Bevacizumab and Erlotinib After Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00720356
• Collaborator: M.D. Anderson Cancer Center (Other)
• Enrollment: 115
• Locations: 9
• Arm: 1
• Actual Duration (Months): 107.9
• Patients Per Site: 12.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving bevacizumab together with erlotinib may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving bevacizumab together with erlotinib works after radiation therapy and temozolomide in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: bevacizumab; Drug: erlotinib hydrochloride	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the overall survival of patients with newly diagnosed glioblastoma multiforme (GBM) with unmethylated MGMT promoter treated with bevacizumab and erlotinib hydrochloride after radiotherapy and temozolomide.

Secondary

• To determine the 12- and 24-month progression-free survival (PFS) of patients with newly diagnosed GBM with unmethylated MGMT promoter treated with this regimen.

• To assess radiographic response rates.

• To perform correlative tissue assays.

• To collect safety data on the combination of bevacizumab and erlotinib hydrochloride in patients with newly diagnosed GBM with unmethylated MGMT promoter treated with bevacizumab and erlotinib hydrochloride after radiotherapy and temozolomide.

OUTLINE: This is a multicenter study.

Patients undergo radiotherapy (either intensity-modulated radiation therapy or 3-D conformal radiotherapy) once daily 5 days a week and receive oral temozolomide concurrently with radiotherapy once daily for 6 weeks (as planned). Patients whose tumor has a methylated MGMT promoter are removed from study.

Approximately 4 weeks after completion of radiotherapy and temozolomide, patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride once daily on days 1-28. Treatment with bevacizumab and erlotinib hydrochloride repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at approximately 30 days and then every 3 months thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Bevacizumab and Erlotinib After Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma Without MGMT Promoter Methylation
• Actual Study Start Date: Jul 7, 2009
• Actual Primary Completion Date: Jun 24, 2014
• Actual Study Completion Date: Jul 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment erlotinib and bevacizumab	Drug: bevacizumab; 10mg/kg administered intravenously every 2 weeks; Other Names: Avastin ; Drug: erlotinib hydrochloride; 150 mg/daily orally; Other Names: erlotinib CP-358, 774 Tarceva

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From start of treatment, during treatment and every 3 months following the end of treatment until death. Median follow up at time of OS data was 33 months.]

   Overall survival (OS) will be measured from the start of treatment until death from any cause. At data cut off patients remaining alive will be censored at the last known date of contact.

Secondary Outcome Measures

1. Progression-free Survival at 12 Months [At 12 months from start of treatment]

   Progression free survival (PFS) will be assessed by CT or MRI scan using McDonald criteria. Progressive disease (PD) is defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Stable or increased dose of steroids. PFS will be measured from the start of treatment until first documentation of PD or death.

2. Response Rate (RR) [From the start of treatment, every 2 cycles (1 cycle = 28 days) during treatment until progressive disease]

   Response Rate (RR) will be defined as the best response seen during treatment measured by CT/MRI scan every 8 weeks during treatment using McDonald Criteria. CR=Complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients off steroids. PR=Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable/decreased dose of steroids. Stable/No Response=Does not qualify for CR, PR, or progression. The designation of Stable/No Response requires a minimum of 8 weeks duration. Stable/decreased dose of steroids. Progressive disease = 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease), worsening of evaluable disease, new lesions/site, failure to return for evaluation due to death or deteriorating condition.

3. Safety of the Combination of Erlotinib and Bevacizumab in This Patient Population [From the start of treatment, at the beginning of every cycle (1 cycle = 28 days) during treatment until 30 days after completion of treatment for up to 49 cycles.]

   Toxicity data for combination treatment of erlotinib and bevacizumab will be collected on day 1 of every cycle (1 cycle = 28 days) during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

4. Progression Free Survival at 18 Months [At 18 months from start of treatment]

   Progression free survival (PFS) will be assessed by CT or MRI scan using McDonald criteria. Progressive disease (PD) is defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Stable or increased dose of steroids. PFS will be measured from the start of treatment until first documentation of PD or death.

Other Outcome Measures

1. Changes in Tumor Blood Flow Based on MR Perfusion [Prior to study treatment (after surgery, but before radiation), just before study treatment (within 14 days prior to first treatment) and then every 2 cycles during study treatment, where 1 cycle equals 28 days for a maximum of 49 cycles.]

