A Study of Avastin (Bevacizumab) And Fotemustine in Patients With Recurrent Glioblastoma

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01474239
• Collaborator: (none)
• Enrollment: 91
• Locations: 10
• Arms: 2
• Duration (Months): 25
• Patients Per Site: 9.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This randomized, non-comparative study will evaluate the efficacy and safety of Avastin (bevacizumab) in patients with recurrent glioblastoma. Patients will be randomized to receive Avastin 10 mg/kg intravenously every 2 weeks or fotemustine 75 mg/m2 on days 1, 8 and 15, followed by, after a 5 weeks interval, 100 mg/m2 intravenously every 3 weeks. Treatment with fotemustine serves as a calibration arm and no formal efficacy comparison will be made between the two treatment arms. The anticipated time of study treatment is until disease progression or unacceptable toxicity.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Drug: bevacizumab [Avastin]; Drug: fotemustine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 91 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Non Comparative Phase II Trial With Bevacizumab and Fotemustine in the Treatment of Recurrent Glioblastoma
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Calibration Arm	Drug: fotemustine; 75 mg/m2 intravenously on days 1, 8 and 15 followed by, after a 5 weeks interval, 100 mg/m2 on day 1 of a 3-weeks cycle. Until disease progression or unacceptable toxicity
Experimental: Investigational Arm	Drug: bevacizumab [Avastin]; 10 mg/kg every 2 weeks intravenously until disease progression or unacceptable toxicity

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Alive 6 Months After Start of Treatment [6 months]

   Overall survival (OS) was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of magnetic resonance imaging (MRI) assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.

2. Overall Survival (OS) [Baseline until death (up to 691 days)]

   OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.

Secondary Outcome Measures

1. Percentage of Participants Who Were Alive and Progression Free 6 Months After Start of Treatment [6 months]

   Progression-free survival (PFS) was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by the Kaplan-Meier method. Progression was assessed using Response Assessment in Neuro-Oncology (RANO) or Macdonald Response Criteria, whichever occurred first. As per the RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per the Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.

2. Progression-Free Survival (PFS) [Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days)]

   PFS was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by the Kaplan-Meier method. Progression was assessed using the RANO or the Macdonald Response Criteria, whichever occurred first. As per RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.

3. Percentage of Participants Alive 9 Months After Start of Treatment [9 months]

   OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.

4. Percentage of Participants Alive 12 Months After Start of Treatment [12 months]

   OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.

5. Percentage of Participants Alive 30 Days After Last Dose of Study Drug [30 days after last dose of study drug (up to Day 600)]

   OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.

6. Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days)]

   Percentage of participants achieving CR or PR as overall response between first drug administration and documented disease progression were calculated. Tumor response was evaluated according to both the RANO and the Macdonald response criteria. As per Macdonald criteria, CR was defined as the disappearance of all enhancing disease, sustained for at least 4 weeks, and no new lesions along with clinical features of clinically stable or improved, with no corticosteroid; PR was defined as a 50% or more decrease of all measurable enhancing lesions, sustained for at least 4 weeks, and no new lesion along with clinical features of clinically stable or improved, with stable or reduced corticosteroids. RANO criteria defined CR and PR the same as Macdonald criteria with the following additions: CR - improved non enhancing T2/FLAIR lesions; PR - no progression of non-measurable disease, stable or improved non enhancing FLAIR/T2 lesions.

7. Change From Screening in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores at Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72 [Screening, Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72]

   EORTC QLQ-C30: included global health status/quality of life (QOL), functional scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; a higher score for Global QOL/functional scales indicates better level of QOL/functioning, or a higher score for symptom scale indicates greater degree of symptoms.

8. Percentage of Participants With Corticosteroid Initiation During the Study Period [Baseline until recurrence (up to 691 days)]

   Corticosteroid initiation was assessed in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage greater than equal to (>/=) 2 mg dexamethasone equivalent.

9. Time to Corticosteroid Initiation [Baseline until recurrence (up to 691 days)]

   Time to corticosteroid initiation was defined as the time from screening to the start date of the first corticosteroid administration in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage ≥2 mg dexamethasone equivalent. Instead, if the participant was not known to have the event, time was censored at the last available visit date. Time to corticosteroid initiation was estimated using Kaplan Meier method.

10. Percentage of Participants in Each Class of Corticosteroid Use [Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, post-treatment follow-up (up to Day 691)]

    Corticosteroid use was classified as: 1. No Change (if corticosteroid dose at each assessment was equal to baseline); 2. Decreased (if corticosteroid dose at each assessment was lower than baseline); 3. Increased (corticosteroid dose at each assessment was greater than baseline).

