Study of Oral Topotecan With Bevacizumab for Recurrent Small Cell Lung Cancer

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00698516
• Collaborator: (none)
• Enrollment: 50
• Locations: 16
• Arm: 1
• Duration (Months): 22
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Combination of Hycamtin (topotecan) and Avastin (bevacizumab) could allow killing of both endothelial and neoplastic cells. We postulate that addition of bevacizumab to topotecan will increase delivery of topotecan to tumor cells and may enhance activity of topotecan in patients with previously treated small cell lung cancer and improve progression free survival.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Small-cell Lung Cancer (SCLC); Lung Cancer, Small Cell	Drug: Oral Hycamtin (topotecan) Capsules + IV Avastin (bevacizumab)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter, Non-comparative, Phase II Study of Oral Topotecan in Combination With Bevacizumab for Second-line Treatment in Subjects With Relapsed Small-cell Lung Cancer (SCLC)
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open label, Single arm Oral topotecan + IV Bevacizumab	Drug: Oral Hycamtin (topotecan) Capsules + IV Avastin (bevacizumab); 2.3 mg/m2 daily x 5 oral topotecan and 15 mg/kg IV bevacizumab on day 1 of every 21 days cycle.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Progression-free Survival (PFS) at 3 Months [3 months]

   PFS = time from initiation of drug to time of first disease progression/death due to any cause. Progression assessed using Response Evaluation Criteria (RECIST): >=20% increase in sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since treatment started, or appearance of new lesion(s). If participant did not progress or die, the time of initiation of post-treatment anti-cancer therapy or time of last contact used. PFS at 3 months calculated by taking the Kaplan-Meier (KM) estimate at 90 days from the initiation of treatment. SE = standard error.

Secondary Outcome Measures

1. PFS - Overall [Baseline to disease progression or death (up to 82.4 weeks)]

   Progression-free survival at any site was defined as the time from initiation of investigational product to the time of first documented disease progression or death due to any cause. Progression was assessed using the RECIST guidelines: >= 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment started, or appearance of new lesion (s). For participants who did not progress or die, the time of initiation of post-treatment anti-cancer therapy or the time of last contact was used.

2. Number of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) [Baseline to disease progression or death (up to 82.4 weeks)]

   Tumor response was determined using the RECIST guidelines.CR, disappearance of all target lesions; PR, >=30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since treatment started; PD, >=20% increase in sum of LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

3. Number of Participants With a Tumor Response (CR and PR) [Baseline to disease progression or death (up to 82.4 weeks)]

   Tumor response was determined using the RECIST guidelines. CR: disappearance of all target lesions. PR: >=30% decrease in sum of LD of target lesions, taking as reference the baseline sum LD.

4. Duration of Tumor Response (CR and PR) [Baseline to disease progression or death (up to 82.4 weeks)]

   Tumor response was determined using the RECIST guidelines. CR: disappearance of all target lesions. PR: >=30% decrease in sum of LD of target lesions, taking as reference the baseline sum LD. Duration of response is defined as the time from start of response (CR or PR) until progression or death due to any cause. For participants who did not progress or die, the time of initiation of post-treatment anti-cancer therapy or the time of last contact was used.

5. Time to Tumor Response (CR and PR) [Baseline to disease progression or death (up to 82.4 weeks)]

   Tumor response was determined using the RECIST guidelines. CR: disappearance of all target lesions. PR: >=30% decrease in sum of LD of target lesions, taking as reference the baseline sum LD. Time to response is defined as the time from initiation of investigational product to the time of first documented response (CR or PR).

6. Overall Survival [Baseline to disease progression or death (up to 82.4 weeks)]

   Overall survival is defined as the time from initiation of investigational product to death due to any cause. For participants who did not die, the time of last contact was used.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of SCLC.

• First recurrence of SCLC after therapy with one prior chemotherapy regimen at initial diagnosis.

• Relapsed SCLC of any duration (both sensitive and resistant relapse).

• ECOG performance status of </= 2.

• Adequate bone marrow reserve, hepatic, renal, and cardiovascular function.

• No prior therapy with bevacizumab or any other VEGF inhibitor or topotecan

Exclusion Criteria:

• Uncontrolled emesis, regardless of etiology.

• Active uncontrolled infection.

• GI conditions or drugs that could impact absorption of oral topotecan.

• Known hypersensitivity to any component of topotecan capsule or compounds chemically related to topotecan.

• Uncontrolled hypertension with BP>150/100.

• Prior h/o hypertensive crisis or encephalopathy.

• NYHA Grade II or greater congestive heart failure.

• H/O myocardial infarction within 6 months.

• H/O stroke or TIA within 6 months.