   Data from consenting patients will be used to assess of changes in tumor blood flow based on MR perfusion using MRI scans. Two scans will be completed prior to treatment on study; the first after surgery buta before radiation, the second within 14 days before starting combination treatment or erlotinib and bevacizumab. Then scans will be completed every 2 cycles during treatment, where one cycle equals 28 days.

2. Gene Methylation Studies (Optional) [At baseline and then plasma only will be collected every odd cycle (1 cycle = 28 days) during treatment for a maximum of 49 cycles.]

   Tissue and plasma collected from consenting patients in the study will be used to correlate tumor tissue with imaging and outcomes. Tissue will be collected before treatment on study begins and plasma will be collected the first day of treatment (before treatment) and every odd cycle after that, whilst on study treatment. Tissue and plasma analysis will be correlated with patients imaging results and response to to treatment

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically confirmed newly diagnosed glioblastoma multiforme (GBM) or gliosarcoma

• Undergoing or plan to undergo treatment with radiotherapy and concurrent temozolomide for 6 weeks

• Unmethylated MGMT promoter status must be determined before completing radiotherapy

• Tumor must be MGMT negative to receive bevacizumab and erlotinib hydrochloride

• Patients who are post biopsy or tumor resection allowed provided a post-operative MRI is done no more than 96 hours after surgery (in order for an accurate assessment to be done post radiotherapy):

• Evaluable or measurable disease after resection of recurrent tumor is not mandated for eligibility

• Patients who started radiotherapy and temozolomide prior to study entry are eligible as long as the gene methylation status is determined before starting bevacizumab and erlotinib hydrochloride

• Radiotherapy plans need to be verified to confirm the treatment plan meets the study requirement based on the PI assessment

• No progressive disease based on MRI or CT scan per the investigators assessment

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%

• Life expectancy > 12 weeks

• WBC > 3,000/μL

• ANC > 1,500/mm³

• Platelet count > 100,000/mm³

• Hemoglobin > 10 g/dL

• SGOT/SGPT < 3 times upper limit of normal (ULN)

• Bilirubin < 3 times ULN

• Creatinine < 1.5 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 3 months after completion of study treatment

• No significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy, would compromise the patient's ability to tolerate this therapy, or any disease that will obscure toxicity or dangerously alter drug metabolism

• No proteinuria at screening, as demonstrated by either of the following:

• Urine protein:creatinine (UPC) ratio < 1.0

• Urine dipstick for proteinuria < 2+ OR ≤ 1g protein by 24-hour urine collection

• No inadequately controlled hypertension (defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg) on antihypertensive medications

• No history of hypertensive crisis or hypertensive encephalopathy

• No New York Heart Association class II-IV congestive heart failure

• No history of myocardial infarction or unstable angina within 6 months prior to study enrollment

• No history of stroke or transient ischemic attack within 6 months of study enrollment

• No symptomatic peripheral vascular disease

• No significant vascular disease (i.e., aortic aneurysm or aortic dissection)

• No evidence of bleeding diathesis or coagulopathy

• No significant traumatic injury within 28 days prior to study enrollment

• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment

• No serious, nonhealing wound, ulcer, or bone fracture

• No known HIV positivity

• HIV testing is not required for study participation

• No history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years

PRIOR CONCURRENT THERAPY:

• No chemotherapy is allowed prior to starting radiotherapy and temozolomide, including polifeprosan 20 with carmustine implant (Gliadel wafers)

• No major surgical procedure or open biopsy within 28 days prior to study enrollment or the anticipation of need for major surgical procedure during the course of the study

• No core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment

• Concurrent nonenzyme-inducing anticonvulsants allowed

• More than 2 weeks (before starting erlotinib hydrochloride and bevacizumab) since prior and no concurrent enzyme-inducing anticonvulsant

• No other concurrent experimental agents

• Not concurrently participating in other clinical trials

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	M.D. Anderson Cancer Center at Orlando	Orlando	Florida	United States	32806-2134
3	Northwestern University, Northwestern Medical Faculty Foundation	Chicago	Illinois	United States	60611-3013
4	Evanston Hospital	Evanston	Illinois	United States	60201-1781
5	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
6	Neuro-Oncology Associates at Baylor University Medical Center, Dallas	Dallas	Texas	United States	75246
7	M.D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
8	The Methodist Hospital Neurological Institute	Houston	Texas	United States	77030
9	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	19024