11. Percentage of Participants With Karnofsky Performance Status (KPS) Deterioration [Baseline until KPS deterioration (up to 691 days)]

    Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks.

12. Time to Karnofsky Performance Status (KPS) Deterioration [Baseline until KPS deterioration (up to 691 days)]

    Time to KPS deterioration was defined as the time from screening to the first date of deterioration of the KPS score. Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Time to KPS deterioration was estimated using Kaplan Meier method. If the participant was not known to have the event, time was censored at the last available visit date.

13. Percentage of Participants With World Health Organization (WHO) Performance Status (PS) Deterioration [Baseline until WHO PS deterioration (Up to 691 days)]

    WHO PS deterioration was defined as a decrease of at least 1 point with respect to the screening value. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks.

14. Time to WHO PS Deterioration [Baseline until WHO PS deterioration (Up to 691 days)]

    Time to WHO PS deterioration was defined as the time from randomization to the first date of deterioration of the WHO performance status score. WHO PS deterioration was defined as a decrease of at least 1 point with respect to the screening value. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adult patients, >/=18 years of age

• Diagnosis of recurrent glioblastoma multiforme (Grade IV)

• Previous treatment with temozolomide and radiotherapy

• First recurrence after standard adjuvant treatment (surgery, followed by radiotherapy and chemotherapy)

• Adequate hematological, biochemical and organ functions

Exclusion Criteria:

• Previous treatment with Avastin or other anti-angiogenic drugs

• Residual relevant toxicity resulting from previous therapy

• Radiotherapy within the 3 months prior to the diagnosis of disease progression

• Chemotherapy in the previous 4 weeks

• Other active or inactive malignancies (except for carcinoma in situ of the cervix, of the prostate or basal cell carcinoma)

• Clinically significant cardiovascular diseases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Napoli	Campania	Italy	80131
2		Bologna	Emilia-Romagna	Italy	40133
3		Roma	Lazio	Italy	00168
4		Genova	Liguria	Italy	16128
5		Milano	Lombardia	Italy	20132
6		Milano	Lombardia	Italy	20133
7		San Giovanni Rotondo	Puglia	Italy	71013
8		Terni	Umbria	Italy	05100
9		Padova	Veneto	Italy	35128
10		Treviso	Veneto	Italy	31100

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: NCT01474239
• Other Study ID Numbers: ML25739
• First Posted: Nov 18, 2011
• Last Update Posted: Mar 15, 2016
• Last Verified: Sep 1, 2015

• Additional relevant MeSH terms: Glioblastoma; Bevacizumab; Fotemustine

Study Results

Participant Flow

Pre-assignment Detail	Study included 28-day screening period. Participants were randomized according to a 2:1 ratio to one of the 2 treatment groups. A total of 99 participants were screened, of which 91 were randomized.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 milligrams per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Period Title: Overall Study
STARTED	59	32
COMPLETED	0	0
NOT COMPLETED	59	32

Baseline Characteristics

Arm/Group Title	Bevacizumab	Fotemustine	Total
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Total of all reporting groups
Overall Participants	59	32	91
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.86 (9.40)	55.63 (10.64)	56.43 (9.81)
Sex: Female, Male (Count of Participants)
Female	20 33.9%	9 28.1%	29 31.9%
Male	39 66.1%	23 71.9%	62 68.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Alive 6 Months After Start of Treatment
Description	Overall survival (OS) was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of magnetic resonance imaging (MRI) assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population included all randomized participants with at least one administration of the study drug.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
Number (95% Confidence Interval) [percentage of participants]	62.07 105.2%	73.33 229.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab
	Comments	The 6-month OS rate (OS-6) for bevacizumab was compared to the expected proportion of 0.60 under null hypothesis (ineffective treatment) with the application of the exact binomial test. The one-tailed statistical hypotheses was p0 less than or equal to (≤) 0.60 (null hypothesis) versus pA greater than or equal to (≥) 0.77 (alternative hypothesis), where p is the estimated probability of survival at 6 months.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4291
	Comments	Statistical significance was assessed with a one-sided alpha error of 10 percent (%).
	Method	Exact Binomial Test
	Comments

2. Primary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Time Frame	Baseline until death (up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
Median (95% Confidence Interval) [months]	7.26	8.66

3. Secondary Outcome

Title	Percentage of Participants Who Were Alive and Progression Free 6 Months After Start of Treatment
Description	Progression-free survival (PFS) was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by the Kaplan-Meier method. Progression was assessed using Response Assessment in Neuro-Oncology (RANO) or Macdonald Response Criteria, whichever occurred first. As per the RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per the Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
Number (95% Confidence Interval) [percentage of participants]	26.32 44.6%	10.71 33.5%

4. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by the Kaplan-Meier method. Progression was assessed using the RANO or the Macdonald Response Criteria, whichever occurred first. As per RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.
Time Frame	Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
Median (95% Confidence Interval) [months]	3.38	3.45

5. Secondary Outcome

Title	Percentage of Participants Alive 9 Months After Start of Treatment
Description	OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
Number (95% Confidence Interval) [percentage of participants]	37.93 64.3%	46.67 145.8%

6. Secondary Outcome

Title	Percentage of Participants Alive 12 Months After Start of Treatment
Description	OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

ITT population. Here, the number of participants analyzed signified participants with evaluable data for this outcome.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	58	30
Number (95% Confidence Interval) [percentage of participants]	25.86 43.8%	40.00 125%

7. Secondary Outcome

Title	Percentage of Participants Alive 30 Days After Last Dose of Study Drug
Description	OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Time Frame	30 days after last dose of study drug (up to Day 600)

Outcome Measure Data

Analysis Population Description

ITT population. Here, the number of participants analyzed signified participants with evaluable data for this outcome.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	58	30
Number (95% Confidence Interval) [percentage of participants]	93.10 157.8%	90.00 281.3%

8. Secondary Outcome

Title	Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR)
Description	Percentage of participants achieving CR or PR as overall response between first drug administration and documented disease progression were calculated. Tumor response was evaluated according to both the RANO and the Macdonald response criteria. As per Macdonald criteria, CR was defined as the disappearance of all enhancing disease, sustained for at least 4 weeks, and no new lesions along with clinical features of clinically stable or improved, with no corticosteroid; PR was defined as a 50% or more decrease of all measurable enhancing lesions, sustained for at least 4 weeks, and no new lesion along with clinical features of clinically stable or improved, with stable or reduced corticosteroids. RANO criteria defined CR and PR the same as Macdonald criteria with the following additions: CR - improved non enhancing T2/FLAIR lesions; PR - no progression of non-measurable disease, stable or improved non enhancing FLAIR/T2 lesions.
Time Frame	Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
RANO Evaluation	28.81 48.8%	9.38 29.3%
MacDonald Evaluation	28.81 48.8%	6.25 19.5%

9. Secondary Outcome

Title	Change From Screening in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores at Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72
Description	EORTC QLQ-C30: included global health status/quality of life (QOL), functional scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; a higher score for Global QOL/functional scales indicates better level of QOL/functioning, or a higher score for symptom scale indicates greater degree of symptoms.
Time Frame	Screening, Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72