• H/O thrombotic or hemorrhagic disorders.

• Clinically significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months.

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days.

• Anticipation of need for major surgical procedure during the study.

• Minor surgical procedures within 7 days prior to treatment start (placement of vascular access devices is permitted).

• H/O abdominal fistula, GI perforation, or intra-abdominal abscess within prior 6 months. Serious, non-healing wound, active ulcer, or untreated bone fracture. - H/O hemoptysis within prior 1 month.

• Concurrent radiotherapy.

• H/O whole lung radiation within 90 days prior to start of treatment.

• Presence or h/o central nervous system or brain metastases.

• H/o another malignancy other than SCLC.

• Concurrent chemotherapy, immunotherapy, or investigational therapy for the treatment of small cell lung cancer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Jonesboro	Arkansas	United States	72401
2	GSK Investigational Site	Gainesville	Florida	United States	32605
3	GSK Investigational Site	Naples	Florida	United States	34119
4	GSK Investigational Site	Athens	Georgia	United States	30607
5	GSK Investigational Site	Macon	Georgia	United States	31201
6	GSK Investigational Site	Marietta	Georgia	United States	30060
7	GSK Investigational Site	Jackson	Mississippi	United States	39202
8	GSK Investigational Site	Cincinnati	Ohio	United States	45236
9	GSK Investigational Site	Mt. Pleasant	South Carolina	United States	29464
10	GSK Investigational Site	Chattanooga	Tennessee	United States	37404
11	GSK Investigational Site	Memphis	Tennessee	United States	38104
12	GSK Investigational Site	Memphis	Tennessee	United States	38120
13	GSK Investigational Site	Nashville	Tennessee	United States	37203
14	GSK Investigational Site	Fort Worth	Texas	United States	76104
15	GSK Investigational Site	Seattle	Washington	United States	98101-2795
16	GSK Investigational Site	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00698516
• Other Study ID Numbers: 104864/111127
• First Posted: Jun 17, 2008
• Last Update Posted: Mar 27, 2012
• Last Verified: Mar 1, 2011

• Keywords provided by GlaxoSmithKline: Bevacizumab; Small Cell Lung Cancer (SCLC); Topotecan
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Bevacizumab; Topotecan

Study Results

Participant Flow

Arm/Group Title	Topotecan and Bevacizumab
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles.
Period Title: Overall Study
STARTED	50
COMPLETED	45
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Topotecan and Bevacizumab
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles.
Overall Participants	50
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.8 (10.75)
Sex: Female, Male (Count of Participants)
Female	26 52%
Male	24 48%
Race/Ethnicity, Customized (participants) [Number]
White	43 86%
African American/African Heritage	6 12%
White and Mixed Race	1 2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Progression-free Survival (PFS) at 3 Months
Description	PFS = time from initiation of drug to time of first disease progression/death due to any cause. Progression assessed using Response Evaluation Criteria (RECIST): >=20% increase in sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since treatment started, or appearance of new lesion(s). If participant did not progress or die, the time of initiation of post-treatment anti-cancer therapy or time of last contact used. PFS at 3 months calculated by taking the Kaplan-Meier (KM) estimate at 90 days from the initiation of treatment. SE = standard error.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants who received at least one dose of study medication

Arm/Group Title	Topotecan and Bevacizumab
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles.
Measure Participants	50
Number [percentageof participants]	65 130%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Topotecan and Bevacizumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	Historical data in target population showed 3-month PFS rates of <=50%. Oral topotecan with IV bevacizumab would provide clinically meaningful improvement in 3-month PFS if it could demonstrate a 40% improvement relative to the historical data.
	Method	Z statistic
	Comments	Z statistic was used to reject the null hypothesis provided Z>=1.65, where Z = (KM estimate at 3 months - null hypothesis value [50%])/Greenwood SE.
Method of Estimation	Estimation Parameter	Greenwood variance
	Estimated Value	65.0
	Confidence Interval	(2-Sided) 95%; 49.3 to 76.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.07
	Estimation Comments

2. Secondary Outcome

Title	PFS - Overall
Description	Progression-free survival at any site was defined as the time from initiation of investigational product to the time of first documented disease progression or death due to any cause. Progression was assessed using the RECIST guidelines: >= 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment started, or appearance of new lesion (s). For participants who did not progress or die, the time of initiation of post-treatment anti-cancer therapy or the time of last contact was used.
Time Frame	Baseline to disease progression or death (up to 82.4 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Topotecan and Bevacizumab: Resistant Participants	Topotecan and Bevacizumab: Sensitive Participants	Topotecan and Bevacizumab: All Participants
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was <= 90 days; therefore, these participants were termed "resistant".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was &gt;90 days; therefore, these participants were termed "sensitive".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. This groups consists of both resistant and sensitive participants.
Measure Participants	23	27	50
Median (95% Confidence Interval) [weeks]	12.64	27.14	17.43