Sponsors and Collaborators

• Northwestern University
• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Jeffrey J. Raizer, MD, Robert H. Lurie Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jeffrey Raizer, Principal Investigator, Northwestern University
• ClinicalTrials.gov Identifier: NCT00720356
• Other Study ID Numbers: NU 07C3; NU 07C3; BTTC08-01; STU00002792
• First Posted: Jul 22, 2008
• Last Update Posted: Oct 26, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Jeffrey Raizer, Principal Investigator, Northwestern University: adult glioblastoma; adult gliosarcoma
• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Bevacizumab; Erlotinib Hydrochloride

Study Results

Participant Flow

Recruitment Details	The study was ready for accrual March 12, 2009 with an accrual goal of up to 50 patients. The first patient was enrolled on July 7 2009. Accrual was suspended on July 29 2010 and reopened on March 30, 2011. The study was closed permanently on November 03, 2011 with an accrual of 48 patients treated on study after screening 115 patients.
Pre-assignment Detail	Registration is a two step process. ICF signed, tissue sent off and MGMT promoter methylation status determined eligibility. Patients with unmethylated MGMT promoters will be complete the second registration step and be treated on study. Patients with methylated MGMT promoters will not be treated on study.

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Period Title: Registration to Study
STARTED	115
Completed Registration Step 1	115
Completed Registration Step 2	48
COMPLETED	48
NOT COMPLETED	67
Period Title: Registration to Study
STARTED	48
COMPLETED	46
NOT COMPLETED	2
Period Title: Registration to Study
STARTED	46
COMPLETED	44
NOT COMPLETED	2
Period Title: Registration to Study
STARTED	48
COMPLETED	43
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Overall Participants	115
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	82 71.3%
>=65 years	33 28.7%
Sex: Female, Male (Count of Participants)
Female	45 39.1%
Male	70 60.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 2.6%
White	109 94.8%
More than one race	0 0%
Unknown or Not Reported	3 2.6%
Region of Enrollment (participants) [Number]
United States	115 100%
Methylated/unmethylated MGMT promoter (Count of Participants)
Methylated MGMT promoter	67 58.3%
Unmethylated MGMT promoter	48 41.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival (OS) will be measured from the start of treatment until death from any cause. At data cut off patients remaining alive will be censored at the last known date of contact.
Time Frame	From start of treatment, during treatment and every 3 months following the end of treatment until death. Median follow up at time of OS data was 33 months.

Outcome Measure Data

Analysis Population Description

2 patients were not evaluable - 1 patient withdrew consent and 1 patient completed less than 1 cycle of treatment

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	46
Median (95% Confidence Interval) [Months]	13.2

2. Secondary Outcome

Title	Progression-free Survival at 12 Months
Description	Progression free survival (PFS) will be assessed by CT or MRI scan using McDonald criteria. Progressive disease (PD) is defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Stable or increased dose of steroids. PFS will be measured from the start of treatment until first documentation of PD or death.
Time Frame	At 12 months from start of treatment

Outcome Measure Data

Analysis Population Description

Two patients were determined not to be evaluable (one patient withdrew consent from the study and one patient completed one cycle)

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	46
Number [percentage of patients]	32

3. Secondary Outcome

Title	Response Rate (RR)
Description	Response Rate (RR) will be defined as the best response seen during treatment measured by CT/MRI scan every 8 weeks during treatment using McDonald Criteria. CR=Complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients off steroids. PR=Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable/decreased dose of steroids. Stable/No Response=Does not qualify for CR, PR, or progression. The designation of Stable/No Response requires a minimum of 8 weeks duration. Stable/decreased dose of steroids. Progressive disease = 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease), worsening of evaluable disease, new lesions/site, failure to return for evaluation due to death or deteriorating condition.
Time Frame	From the start of treatment, every 2 cycles (1 cycle = 28 days) during treatment until progressive disease

Outcome Measure Data

Analysis Population Description

Two patients were determined not to be evaluable (one patient withdrew consent from the study and one patient complete one cycle of treatment only)

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	46
Complete Response	4 3.5%
Partial Response	12 10.4%
Stable/no response	28 24.3%
Progressive Disease	0 0%
No Evaluable Disease (NED)	2 1.7%

4. Secondary Outcome

Title	Safety of the Combination of Erlotinib and Bevacizumab in This Patient Population
Description	Toxicity data for combination treatment of erlotinib and bevacizumab will be collected on day 1 of every cycle (1 cycle = 28 days) during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Time Frame	From the start of treatment, at the beginning of every cycle (1 cycle = 28 days) during treatment until 30 days after completion of treatment for up to 49 cycles.