Outcome Measure Data

Analysis Population Description

ITT population. Here, the number of participants analyzed signified participants with evaluable data for this outcome, and "n" signified participants with evaluable data for specified category for each arm, respectively.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	58	31
Physical Functioning (Fn): Screening (n=58,31)	71.95 (25.65)	78.92 (25.07)
Physical Fn: Change at Week 8 (n=27,16)	10.37 (19.07)	7.08 (12.76)
Physical Fn: Change at Week 16 (n=15,7)	7.56 (19.17)	8.57 (13.72)
Physical Fn: Change at Week 24 (n=14,1)	13.81 (24.17)	0.00 (NA)
Physical Fn: Change at Week 32 (n=7,2)	18.10 (28.21)	13.33 (9.43)
Physical Fn: Change at Week 40 (n=9,1)	4.44 (19.72)	6.67 (NA)
Physical Fn: Change at Week 48 (n=4,1)	3.33 (16.78)	6.67 (NA)
Physical Fn: Change at Week 56 (n=4,0)	6.67 (9.43)	NA (NA)
Physical Fn: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
Physical Fn: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)
Role Fn: Screening (n=58,31)	67.82 (31.04)	73.66 (32.14)
Role Fn: Change at Week 8 (n=27,16)	6.17 (34.01)	4.17 (21.52)
Role Fn: Change at Week 16 (n=15,7)	2.22 (25.87)	2.38 (26.23)
Role Fn: Change at Week 24 (n=14,1)	14.29 (33.88)	0.00 (NA)
Role Fn: Change at Week 32 (n=7,2)	16.67 (28.87)	0.00 (0.00)
Role Fn: Change at Week 40 (n=9,1)	0.00 (22.05)	0.00 (NA)
Role Fn: Change at Week 48 (n=4,1)	0.00 (36.00)	0.00 (NA)
Role Fn: Change at Week 56 (n=4,0)	-12.50 (36.96)	NA (NA)
Role Fn: Change at Week 64 (n=1,0)	-50.00 (NA)	NA (NA)
Role Fn: Change at Week 72 (n=1,0)	-50.00 (NA)	NA (NA)
Emotional Fn: Screening (n=58,31)	73.56 (23.47)	74.19 (23.41)
Emotional Fn: Change at Week 8 (n=27,16)	-8.02 (23.62)	8.33 (24.91)
Emotional Fn: Change at Week 16 (n=15,7)	-0.56 (14.25)	-2.38 (27.52)
Emotional Fn: Change at Week 24 (n=14,1)	10.12 (29.63)	-33.33 (NA)
Emotional Fn: Change at Week 32 (n=7,2)	-2.38 (15.00)	16.67 (0.00)
Emotional Fn: Change at Week 40 (n=9,1)	-5.56 (24.65)	8.33 (NA)
Emotional Fn: Change at Week 48 (n=4,1)	14.58 (27.53)	8.33 (NA)
Emotional Fn: Change at Week 56 (n=4,0)	-4.17 (27.64)	NA (NA)
Emotional Fn: Change at Week 64 (n=1,0)	8.33 (NA)	NA (NA)
Emotional Fn: Change at Week 72 (n=1,0)	8.33 (NA)	NA (NA)
Cognitive Fn: Screening (n=58,31)	70.40 (25.18)	79.03 (24.33)
Cognitive Fn: Change at Week 8 (n=27,16)	4.94 (23.49)	7.29 (23.55)
Cognitive Fn: Change at Week 16 (n=15,7)	2.22 (17.67)	-4.76 (34.31)
Cognitive Fn: Change at Week 24 (n=14,1)	10.71 (24.11)	0.00 (NA)
Cognitive Fn: Change at Week 32 (n=7,2)	0.00 (16.67)	8.33 (11.79)
Cognitive Fn: Change at Week 40 (n=9,1)	-1.85 (19.44)	0.00 (NA)
Cognitive Fn: Change at Week 48 (n=4,1)	0.00 (0.00)	0.00 (NA)
Cognitive Fn: Change at Week 56 (n=4,0)	-4.17 (20.97)	NA (NA)
Cognitive Fn: Change at Week 64 (n=1,0)	16.67 (NA)	NA (NA)
Cognitive Fn: Change at Week 72 (n=1,0)	16.67 (NA)	NA (NA)
Social Fn: Screening (n=58,31)	72.99 (28.07)	81.18 (24.24)
Social Fn: Change at Week 8 (n=27,16)	1.85 (31.12)	4.17 (23.96)
Social Fn: Change at Week 16 (n=15,7)	1.11 (27.07)	-2.38 (26.23)
Social Fn: Change at Week 24 (n=14,1)	13.10 (39.32)	0.00 (NA)
Social Fn: Change at Week 32 (n=7,2)	-7.14 (38.32)	8.33 (11.79)