3. Secondary Outcome

Title	Number of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)
Description	Tumor response was determined using the RECIST guidelines.CR, disappearance of all target lesions; PR, >=30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since treatment started; PD, >=20% increase in sum of LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	Baseline to disease progression or death (up to 82.4 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Topotecan and Bevacizumab: Resistant Participants	Topotecan and Bevacizumab: Sensitive Participants	Topotecan and Bevacizumab: All Participants
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was <= 90 days; therefore, these participants were termed "resistant".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was &gt;90 days; therefore, these participants were termed "sensitive".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. This groups consists of both resistant and sensitive participants.
Measure Participants	23	27	50
CR	0 0%	0 NaN	0 NaN
PR	2 4%	6 NaN	8 NaN
SD	9 18%	11 NaN	20 NaN
PD	9 18%	4 NaN	13 NaN
Unknown	3 6%	6 NaN	9 NaN

4. Secondary Outcome

Title	Number of Participants With a Tumor Response (CR and PR)
Description	Tumor response was determined using the RECIST guidelines. CR: disappearance of all target lesions. PR: >=30% decrease in sum of LD of target lesions, taking as reference the baseline sum LD.
Time Frame	Baseline to disease progression or death (up to 82.4 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Topotecan and Bevacizumab: Resistant Participants	Topotecan and Bevacizumab: Sensistive Participants	Topotecan and Bevacizumab: All Participants
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was <= 90 days; therefore, these participants were termed "resistant".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was &gt;90 days; therefore, these participants were termed "sensitive".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. This groups consists of both resistant and sensitive participants.
Measure Participants	23	27	50
Number [participants]	2 4%	6 NaN	8 NaN

5. Secondary Outcome

Title	Duration of Tumor Response (CR and PR)
Description	Tumor response was determined using the RECIST guidelines. CR: disappearance of all target lesions. PR: >=30% decrease in sum of LD of target lesions, taking as reference the baseline sum LD. Duration of response is defined as the time from start of response (CR or PR) until progression or death due to any cause. For participants who did not progress or die, the time of initiation of post-treatment anti-cancer therapy or the time of last contact was used.
Time Frame	Baseline to disease progression or death (up to 82.4 weeks)

Outcome Measure Data

Analysis Population Description

Participants from the ITT Population who had CR and PR

Arm/Group Title	Topotecan and Bevacizumab
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles.
Measure Participants	8
Median (95% Confidence Interval) [weeks]	20.6

6. Secondary Outcome

Title	Time to Tumor Response (CR and PR)
Description	Tumor response was determined using the RECIST guidelines. CR: disappearance of all target lesions. PR: >=30% decrease in sum of LD of target lesions, taking as reference the baseline sum LD. Time to response is defined as the time from initiation of investigational product to the time of first documented response (CR or PR).
Time Frame	Baseline to disease progression or death (up to 82.4 weeks)

Outcome Measure Data

Analysis Population Description

Participants from the ITT Population who had CR and PR

Arm/Group Title	Topotecan and Bevacizumab
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles.
Measure Participants	8
Median (95% Confidence Interval) [weeks]	5.8

7. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from initiation of investigational product to death due to any cause. For participants who did not die, the time of last contact was used.
Time Frame	Baseline to disease progression or death (up to 82.4 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Topotecan and Bevacizumab: Resistant Participants	Topotecan and Bevacizumab: Sensitive Participants	Topotecan and Bevacizumab: All Participants
Arm/Group Description	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was <= 90 days; therefore, these participants were termed "resistant".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. The time to progression from the end of prior chemotherapy was &gt;90 days; therefore, these participants were termed "sensitive".	Participants were to receive oral topotecan 2.3 milligrams (mg)/meters squared (m^2)/day for 5 consecutive days (Days 1 to 5) and intravenous (IV) bevacizumab 15 mg/kilograms (kg) on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GlaxoSmithKline's study physician was needed for participants who required treatment beyond 8 cycles. This groups consists of both resistant and sensitive participants.
Measure Participants	23	27	50
Median (95% Confidence Interval) [weeks]	26.4	37.0	32.0

