A Study of Avastin (Bevacizumab) in Combination With Gemcitabine With or Without Cisplatin in First-Line Treatment of Elderly Patients With Non-Small Cell Lung Cancer

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01077713
• Collaborator: (none)
• Enrollment: 86
• Locations: 26
• Arms: 2
• Duration (Months): 52.9
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This 2 arm study will evaluate the efficacy and safety of Avastin + gemcitabine, and Avastin

• gemcitabine + attenuated doses of cisplatin, as first line treatment in elderly patients with non-squamous non-small cell lung cancer. Patients will be randomised to receive either Avastin 7.5mg/kg iv on day 1 + gemcitabine 1200mg/m2 on days 1-8 of each 3 week cycle, or Avastin 7.5mg/kg iv on day 1 + cisplatin 60mg/m2 on day 1 + gemcitabine 1000mg/m2 on days 1-8 of each 3 week cycle. After 6 cycles of combination therapy, all patients will continue to receive Avastin monotherapy. The anticipated time on study treatment is until disease progression, and the target sample size is <100 individuals.

Condition or Disease	Intervention/Treatment	Phase
Non-Squamous Non-Small Cell Lung Cancer	Drug: bevacizumab [Avastin]; Drug: cisplatin; Drug: gemcitabine; Drug: gemcitabine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 86 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomised Phase II Trial of Bevacizumab (AVASTIN®) in Combination With Gemcitabine or Attenuated Doses of Cisplatin and Gemcitabine as First-line Treatment of Elderly Patients With Advanced Non-squamous Non-small Cell Lung Cancer - EAGLES
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: bevacizumab [Avastin]; 7.5mg/kg iv on day 1 of each 3 week cycle; Drug: gemcitabine; 1200mg/m2 on days 1-8 of each 3 week cycle
Experimental: 2	Drug: bevacizumab [Avastin]; 7.5mg/kg iv on day 1 of each 3 week cycle; Drug: cisplatin; 60mg/m2 on day 1 of each 3 week cycle; Drug: gemcitabine; 1000mg/m2 on days 1-8 of each 3 week cycle

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Alive and Without Progressive Disease at Month 6 [Month 6]

   Disease progression was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (v 1.1). Disease progression was defined at least a 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 millimeter (mm), progression of existing non-target lesions, or presence of new lesions.

Secondary Outcome Measures

1. Percentage of Participants With Disease Progression or Death [Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death, or consent withdrawal (up to 53 months)]

   Disease progression was assessed according to RECIST criteria v1.1. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions.

2. Progression Free Survival (PFS) [Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death, or consent withdrawal (up to 53 months)]

   PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Disease progression was assessed according to RECIST criteria v 1.1. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method.

3. Percentage of Participants Alive at 12 Months After Randomization [1 year]

4. Percentage of Participants Who Died [From randomization to death or end of the study (up to 53 months)]

5. Overall Survival (OS) [From randomization to death or end of the study (up to 53 months)]

   OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method.

6. Percentage of Participants by Best Overall Response [Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death or consent withdrawal (up to 53 months)]

   Best overall response was defined as the best response recorded from the start of the treatment until disease progression/recurrence, assessed according to RECIST criteria v 1.1. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to less than (<) 10 millimeter (mm) in short axis; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions; Progressive Disease (PD): at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

7. Percentage of Participants With an Objective Response [Cycle 3 Day 15, Cycle 6 Day 15 and at Month 6]

   Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions.

8. Percentage of Participants With Disease Control [Cycle 3 Day 15, Cycle 6 Day 15 and at Month 6]

   Disease control was defined as having CR/PR/SD as per RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions.

9. Duration of Response (DoR) [Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death or consent withdrawal (up to 53 months)]

   DoR was defined for participants who had achieved an objective response (CR/PR) (whichever status was recorded first) as the time period from first documentation of a response to the date of first occurrence of investigator documented disease progression or death. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined as increase by at least 20% in the sum of the longest diameters of each target lesion, taking as a reference the smallest sum of the longest diameters or appearance of one or more new lesions. DoR was estimated using Kaplan Meier method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 70 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• adult patients, >=70 years of age;

• inoperable, locally advanced, metastatic non-squamous non-small cell lung cancer;

• =1 measurable lesion;

• ECOG performance status 0-1.