Social Fn: Change at Week 40 (n=9,1)	-5.56 (22.05)	16.67 (NA)
Social Fn: Change at Week 48 (n=4,1)	-4.17 (36.96)	16.67 (NA)
Social Fn: Change at Week 56 (n=4,0)	-12.50 (28.46)	NA (NA)
Social Fn: Change at Week 64 (n=1,0)	-66.67 (NA)	NA (NA)
Social Fn: Change at Week 72 (n=1,0)	-66.67 (NA)	NA (NA)
QOL: Screening (n=58,31)	58.05 (26.40)	66.13 (24.90)
QOL: Change at Week 8 (n=27,16)	-3.09 (20.17)	6.25 (22.87)
QOL: Change at Week 16 (n=15,7)	-4.44 (14.39)	7.14 (23.78)
QOL: Change at Week 24 (n=14,1)	4.76 (21.11)	0.00 (NA)
QOL: Change at Week 32 (n=7,2)	3.57 (17.91)	-12.50 (17.68)
QOL: Change at Week 40 (n=9,1)	-2.78 (25.34)	0.00 (NA)
QOL: Change at Week 48 (n=4,1)	10.42 (14.23)	0.00 (NA)
QOL: Change at Week 56 (n=4,0)	2.08 (34.94)	NA (NA)
QOL: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
QOL: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)
Fatigue: Screening (n=58,31)	31.99 (25.50)	24.01 (22.05)
Fatigue: Change at Week 8 (n=27,16)	-3.29 (32.59)	-13.19 (25.73)
Fatigue: Change at Week 16 (n=15,7)	2.22 (21.50)	-9.52 (17.48)
Fatigue: Change at Week 24 (n=14,1)	-6.35 (29.79)	-11.11 (NA)
Fatigue: Change at Week 32 (n=7,2)	3.17 (17.82)	-5.56 (7.86)
Fatigue: Change at Week 40 (n=9,1)	9.88 (23.20)	-11.11 (NA)
Fatigue: Change at Week 48 (n=4,1)	-8.33 (18.98)	-11.11 (NA)
Fatigue: Change at Week 56 (n=4,0)	2.78 (30.60)	NA (NA)
Fatigue: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
Fatigue: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)
Nausea: Screening (n=58,31)	2.01 (7.70)	1.08 (4.16)
Nausea: Change at Week 8 (n=27,16)	1.85 (10.68)	-8.33 (14.91)
Nausea: Change at Week 16 (n=15,7)	0.00 (6.30)	-14.29 (20.25)
Nausea: Change at Week 24 (n=14,1)	-5.95 (10.56)	0.00 (NA)
Nausea: Change at Week 32 (n=7,2)	-2.38 (6.30)	0.00 (0.00)
Nausea: Change at Week 40 (n=9,1)	-9.26 (8.78)	0.00 (NA)
Nausea: Change at Week 48 (n=4,1)	0.00 (0.00)	-16.67 (NA)
Nausea: Change at Week 56 (n=4,0)	-4.17 (8.33)	NA (NA)
Nausea: Change at Week 64 (n=1,0)	-16.67 (NA)	NA (NA)
Nausea: Change at Week 72 (n=1,0)	-16.67 (NA)	NA (NA)
Pain: Screening (n=58,31)	6.90 (16.82)	14.52 (23.47)
Pain: Change at Week 8 (n=27,16)	-1.85 (24.61)	-6.25 (26.44)
Pain: Change at Week 16 (n=15,7)	-10.00 (19.72)	-2.38 (20.25)
Pain: Change at Week 24 (n=14,1)	-8.33 (28.31)	0.00 (NA)
Pain: Change at Week 32 (n=7,2)	0.00 (16.67)	-8.33 (11.79)
Pain: Change at Week 40 (n=9,1)	-7.41 (18.84)	0.00 (NA)
Pain: Change at Week 48 (n=4,1)	-29.17 (28.46)	0.00 (NA)
Pain: Change at Week 56 (n=4,0)	0.00 (19.25)	NA (NA)
Pain: Change at Week 64 (n=1,0)	-16.67 (NA)	NA (NA)
Pain: Change at Week 72 (n=1,0)	-16.67 (NA)	NA (NA)
Dyspnea: Screening (n=58,31)	11.49 (22.12)	3.23 (10.02)
Dyspnea: Change at Week 8 (n=27,16)	4.94 (28.80)	-6.25 (21.84)
Dyspnea: Change at Week 16 (n=15,7)	0.00 (25.20)	4.76 (12.60)
Dyspnea: Change at Week 24 (n=14,1)	-9.52 (27.51)	0.00 (NA)
Dyspnea: Change at Week 32 (n=7,2)	0.00 (27.22)	0.00 (0.00)
Dyspnea: Change at Week 40 (n=9,1)	3.70 (20.03)	0.00 (NA)
Dyspnea: Change at Week 48 (n=4,1)	-8.33 (16.67)	0.00 (NA)
Dyspnea: Change at Week 56 (n=4,0)	0.00 (27.22)	NA (NA)
Dyspnea: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
Dyspnea: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)