Outcome Measure Data

Analysis Population Description

All patients that received at least one dose of study drug were evaluable for toxicity. Data for grade 3 and 4 toxicities during treatment were collected.

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	48
Hyberbilirubinemia	1
Cerebrovascular ischemia	1
Dehydration	1
Dermatology/Skin	1
Hypertension	3
Fatigue	3
Leukocytes	1
Lymphopenia	12
Heartburn	1
Pain (not otherwise specified)	1
Pain abdomen	1
Pain head/headache	1
Bowel perforation	1
Hypophosphatemia	1
Rash/desqyamation	5
Rash/acneform	2
Syncope	1
Thrombosis/embolism	2
Wound complication	1

5. Secondary Outcome

Title	Progression Free Survival at 18 Months
Description	Progression free survival (PFS) will be assessed by CT or MRI scan using McDonald criteria. Progressive disease (PD) is defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Stable or increased dose of steroids. PFS will be measured from the start of treatment until first documentation of PD or death.
Time Frame	At 18 months from start of treatment

Outcome Measure Data

Analysis Population Description

Most patients had progressed before the 18 month time point. Data was not collected for PFS at 18 months.

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	0

6. Other Pre-specified Outcome

Title	Changes in Tumor Blood Flow Based on MR Perfusion
Description	Data from consenting patients will be used to assess of changes in tumor blood flow based on MR perfusion using MRI scans. Two scans will be completed prior to treatment on study; the first after surgery buta before radiation, the second within 14 days before starting combination treatment or erlotinib and bevacizumab. Then scans will be completed every 2 cycles during treatment, where one cycle equals 28 days.
Time Frame	Prior to study treatment (after surgery, but before radiation), just before study treatment (within 14 days prior to first treatment) and then every 2 cycles during study treatment, where 1 cycle equals 28 days for a maximum of 49 cycles.

Outcome Measure Data

Analysis Population Description

This was an optional portion of the study that patients could participate in. Data was not collected or analyzed for this outcome measure.

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	0

7. Other Pre-specified Outcome

Title	Gene Methylation Studies (Optional)
Description	Tissue and plasma collected from consenting patients in the study will be used to correlate tumor tissue with imaging and outcomes. Tissue will be collected before treatment on study begins and plasma will be collected the first day of treatment (before treatment) and every odd cycle after that, whilst on study treatment. Tissue and plasma analysis will be correlated with patients imaging results and response to to treatment
Time Frame	At baseline and then plasma only will be collected every odd cycle (1 cycle = 28 days) during treatment for a maximum of 49 cycles.

Outcome Measure Data

Analysis Population Description

This was an optional portion of the study for consenting patients. No data was collected and analyzed for this outcome measure.

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	0

8. Post-Hoc Outcome

Title	Progression Free Survival at 6 Months
Description	Progression free survival (PFS) will be assessed by CT or MRI scan using McDonald criteria. Progressive disease (PD) is defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Stable or increased dose of steroids. PFS will be measured from the start of treatment until first documentation of PD or death.
Time Frame	At 6 months from start of treatment

Outcome Measure Data

Analysis Population Description

Two patients were not evaluable.