Exclusion Criteria:

• neoadjuvant/adjuvant chemotherapy within 6 months prior to enrollment;

• radical radiotherapy with curative intent within 28 days prior to enrollment;

• history of >=grade 2 hemoptysis in 3 months prior to enrollment;

• evidence of CNS metastases;

• current or recent (within 10 days of first dose of Avastin)use of aspirin (>325 mg/day)or full dose anticoagulants or thrombolytic agents for therapeutic purposes.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Rionero in Vulture	Basilicata	Italy	85028
2		Catanzaro	Calabria	Italy	88100
3		Avellino	Campania	Italy	83100
4		Napoli	Campania	Italy	80131
5		Bologna	Emilia-Romagna	Italy	40139
6		Aviano	Friuli-Venezia Giulia	Italy	33081
7		Udine	Friuli-Venezia Giulia	Italy	33100
8		Roma	Lazio	Italy	00128
9		Roma	Lazio	Italy	00152
10		Roma	Lazio	Italy	00189
11		Viterbo	Lazio	Italy	01100
12		Genova	Liguria	Italy	16149
13		Bergamo	Lombardia	Italy	24128
14		Milano	Lombardia	Italy	20142
15		Monza	Lombardia	Italy	20052
16		Rho	Lombardia	Italy	20017
17		Sondalo	Lombardia	Italy	23039
18		Sondrio	Lombardia	Italy	23100
19		Ancona	Marche	Italy	60121
20		Pesaro	Marche	Italy	61122
21		Novara	Piemonte	Italy	28100
22		Catania	Sicilia	Italy	95100
23		Lido Di Camaiore	Toscana	Italy	55043
24		Perugia	Umbria	Italy	06156
25		Mirano	Veneto	Italy	30035
26		Padova	Veneto	Italy	35128

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01077713
• Other Study ID Numbers: ML21868; 2008-008739-27
• First Posted: Mar 1, 2010
• Last Update Posted: Oct 8, 2015
• Last Verified: Sep 1, 2015

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Gemcitabine; Bevacizumab

Study Results

Participant Flow

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1 and gemcitabine 1200 milligrams per square meter (mg/m^2) IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Period Title: Overall Study
STARTED	44	42
COMPLETED	8	6
NOT COMPLETED	36	36

Baseline Characteristics

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin	Total
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.	Total of all reporting groups
Overall Participants	44	42	86
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.2 (3.2)	73.8 (3.5)	74.0 (3.3)
Sex: Female, Male (Count of Participants)
Female	16 36.4%	12 28.6%	28 32.6%
Male	28 63.6%	30 71.4%	58 67.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Alive and Without Progressive Disease at Month 6
Description	Disease progression was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (v 1.1). Disease progression was defined at least a 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 millimeter (mm), progression of existing non-target lesions, or presence of new lesions.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) set included all participants in the RND set who received at least one dose of any study medication; participants were classified according to treatment received.

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Number (95% Confidence Interval) [percentage of participants]	25.6 58.2%	30.0 71.4%

2. Secondary Outcome

Title	Percentage of Participants With Disease Progression or Death
Description	Disease progression was assessed according to RECIST criteria v1.1. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions.
Time Frame	Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death, or consent withdrawal (up to 53 months)

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Number [percentage of participants]	86.0 195.5%	90.0 214.3%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Disease progression was assessed according to RECIST criteria v 1.1. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method.
Time Frame	Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death, or consent withdrawal (up to 53 months)

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Median (95% Confidence Interval) [months]	4.33	6.82

4. Secondary Outcome

Title	Percentage of Participants Alive at 12 Months After Randomization
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Number (95% Confidence Interval) [percentage of participants]	37.2 84.5%	47.5 113.1%