Insomnia: Screening (n=58,31)	18.39 (28.73)	18.28 (22.51)
Insomnia: Change at Week 8 (n=27,16)	1.23 (25.29)	-8.33 (33.33)
Insomnia: Change at Week 16 (n=15,7)	2.22 (32.04)	-4.76 (29.99)
Insomnia: Change at Week 24 (n=14,1)	-9.52 (46.09)	-33.33 (NA)
Insomnia: Change at Week 32 (n=7,2)	28.57 (23.00)	16.67 (23.57)
Insomnia: Change at Week 40 (n=9,1)	14.81 (24.22)	33.33 (NA)
Insomnia: Change at Week 48 (n=4,1)	25.00 (31.91)	33.33 (NA)
Insomnia: Change at Week 56 (n=4,0)	33.33 (27.22)	NA (NA)
Insomnia: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
Insomnia: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)
Appetite loss: Screening (n=58,31)	7.47 (19.79)	5.38 (12.46)
Appetite loss: Change at Week 8 (n=27,16)	0.00 (22.65)	-10.42 (23.47)
Appetite loss: Change at Week 16 (n=15,7)	-2.22 (8.61)	-14.29 (26.23)
Appetite loss: Change at Week 24 (n=14,1)	-7.14 (19.30)	0.00 (NA)
Appetite loss: Change at Week 32 (n=7,2)	-4.76 (12.60)	0.00 (0.00)
Appetite loss: Change at Week 40 (n=9,1)	-7.41 (14.70)	0.00 (NA)
Appetite loss: Change at Week 48 (n=4,1)	-16.67 (19.25)	0.00 (NA)
Appetite loss: Change at Week 56 (n=4,0)	-16.67 (19.25)	NA (NA)
Appetite loss: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
Appetite loss: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)
Constipation: Screening (n=58,31)	17.82 (24.36)	17.20 (25.63)
Constipation: Change at Week 8 (n=26,16)	3.85 (25.52)	-4.17 (26.87)
Constipation: Change at Week 16 (n=15,7)	4.44 (17.21)	-9.52 (25.20)
Constipation: Change at Week 24 (n=14,1)	2.38 (20.52)	0.00 (NA)
Constipation: Change at Week 32 (n=7,2)	-0.00 (38.49)	16.67 (23.57)
Constipation: Change at Week 40 (n=9,1)	3.70 (26.06)	0.00 (NA)
Constipation: Change at Week 48 (n=4,1)	-16.67 (19.25)	0.00 (NA)
Constipation: Change at Week 56 (n=4,0)	0.00 (27.22)	NA (NA)
Constipation: Change at Week 64 (n=1,0)	-33.33 (NA)	NA (NA)
Constipation: Change at Week 72 (n=1,0)	-33.33 (NA)	NA (NA)
Diarrhea: Screening (n=58,31)	1.15 (6.14)	2.15 (8.32)
Diarrhea: Change at Week 8 (n=27,16)	0.00 (9.25)	0.00 (0.00)
Diarrhea: Change at Week 16 (n=15,7)	-6.67 (18.69)	0.00 (0.00)
Diarrhea: Change at Week 24 (n=14,1)	-7.14 (19.30)	0.00 (NA)
Diarrhea: Change at Week 32 (n=7,2)	-4.76 (12.60)	0.00 (0.00)
Diarrhea: Change at Week 40 (n=9,1)	0.00 (0.00)	0.00 (NA)
Diarrhea: Change at Week 48 (n=4,1)	0.00 (0.00)	0.00 (NA)
Diarrhea: Change at Week 56 (n=4,0)	0.00 (0.00)	NA (NA)
Diarrhea: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
Diarrhea: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)
Financial Fn: Screening (n=58,31)	17.82 (25.91)	25.81 (34.11)
Financial Fn: Change at Week 8 (n=27,16)	6.17 (26.21)	-4.17 (11.39)
Financial Fn: Change at Week 16 (n=15,7)	2.22 (15.26)	9.52 (46.00)
Financial Fn: Change at Week 24 (n=14,1)	-4.76 (22.10)	0.00 (NA)
Financial Fn: Change at Week 32 (n=7,2)	0.00 (19.25)	-16.67 (23.57)
Financial Fn: Change at Week 40 (n=9,1)	-3.70 (26.06)	0.00 (NA)
Financial Fn: Change at Week 48 (n=4,1)	-16.67 (19.25)	0.00 (NA)
Financial Fn: Change at Week 56 (n=4,0)	-8.33 (31.91)	NA (NA)
Financial Fn: Change at Week 64 (n=1,0)	0.00 (NA)	NA (NA)
Financial Fn: Change at Week 72 (n=1,0)	0.00 (NA)	NA (NA)