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	46
Number [percentage of patients]	66.3

9. Post-Hoc Outcome

Title	Overall Survival at 12 Months
Description	Overall Survival (OS) is measured from start of treatment until death from any cause.
Time Frame	At 12 months from start of treatment

Outcome Measure Data

Analysis Population Description

Two patients were not evaluable

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	46
Number [percentage of patients]	54.5

10. Post-Hoc Outcome

Title	Overall Survival at 24 Months
Description	Overall Survival (OS) will be measured from start of treatment until death of any cause
Time Frame	At 24 months from first treatment

Outcome Measure Data

Analysis Population Description

Two patients were not evaluable

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	46
Number [percentage of patients]	32.8

11. Post-Hoc Outcome

Title	Median Progression Free Survival
Description	Progression free survival (PFS) will be assessed by CT or MRI scan using McDonald criteria. Progressive disease (PD) is defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Stable or increased dose of steroids. PFS will be measured from the start of treatment until first documentation of PD or death.
Time Frame	From the start of treatment and every 2 cycles, where 1 cycle equals 28 days, during treatment. Median follow up at time of data was 33 months.

Outcome Measure Data

Analysis Population Description

Two patients were not evaluable

Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
Measure Participants	46
Median (95% Confidence Interval) [months]	9.2

Adverse Events

Time Frame	Adverse events (AE) were collected over a 9 year period for the study. AEs were assessed and recorded at the beginning of each cycle (1 cycle =28 days) while on treatment and 30 days beyond the last treatment for a maximum of 69 cycles (the most number of cycles any patient was treated on study)
Arm/Group Title	Erlotinib and Bevacizumab Combination Treatment
Arm/Group Description	Erlotinib and bevacizumab Bevacizumab: 10mg/kg administered intravenously every 2 weeks Erlotinib hydrochloride: 150 mg/daily orally
All Cause Mortality
	Erlotinib and Bevacizumab Combination Treatment
	Affected / at Risk (%)	# Events
Total	43/48 (89.6%)
Serious Adverse Events
	Erlotinib and Bevacizumab Combination Treatment
	Affected / at Risk (%)	# Events
Total	15/48 (31.3%)
Cardiac disorders
Hypertension	1/48 (2.1%)	1
Gastrointestinal disorders
Nausea	1/48 (2.1%)	1
Vomiting	1/48 (2.1%)	1
Dehydration	1/48 (2.1%)	1
Small bowel perforation	1/48 (2.1%)	1
Infections and infestations
Infection	1/48 (2.1%)	1
Injury, poisoning and procedural complications
Death	1/48 (2.1%)	1
International Normalized Ratio of Prothrombin time (INR)	1/48 (2.1%)	1
Metabolism and nutrition disorders
Creatinine	1/48 (2.1%)	1
Potassium - serum low	1/48 (2.1%)	1
Musculoskeletal and connective tissue disorders
General Muscle Weakness	1/48 (2.1%)	1
Back pain	2/48 (4.2%)	2
Nervous system disorders
CNS cerebrovascular ischemia	1/48 (2.1%)	1
Confusion	1/48 (2.1%)	1
Facial droop	1/48 (2.1%)	1
Neuropathy - Motor	1/48 (2.1%)	1
Seizure	5/48 (10.4%)	5
Headache	2/48 (4.2%)	2
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/48 (2.1%)	1
Skin and subcutaneous tissue disorders
Wound complication (non infectious)	1/48 (2.1%)	1
Vascular disorders
Thrombosis	2/48 (4.2%)	2
Other (Not Including Serious) Adverse Events
	Erlotinib and Bevacizumab Combination Treatment
	Affected / at Risk (%)	# Events
Total	48/48 (100%)
Blood and lymphatic system disorders
Hemoglobin (anemia)	10/48 (20.8%)