Adverse Events

Arm/Group Title	Topotecan and Bevacizumab
Arm/Group Description	Participants were to receive oral topotecan 2.3 mg/m^2/day for 5 consecutive days (Days 1 to 5) and IV bevacizumab 15 mg/kg on Day 1 of each 21-day cycle. Treatment was to be continued for up to 8 cycles (a minimum of 4 cycles was recommended) or until disease progression or development of unacceptable toxicity, whichever occurred first. Prior approval from GSK's study physician was needed for subjects who required treatment beyond 8 cycles.
All Cause Mortality
	Topotecan and Bevacizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Topotecan and Bevacizumab
	Affected / at Risk (%)	# Events
Total	18/50 (36%)
Blood and lymphatic system disorders
Febrile neutropenia	2/50 (4%)
Thrombocytopenia	2/50 (4%)
Neutropenia	1/50 (2%)
Pancytopenia	1/50 (2%)
Cardiac disorders
Pericardial effusion	1/50 (2%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	2/50 (4%)
Gastrointestinal disorders
Diarrhoea	3/50 (6%)
Nausea	2/50 (4%)
Vomiting	2/50 (4%)
Dysphagia	1/50 (2%)
Upper gastrointestinal haemorrhage	1/50 (2%)
General disorders
Asthenia	1/50 (2%)
Chest pain	1/50 (2%)
Fatigue	1/50 (2%)
Pain	1/50 (2%)
Pyrexia	1/50 (2%)
Infections and infestations
Pneumonia	4/50 (8%)
Sepsis	2/50 (4%)
Bronchitis	1/50 (2%)
Neutropenic infection	1/50 (2%)
Urinary tract infection	1/50 (2%)
Metabolism and nutrition disorders
Dehydration	2/50 (4%)
Decreased appetite	1/50 (2%)
Diabetic ketoacidosis	1/50 (2%)
Hyponatraemia	1/50 (2%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/50 (2%)
Nervous system disorders
Depressed level of consciousness	1/50 (2%)
Somnolence	1/50 (2%)
Psychiatric disorders
Depression	1/50 (2%)
Mental status changes	1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	2/50 (4%)
Acute respiratory failure	1/50 (2%)
Pneumothorax	1/50 (2%)
Respiratory distress	1/50 (2%)
Respiratory failure	1/50 (2%)
Other (Not Including Serious) Adverse Events
	Topotecan and Bevacizumab
	Affected / at Risk (%)	# Events
Total	50/50 (100%)
Blood and lymphatic system disorders
Anaemia	27/50 (54%)
Neutropenia	22/50 (44%)
Thrombocytopenia	21/50 (42%)
Leukopenia	11/50 (22%)
Pancytopenia	3/50 (6%)
Gastrointestinal disorders
Nausea	30/50 (60%)
Diarrhoea	27/50 (54%)
Vomiting	19/50 (38%)
Constipation	17/50 (34%)
Abdominal pain	6/50 (12%)
Abdominal pain upper	4/50 (8%)
Dysphagia	4/50 (8%)
Oral pain	3/50 (6%)
General disorders
Fatigue	32/50 (64%)
Asthenia	12/50 (24%)
Pain	4/50 (8%)
Chills	3/50 (6%)
Gait disturbance	3/50 (6%)
Pyrexia	3/50 (6%)
Infections and infestations
Urinary tract infection	4/50 (8%)
Nasopharyngitis	3/50 (6%)
Upper respiratory tract infection	3/50 (6%)
Injury, poisoning and procedural complications
Fall	3/50 (6%)
Investigations
Weight decreased	8/50 (16%)
Platelet count decreased	4/50 (8%)
Metabolism and nutrition disorders
Decreased appetite	24/50 (48%)
Dehydration	14/50 (28%)
Hypokalaemia	7/50 (14%)
Hypomagnesaemia	6/50 (12%)
Hyponatraemia	4/50 (8%)
Musculoskeletal and connective tissue disorders
Back pain	8/50 (16%)
Arthralgia	6/50 (12%)
Musculoskeletal pain	5/50 (10%)
Muscular weakness	4/50 (8%)
Bone pain	3/50 (6%)
Muscle spasms	3/50 (6%)
Neck pain	3/50 (6%)
Nervous system disorders
Dizziness	10/50 (20%)
Headache	10/50 (20%)
Dysgeusia	6/50 (12%)
Psychiatric disorders
Anxiety	6/50 (12%)
Insomnia	6/50 (12%)
Confusional state	5/50 (10%)
Depression	4/50 (8%)
Renal and urinary disorders
Proteinuria	4/50 (8%)
Respiratory, thoracic and mediastinal disorders
Cough	15/50 (30%)
Epistaxis	14/50 (28%)
Dyspnoea	13/50 (26%)
Dysphonia	6/50 (12%)
Oropharyngeal pain	4/50 (8%)
Skin and subcutaneous tissue disorders
Alopecia	6/50 (12%)
Vascular disorders
Hypotension	3/50 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.