10. Secondary Outcome

Title	Percentage of Participants With Corticosteroid Initiation During the Study Period
Description	Corticosteroid initiation was assessed in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage greater than equal to (>/=) 2 mg dexamethasone equivalent.
Time Frame	Baseline until recurrence (up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population. Number of participants analyzed signified participants who were not receiving corticosteroids at screening.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	17	12
Number [percentage of participants]	58.82 99.7%	41.67 130.2%

11. Secondary Outcome

Title	Time to Corticosteroid Initiation
Description	Time to corticosteroid initiation was defined as the time from screening to the start date of the first corticosteroid administration in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage ≥2 mg dexamethasone equivalent. Instead, if the participant was not known to have the event, time was censored at the last available visit date. Time to corticosteroid initiation was estimated using Kaplan Meier method.
Time Frame	Baseline until recurrence (up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population. Number of participants analyzed signified participants who were not receiving corticosteroids at screening.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	17	12
Median (95% Confidence Interval) [months]	4.49	5.93

12. Secondary Outcome

Title	Percentage of Participants in Each Class of Corticosteroid Use
Description	Corticosteroid use was classified as: 1. No Change (if corticosteroid dose at each assessment was equal to baseline); 2. Decreased (if corticosteroid dose at each assessment was lower than baseline); 3. Increased (corticosteroid dose at each assessment was greater than baseline).
Time Frame	Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, post-treatment follow-up (up to Day 691)

Outcome Measure Data

Analysis Population Description

ITT population. Here, the number of participants analyzed signified participants with evaluable data for this outcome, and "n" signified participants with evaluable data for specified category for each arm, respectively.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	52	28
Week 8: Increased (n=52,28)	17.31 29.3%	17.86 55.8%
Week 8: Decreased (n=52,28)	23.08 39.1%	21.43 67%
Week 8: No Change (n=52,28)	59.62 101.1%	60.71 189.7%
Week 16: Increased (n=33,18)	21.21 35.9%	22.22 69.4%
Week 16: Decreased (n=33,18)	36.36 61.6%	27.78 86.8%
Week 16: No Change (n=33,18)	42.42 71.9%	50.00 156.3%
Week 24: Increased (n=21,5)	28.57 48.4%	20.00 62.5%
Week 24: Decreased (n=21,5)	33.33 56.5%	40.00 125%
Week 24: No Change (n=21,5)	38.10 64.6%	40.00 125%
Week 32: Increased (n=14,3)	14.29 24.2%	33.33 104.2%
Week 32: Decreased (n=14,3)	42.86 72.6%	0.00 0%
Week 32: No Change (n=14,3)	42.86 72.6%	66.67 208.3%
Week 40: Increased (n=10,2)	0.00 0%	50.00 156.3%
Week 40: Decreased (n=10,2)	60.00 101.7%	0.00 0%
Week 40: No Change (n=10,2)	40.00 67.8%	50.00 156.3%
Week 48: Increased (n=8,1)	0.00 0%	0.00 0%
Week 48: Decreased (n=8,1)	50.00 84.7%	0.00 0%
Week 48: No Change (n=8,1)	50.00 84.7%	100.00 312.5%
Week 56: Increased (n=6,1)	0.00 0%	0.00 0%
Week 56: Decreased (n=6,1)	33.33 56.5%	0.00 0%
Week 56: No Change (n=6,1)	66.67 113%	100.00 312.5%
Week 64: Increased (n=3,1)	0.00 0%	0.00 0%
Week 64: Decreased (n=3,1)	0.00 0%	0.00 0%
Week 64: No Change (n=3,1)	100.00 169.5%	100.00 312.5%
Week 72: Increased (n=3,0)	0.00 0%	NA NaN
Week 72: Decreased (n=3,0)	0.00 0%	NA NaN
Week 72: No Change (n=3,0)	100.00 169.5%	NA NaN
Week 80: Increased (n=1,0)	0.00 0%	NA NaN
Week 80: Decreased (n=1,0)	0.00 0%	NA NaN
Week 80: No Change (n=1,0)	100.00 169.5%	NA NaN
Week 88: Increased (n=1,0)	100.00 169.5%	NA NaN
Week 88: Decreased (n=1,0)	0.00 0%	NA NaN
Week 88: No Change (n=1,0)	0.00 0%	NA NaN
Follow-up: Increased (n=9,3)	33.33 56.5%	0.00 0%
Follow-up: Decreased (n=9,3)	0.00 0%	33.33 104.2%
Follow-up: No Change (n=9,3)	66.67 113%	66.67 208.3%

13. Secondary Outcome

Title	Percentage of Participants With Karnofsky Performance Status (KPS) Deterioration
Description	Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks.
Time Frame	Baseline until KPS deterioration (up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population. Here, number of participants analyzed signified participants with evaluable data for this outcome.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	37	14
Number [percentage of participants]	18.92 32.1%	14.29 44.7%

14. Secondary Outcome

Title	Time to Karnofsky Performance Status (KPS) Deterioration
Description	Time to KPS deterioration was defined as the time from screening to the first date of deterioration of the KPS score. Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Time to KPS deterioration was estimated using Kaplan Meier method. If the participant was not known to have the event, time was censored at the last available visit date.
Time Frame	Baseline until KPS deterioration (up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population. Here, number of participants analyzed signified participants with evaluable data for this outcome.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	37	14
Median (95% Confidence Interval) [months]	NA	NA

15. Secondary Outcome

Title	Percentage of Participants With World Health Organization (WHO) Performance Status (PS) Deterioration
Description	WHO PS deterioration was defined as a decrease of at least 1 point with respect to the screening value. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks.
Time Frame	Baseline until WHO PS deterioration (Up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
Number [percentage of participants]	47.46 80.4%	37.50 117.2%