5. Secondary Outcome

Title	Percentage of Participants Who Died
Time Frame	From randomization to death or end of the study (up to 53 months)

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Number [percentage of participants]	69.8 158.6%	72.5 172.6%

6. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method.
Time Frame	From randomization to death or end of the study (up to 53 months)

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Median (95% Confidence Interval) [months]	5.66	12.0

7. Secondary Outcome

Title	Percentage of Participants by Best Overall Response
Description	Best overall response was defined as the best response recorded from the start of the treatment until disease progression/recurrence, assessed according to RECIST criteria v 1.1. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to less than (<) 10 millimeter (mm) in short axis; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions; Progressive Disease (PD): at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death or consent withdrawal (up to 53 months)

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
CR	0.0 0%	0.0 0%
PR	14.0 31.8%	35.0 83.3%
SD	39.5 89.8%	37.5 89.3%
PD	16.3 37%	12.5 29.8%
Not Assessable	30.2 68.6%	15.0 35.7%

8. Secondary Outcome

Title	Percentage of Participants With an Objective Response
Description	Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions.
Time Frame	Cycle 3 Day 15, Cycle 6 Day 15 and at Month 6

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Cycle 3	11.6 26.4%	27.5 65.5%
Cycle 6	9.3 21.1%	15.0 35.7%
Month 6	4.7 10.7%	10.0 23.8%

9. Secondary Outcome

Title	Percentage of Participants With Disease Control
Description	Disease control was defined as having CR/PR/SD as per RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions.
Time Frame	Cycle 3 Day 15, Cycle 6 Day 15 and at Month 6

Outcome Measure Data

Analysis Population Description

ITT set

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Cycle 3	53.5 121.6%	67.5 160.7%
Cycle 6	27.9 63.4%	37.5 89.3%
Month 6	25.6 58.2%	30.0 71.4%

10. Secondary Outcome

Title	Duration of Response (DoR)
Description	DoR was defined for participants who had achieved an objective response (CR/PR) (whichever status was recorded first) as the time period from first documentation of a response to the date of first occurrence of investigator documented disease progression or death. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined as increase by at least 20% in the sum of the longest diameters of each target lesion, taking as a reference the smallest sum of the longest diameters or appearance of one or more new lesions. DoR was estimated using Kaplan Meier method.
Time Frame	Baseline; Day 15 of Cycles 3 and 6; Month 6 and then every 3 months until disease progression, death or consent withdrawal (up to 53 months)

Outcome Measure Data

Analysis Population Description

ITT set.

Arm/Group Title	Bevacizumab + Gemcitabine	Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.	Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
Measure Participants	43	40
Median (95% Confidence Interval) [months]	5.23	5.97

