	5.56	8.93

7. Secondary Outcome

Title	Occurrence of Anti-bevacizumab Antibodies
Description	Secondary outcome measure for immunogenicity assessment
Time Frame	Day 1 (before the drug administration), Day 15, 64 and 127

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BCD-021 (CISC BIOCAD)	Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.	In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1.
Measure Participants	68	66
Number [percentage of patients]	1.47	1.52

Adverse Events

Time Frame	6 therapy cycles
Adverse Event Reporting Description	The safety analysis included all subjects who received at least one dose of BCD-021 or Avastin® (n = 134).
Arm/Group Title	BCD-021 (CISC BIOCAD)		Avastin (F. Hoffmann-La Roche Ltd)
Arm/Group Description	In this arm patients received 6 courses of treatment with BCD-021 in combination with carboplatin and paclitaxel. BCD-021 was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks (on Day 1 of each course). Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1. Data on adverse events was collected from date of signing informed consent up to 18 weeks after first injection of study drug.		In this arm patients received 6 courses of treatment with Avastin in combination with carboplatin and paclitaxel. Avastin was administered at a dose of 15 mg/kg as 90 min intravenous infusion every 3 weeks on Day 1. Paclitaxel was administered at a dose of 175 mg/m2 as 3 hour intravenous infusion every 3 weeks on Day 1 and carboplatin (AUC 6 mg/ml×min) as 15 - 30 min intravenous infusion just after paclitaxel every 3 weeks on Day 1. Data on adverse events was collected from date of signing informed consent up to 18 weeks after first injection of study drug.
All Cause Mortality
	BCD-021 (CISC BIOCAD)		Avastin (F. Hoffmann-La Roche Ltd)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	BCD-021 (CISC BIOCAD)		Avastin (F. Hoffmann-La Roche Ltd)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/68 (20.6%)		8/66 (12.1%)
Blood and lymphatic system disorders
Neutropenia	1/68 (1.5%)	1	0/66 (0%)	0
Leucopenia	1/68 (1.5%)	1	0/66 (0%)	0
Cardiac disorders
Transient ischemic attack	1/68 (1.5%)	1	0/66 (0%)	0
Ear and labyrinth disorders
Sensorineural hearing loss	0/68 (0%)	0	1/66 (1.5%)	1
Gastrointestinal disorders
Paraproctitis	1/68 (1.5%)	2	1/66 (1.5%)	1
General disorders
Endogenous intoxication	1/68 (1.5%)	1	0/66 (0%)	0
Death for an unknown reason	1/68 (1.5%)	1	1/66 (1.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Disease progression	2/68 (2.9%)	2	1/66 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonia	2/68 (2.9%)	2	0/66 (0%)	0
Pulmonary hemorrhage	4/68 (5.9%)	4	2/66 (3%)	2
Hemoptysis with febrile fever	1/68 (1.5%)	1	0/66 (0%)	0
Spontaneous pneumothorax with hydrothorax	0/68 (0%)	0	1/66 (1.5%)	1
Dyspnea	0/68 (0%)	0	1/66 (1.5%)	1
Other (Not Including Serious) Adverse Events
	BCD-021 (CISC BIOCAD)		Avastin (F. Hoffmann-La Roche Ltd)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	68/68 (100%)		66/66 (100%)
Blood and lymphatic system disorders
Leucopenia	54/68 (79.4%)		50/66 (75.8%)
Leucocytosis	33/68 (48.5%)		32/66 (48.5%)
Neutropenia	58/68 (85.3%)		52/66 (78.8%)
Anemia	60/68 (88.2%)		56/66 (84.8%)
Trombocytopenia	47/68 (69.1%)		41/66 (62.1%)
Elevated absolute neutrophil count	28/68 (41.2%)		33/66 (50%)
Elevated hemoglobin	5/68 (7.4%)		3/66 (4.5%)
Lymphopenia	33/68 (48.5%)		31/66 (47%)
Lymphocytosis	14/68 (20.6%)		18/66 (27.3%)
Erythropenia	23/68 (33.8%)		18/66 (27.3%)
Erythrocytosis	10/68 (14.7%)		5/66 (7.6%)
Trombocytosis	19/68 (27.9%)		28/66 (42.4%)
Cardiac disorders
Tachycardia	20/68 (29.4%)		10/66 (15.2%)
Gastrointestinal disorders
nausea	9/68 (13.2%)		9/66 (13.6%)
diarrhea	6/68 (8.8%)		3/66 (4.5%)
General disorders
Fever	4/68 (5.9%)		4/66 (6.1%)
Generalized weakness	12/68 (17.6%)		11/66 (16.7%)
Hepatobiliary disorders
Elevated alkaline phosphotase	24/68 (35.3%)		20/66 (30.3%)
Elevated AST	21/68 (30.9%)		15/66 (22.7%)
Elevated ALT	18/68 (26.5%)		19/66 (28.8%)
Hyperbilirubinemia	1/68 (1.5%)		4/66 (6.1%)
Elevated direct bilirubin	4/68 (5.9%)		2/66 (3%)
Infections and infestations
Acute respiratory viral infection	0/68 (0%)		4/66 (6.1%)
Investigations
Elevated lactate dehydrohenase	33/68 (48.5%)		25/66 (37.9%)
Metabolism and nutrition disorders
Hyperglycemia	42/68 (61.8%)		37/66 (56.1%)
Hyperuricemia	22/68 (32.4%)		14/66 (21.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/68 (10.3%)		9/66 (13.6%)
Myalgia	5/68 (7.4%)		5/66 (7.6%)
Ossalgia	5/68 (7.4%)		4/66 (6.1%)
Nervous system disorders
Peripheral neuropathy	8/68 (11.8%)		8/66 (12.1%)
Renal and urinary disorders
Elevated urea	11/68 (16.2%)		12/66 (18.2%)
Elevated creatinine	16/68 (23.5%)		12/66 (18.2%)
Respiratory, thoracic and mediastinal disorders
Lung hemorrhage	4/68 (5.9%)		2/66 (3%)
Dyspnea	5/68 (7.4%)		6/66 (9.1%)
Skin and subcutaneous tissue disorders
Alopecia	21/68 (30.9%)		16/66 (24.2%)
Vascular disorders
Arterial hypertension	18/68 (26.5%)		15/66 (22.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.