16. Secondary Outcome

Title	Time to WHO PS Deterioration
Description	Time to WHO PS deterioration was defined as the time from randomization to the first date of deterioration of the WHO performance status score. WHO PS deterioration was defined as a decrease of at least 1 point with respect to the screening value. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks.
Time Frame	Baseline until WHO PS deterioration (Up to 691 days)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Bevacizumab	Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.	Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
Measure Participants	59	32
Median (95% Confidence Interval) [months]	8.87	NA

Adverse Events

Time Frame	Up to 691 days
Arm/Group Title	Bevacizumab		Fotemustine
Arm/Group Description	Participants received bevacizumab 10 mg/kg via IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.		Participants received fotemustine 75 mg/m^2 via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
All Cause Mortality
	Bevacizumab		Fotemustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bevacizumab		Fotemustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/59 (28.8%)		6/32 (18.8%)
Blood and lymphatic system disorders
Leukopenia	0/59 (0%)		1/32 (3.1%)
Pancytopenia	0/59 (0%)		1/32 (3.1%)
Thrombocytopenia	0/59 (0%)		1/32 (3.1%)
Cardiac disorders
Acute myocardial infarction	1/59 (1.7%)		0/32 (0%)
Gastrointestinal disorders
Abdominal pain	1/59 (1.7%)		0/32 (0%)
Ascites	1/59 (1.7%)		0/32 (0%)
Intestinal perforation	2/59 (3.4%)		0/32 (0%)
General disorders
Condition aggravated	1/59 (1.7%)		0/32 (0%)
Pyrexia	1/59 (1.7%)		0/32 (0%)
Infections and infestations
Anal abscess	0/59 (0%)		1/32 (3.1%)
Orchitis	1/59 (1.7%)		0/32 (0%)
Respiratory tract infection	1/59 (1.7%)		0/32 (0%)
Injury, poisoning and procedural complications
Road traffic accident	0/59 (0%)		1/32 (3.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage	1/59 (1.7%)		0/32 (0%)
Nervous system disorders
Cerebral haemorrhage	1/59 (1.7%)		0/32 (0%)
Cerebral ischaemia	1/59 (1.7%)		0/32 (0%)
Convulsion	2/59 (3.4%)		0/32 (0%)
Epilepsy	1/59 (1.7%)		0/32 (0%)
Partial seizures with secondary generalisation	1/59 (1.7%)		0/32 (0%)
Status epilepticus	0/59 (0%)		1/32 (3.1%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	2/59 (3.4%)		0/32 (0%)
Pulmonary embolism	1/59 (1.7%)		0/32 (0%)
Vascular disorders
Thrombophlebitis	1/59 (1.7%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Bevacizumab		Fotemustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/59 (59.3%)		25/32 (78.1%)
Blood and lymphatic system disorders
Anaemia	1/59 (1.7%)		5/32 (15.6%)
Leukopenia	1/59 (1.7%)		3/32 (9.4%)
Neutropenia	2/59 (3.4%)		8/32 (25%)
Thrombocytopenia	2/59 (3.4%)		14/32 (43.8%)
Gastrointestinal disorders
Constipation	3/59 (5.1%)		2/32 (6.3%)
Diarrhoea	3/59 (5.1%)		0/32 (0%)
Nausea	2/59 (3.4%)		4/32 (12.5%)
General disorders
Asthenia	13/59 (22%)		4/32 (12.5%)
Fatigue	1/59 (1.7%)		2/32 (6.3%)
Oedema peripheral	1/59 (1.7%)		2/32 (6.3%)
Pyrexia	5/59 (8.5%)		3/32 (9.4%)
Infections and infestations
Fungal infection	1/59 (1.7%)		3/32 (9.4%)
Urinary tract infection	3/59 (5.1%)		1/32 (3.1%)
Investigations
Transaminases increased	3/59 (5.1%)		4/32 (12.5%)
Weight increased	4/59 (6.8%)		1/32 (3.1%)
Nervous system disorders
Convulsion	4/59 (6.8%)		2/32 (6.3%)
Epilepsy	2/59 (3.4%)		2/32 (6.3%)
Headache	5/59 (8.5%)		1/32 (3.1%)
Partial seizures with secondary generalisation	3/59 (5.1%)		0/32 (0%)
Psychiatric disorders
Anxiety	1/59 (1.7%)		2/32 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/59 (5.1%)		1/32 (3.1%)
Vascular disorders
Hypertension	13/59 (22%)		1/32 (3.1%)

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.