Adverse Events

Time Frame	From baseline to 28 days after last dose of any study drug (up to 54 months)
Adverse Event Reporting Description	Safety set included all participants in the RND set who received at least one dose of any study medication. Participants were classified according to treatment received.
Arm/Group Title	Bevacizumab + Gemcitabine		Bevacizumab + Gemcitabine + Cisplatin
Arm/Group Description	Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.		Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1 and 8 of each 21-day cycle for a maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
All Cause Mortality
	Bevacizumab + Gemcitabine		Bevacizumab + Gemcitabine + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bevacizumab + Gemcitabine		Bevacizumab + Gemcitabine + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/43 (39.5%)		10/40 (25%)
Cardiac disorders
Atrial fibrillation	0/43 (0%)		1/40 (2.5%)
Cardiac arrest	1/43 (2.3%)		0/40 (0%)
Cardiac failure	1/43 (2.3%)		0/40 (0%)
Myocardial infarction	0/43 (0%)		1/40 (2.5%)
Gastrointestinal disorders
Nausea	0/43 (0%)		1/40 (2.5%)
General disorders
General physical health deterioration	2/43 (4.7%)		0/40 (0%)
Pyrexia	1/43 (2.3%)		0/40 (0%)
Infections and infestations
Bronchopneumonia	1/43 (2.3%)		0/40 (0%)
Pneumonia	0/43 (0%)		1/40 (2.5%)
Urinary tract infection	1/43 (2.3%)		0/40 (0%)
Injury, poisoning and procedural complications
Fall	0/43 (0%)		1/40 (2.5%)
Overdose	1/43 (2.3%)		0/40 (0%)
Nervous system disorders
Aphasia	1/43 (2.3%)		0/40 (0%)
Dizziness	0/43 (0%)		1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/43 (2.3%)		0/40 (0%)
Dyspnoea	2/43 (4.7%)		0/40 (0%)
Haemoptysis	2/43 (4.7%)		0/40 (0%)
Lung disease	1/43 (2.3%)		0/40 (0%)
Pneumonitis	1/43 (2.3%)		0/40 (0%)
Pulmonary Haemorrhage	0/43 (0%)		1/40 (2.5%)
Pulmonary oedema	0/43 (0%)		1/40 (2.5%)
Respiratory failure	2/43 (4.7%)		0/40 (0%)
Surgical and medical procedures
Hospitalisation	1/43 (2.3%)		0/40 (0%)
Vascular disorders
Embolism	1/43 (2.3%)		2/40 (5%)
Hypertension	0/43 (0%)		1/40 (2.5%)
Thrombosis	0/43 (0%)		1/40 (2.5%)
Other (Not Including Serious) Adverse Events
	Bevacizumab + Gemcitabine		Bevacizumab + Gemcitabine + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/43 (88.4%)		37/40 (92.5%)
Blood and lymphatic system disorders
Anaemia	5/43 (11.6%)		12/40 (30%)
Leukopenia	0/43 (0%)		11/40 (27.5%)
Neutropenia	12/43 (27.9%)		23/40 (57.5%)
Thrombocytopenia	5/43 (11.6%)		16/40 (40%)
Gastrointestinal disorders
Abdominal pain	0/43 (0%)		2/40 (5%)
Abdominal pain upper	0/43 (0%)		2/40 (5%)
Constipation	3/43 (7%)		8/40 (20%)
Diarrhoea	3/43 (7%)		5/40 (12.5%)
Nausea	8/43 (18.6%)		17/40 (42.5%)
Vomiting	5/43 (11.6%)		6/40 (15%)
General disorders
Asthenia	9/43 (20.9%)		10/40 (25%)
Chest pain	4/43 (9.3%)		2/40 (5%)
Fatigue	8/43 (18.6%)		15/40 (37.5%)
Mucosal inflammation	0/43 (0%)		5/40 (12.5%)
Pain	0/43 (0%)		2/40 (5%)
Pyrexia	8/43 (18.6%)		8/40 (20%)
Infections and infestations
Tooth abscess	0/43 (0%)		2/40 (5%)
Investigations
Blood creatinine increased	0/43 (0%)		4/40 (10%)
Platelet count decreased	4/43 (9.3%)		5/40 (12.5%)
Metabolism and nutrition disorders
Hyperkalaemia	0/43 (0%)		2/40 (5%)
Hypocalcaemia	0/43 (0%)		3/40 (7.5%)
Hyponatraemia	0/43 (0%)		2/40 (5%)
Musculoskeletal and connective tissue disorders
Back pain	0/43 (0%)		3/40 (7.5%)
Bone pain	5/43 (11.6%)		4/40 (10%)
Pain in extremity	3/43 (7%)		0/40 (0%)
Nervous system disorders
Dizziness	3/43 (7%)		8/40 (20%)
Paraesthesia	0/43 (0%)		2/40 (5%)
Renal and urinary disorders
Proteinuria	5/43 (11.6%)		0/40 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	4/43 (9.3%)		6/40 (15%)
Dyspnoea	4/43 (9.3%)		7/40 (17.5%)
Epistaxis	0/43 (0%)		2/40 (5%)
Haemoptysis	5/43 (11.6%)		4/40 (10%)
Productive cough	0/43 (0%)		3/40 (7.5%)
Vascular disorders
Embolism	0/43 (0%)		5/40 (12.5%)
Hypertension	11/43 (25.6%)		9/40 (22.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.