Leukocytes (total white blood cells)	11/48 (22.9%)
Lymphopenia	25/48 (52.1%)
Platelets (thrombocytopenia)	10/48 (20.8%)
Edema in limbs	7/48 (14.6%)
Cardiac disorders
Hypertension	12/48 (25%)
Sinus bradycardia	3/48 (6.3%)
Eye disorders
Dry eye syndrome	6/48 (12.5%)
Vision impairment (hemianopsia/quadrantanopia)	4/48 (8.3%)
Gastrointestinal disorders
Anorexia	14/48 (29.2%)
Constipation	11/48 (22.9%)
Dehydration	4/48 (8.3%)
Diarrhea	39/48 (81.3%)
Dry mouth	3/48 (6.3%)
Flatulence	4/48 (8.3%)
Heartburn	7/48 (14.6%)
Hemorrhoids	10/48 (20.8%)
Incontinence anal	3/48 (6.3%)
Mucositis/stomatitis	5/48 (10.4%)
Nausea	24/48 (50%)
Taste alteration (dysgeusia)	6/48 (12.5%)
Vomiting	9/48 (18.8%)
Hemmorhage, GI rectum	5/48 (10.4%)
Abdominal pain	11/48 (22.9%)
General disorders
Fatigue	29/48 (60.4%)
Fever	3/48 (6.3%)
Insomnia	4/48 (8.3%)
Rigors	5/48 (10.4%)
Weight loss	11/48 (22.9%)
Immune system disorders
Allergic rhinitis	6/48 (12.5%)
Infections and infestations
Sinus infection	4/48 (8.3%)
Urinary tract infection	6/48 (12.5%)
Skin rash	3/48 (6.3%)
Metabolism and nutrition disorders
Albumin - serum low	19/48 (39.6%)
Alkaline phosphatase	3/48 (6.3%)
Serum glutamic pyruvic transaminase (ALT/SGPT)	7/48 (14.6%)
serum glutamic oxaloacetic transaminase (AST/SGOT)	11/48 (22.9%)
Bicarbonate - serum low	3/48 (6.3%)
Bilirubin, serum high	22/48 (45.8%)
Calcium, serum low	8/48 (16.7%)
Creatinine, high	6/48 (12.5%)
Glucose, serum high	19/48 (39.6%)
Glucose, serum low	8/48 (16.7%)
Lactic acid dehydrogenase (LDH)	5/48 (10.4%)
Magnesium, serum low	15/48 (31.3%)
Phosphate, serum high	3/48 (6.3%)
Phosphate, serum low	4/48 (8.3%)
Potassium, serum high	8/48 (16.7%)
Potassium, serum low	11/48 (22.9%)
Proteinuria	6/48 (12.5%)
Sodium, serum high	7/48 (14.6%)
Decreased Uric acid	3/48 (6.3%)
Chloride, serum high	4/48 (8.3%)
Carbon dioxide increased	6/48 (12.5%)
Protein - decreased	4/48 (8.3%)
Increased Blood Urea Nitrogen (BUN)	6/48 (12.5%)
Musculoskeletal and connective tissue disorders
Extremity lower (gait/walking)	9/48 (18.8%)
Joint function	4/48 (8.3%)
Muscle weakness, generalized or specific area - lower extremity	6/48 (12.5%)
Muscle weakness, generalized or specific area - whole body	7/48 (14.6%)
Back pain	6/48 (12.5%)
Extremity- limb pain	8/48 (16.7%)
Joint pain	5/48 (10.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cognitive disturbance	4/48 (8.3%)
Nervous system disorders
Ataxia (incoordination)	3/48 (6.3%)
Confusion	4/48 (8.3%)
Dizziness	12/48 (25%)
Memory impairment	12/48 (25%)
Sensory Neuropathy	5/48 (10.4%)
Pyramidal tract dysfunction (increased tone, hyperreflexia, positive Babinski, decreased fine motor)	3/48 (6.3%)
Seizure	7/48 (14.6%)
Speech impairment (e.g. dysphasia/ aphasia)	5/48 (10.4%)
Tremor	5/48 (10.4%)
Headache	23/48 (47.9%)
Psychiatric disorders
Mood alteration - Agitation	5/48 (10.4%)
Mood alteration - Anxiety	5/48 (10.4%)
Mood alteration - Depression	9/48 (18.8%)
Renal and urinary disorders
Urinary incontinence	4/48 (8.3%)
Respiratory, thoracic and mediastinal disorders
Nosebleed	11/48 (22.9%)
Upper airway infection	3/48 (6.3%)
Throat pain	3/48 (6.3%)
Cough	10/48 (20.8%)
Dyspnea (shortness of breath)	3/48 (6.3%)
Voice changes/dysarthria ( hoarseness, loss or alteration in voice, laryngitis)	5/48 (10.4%)
Skin and subcutaneous tissue disorders
Brusing	5/48 (10.4%)
Cheilitis	4/48 (8.3%)
Dry skin	16/48 (33.3%)
Nail changes	7/48 (14.6%)
Pruirtus/itching	18/48 (37.5%)
Rash acne	13/48 (27.1%)
Rash/desquamation	36/48 (75%)
Petechiae/purpura	4/48 (8.3%)
Vascular disorders
Thrombosis/embolism	3/48 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.