CompletedNCT00720356Updated Oct 26, 2018Results posted

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

A Phase 2 interventional study of bevacizumab and erlotinib hydrochloride in Brain and Central Nervous System Tumors, sponsored by Northwestern University. Completed at 9 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-10-26.

Sponsored by Northwestern University · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 115
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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.

Conditions studied

Brain and Central Nervous System Tumors

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Keywords

adult glioblastoma
adult gliosarcoma

In context

Glioblastoma

1,920 studies on the registry are indexed under Glioblastoma; 450 are open to participants now.

This study's enrollment of 115 is above the median of 36 across 1,618 interventional studies indexed under Glioblastoma.

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Lead sponsor

Northwestern University is the lead sponsor of 1,396 studies on the registry; 199 are open to participants now.

Of its 102 completed or terminated interventional studies of FDA-regulated products, 73 (72%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility criteria

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

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 115 participants (actual)

Study arms

Experimental
Treatment
erlotinib and bevacizumab
Drug: bevacizumab · Drug: erlotinib hydrochloride

Interventions

Drugbevacizumab
10mg/kg administered intravenously every 2 weeks
Also known as: Avastin
Drugerlotinib hydrochloride
150 mg/daily orally
Also known as: erlotinib, CP-358, 774, Tarceva

What researchers measure

Primary outcomes

Overall Survival
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.

Secondary outcomes

Progression-free Survival at 12 Months
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
Response Rate (RR)
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
Safety of the Combination of Erlotinib and Bevacizumab in This Patient Population
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.
Progression Free Survival at 18 Months
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

Other outcomes

Changes in Tumor Blood Flow Based on MR Perfusion
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.
Gene Methylation Studies (Optional)
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.

Results

Posted Oct 26, 2018

Participant flow

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.

Registration to Study

Participant flow — Registration to Study
Milestone	Erlotinib and Bevacizumab Combination Treatment
Started	115
Completed registration step 1	115
Completed registration step 2	48
Completed	48
Not completed	67
Withdrew: Determined to have methylated mgmt	67

Reached 1st Response/2 Cycles

Participant flow — Reached 1st Response/2 Cycles
Milestone	Erlotinib and Bevacizumab Combination Treatment
Started	48
Completed	46
Not completed	2
Withdrew: Progressive disease	1
Withdrew: Withdrawal by subject	1

Went on to be Treated Cycle 3

Participant flow — Went on to be Treated Cycle 3
Milestone	Erlotinib and Bevacizumab Combination Treatment
Started	46
Completed	44
Not completed	2
Withdrew: Adverse event	1
Withdrew: Physician decision	1

Follow up Until Death

Participant flow — Follow up Until Death
Milestone	Erlotinib and Bevacizumab Combination Treatment
Started	48
Completed	43
Not completed	5
Withdrew: Withdrawal by subject	1
Withdrew: Alive at last data collection	4

Outcome measures

PrimaryOverall Survival

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.
Reported as:: Median · Months

Overall Survival
Months	Erlotinib and Bevacizumab Combination Treatment
Overall Survival	13.2 (10.8 to 19.6)

SecondaryProgression-free Survival at 12 Months

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
Reported as:: Number · percentage of patients

Progression-free Survival at 12 Months
percentage of patients	Erlotinib and Bevacizumab Combination Treatment
Progression-free Survival at 12 Months	32

SecondaryResponse Rate (RR)

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
Reported as:: Count of participants · Participants

Response Rate (RR)
Participants	Erlotinib and Bevacizumab Combination Treatment
Complete Response	4
Partial Response	12
Stable/no response	28
Progressive Disease	0
No Evaluable Disease (NED)	2

SecondarySafety of the Combination of Erlotinib and Bevacizumab in This Patient Population

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.
Reported as:: Number · patients

Safety of the Combination of Erlotinib and Bevacizumab in This Patient Population
patients	Erlotinib and Bevacizumab Combination Treatment
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

SecondaryProgression Free Survival at 18 Months

Time frame:: At 18 months from start of treatment

No measurements were reported for this outcome.

Other pre-specifiedChanges in Tumor Blood Flow Based on MR Perfusion

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.

No measurements were reported for this outcome.

Other pre-specifiedGene Methylation Studies (Optional)

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.

No measurements were reported for this outcome.

Post-hocProgression Free Survival at 6 Months

Time frame:: At 6 months from start of treatment
Reported as:: Number · percentage of patients

Progression Free Survival at 6 Months
percentage of patients	Erlotinib and Bevacizumab Combination Treatment
Progression Free Survival at 6 Months	66.3

Post-hocOverall Survival at 12 Months

Overall Survival (OS) is measured from start of treatment until death from any cause.

Time frame:: At 12 months from start of treatment
Reported as:: Number · percentage of patients

Overall Survival at 12 Months
percentage of patients	Erlotinib and Bevacizumab Combination Treatment
Overall Survival at 12 Months	54.5

Post-hocOverall Survival at 24 Months

Overall Survival (OS) will be measured from start of treatment until death of any cause

Time frame:: At 24 months from first treatment
Reported as:: Number · percentage of patients

Overall Survival at 24 Months
percentage of patients	Erlotinib and Bevacizumab Combination Treatment
Overall Survival at 24 Months	32.8

Post-hocMedian Progression Free Survival

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.
Reported as:: Median · months

Median Progression Free Survival
months	Erlotinib and Bevacizumab Combination Treatment
Median Progression Free Survival	9.2 (6.4 to 11.3)

Adverse events

Collected over 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). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Erlotinib and Bevacizumab Combination Treatment	43/48 (89.6%)	15/48 (31.3%)	48/48 (100%)

Most frequent serious events

Showing 10 of 21

Most frequent serious events
Event	Erlotinib and Bevacizumab Combination Treatment
SeizureNervous system disorders	5/48
Back painMusculoskeletal and connective tissue disorders	2/48
HeadacheNervous system disorders	2/48
ThrombosisVascular disorders	2/48
HypertensionCardiac disorders	1/48
NauseaGastrointestinal disorders	1/48
VomitingGastrointestinal disorders	1/48
DehydrationGastrointestinal disorders	1/48
Small bowel perforationGastrointestinal disorders	1/48
InfectionInfections and infestations	1/48

Most frequent other events

Showing 10 of 93

Most frequent other events
Event	Erlotinib and Bevacizumab Combination Treatment
DiarrheaGastrointestinal disorders	39/48
Rash/desquamationSkin and subcutaneous tissue disorders	36/48
FatigueGeneral disorders	29/48
LymphopeniaBlood and lymphatic system disorders	25/48
NauseaGastrointestinal disorders	24/48
HeadacheNervous system disorders	23/48
Bilirubin, serum highMetabolism and nutrition disorders	22/48
Albumin - serum lowMetabolism and nutrition disorders	19/48
Glucose, serum highMetabolism and nutrition disorders	19/48
Pruirtus/itchingSkin and subcutaneous tissue disorders	18/48

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Treatment
<=18 years	0
Between 18 and 65 years	82
>=65 years	33

Sex: Female, Male
Sex: Female, Male(Participants)	Treatment
Female	45
Male	70

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Treatment
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	3
White	109
More than one race	0
Unknown or Not Reported	3

Region of Enrollment
Region of Enrollment(participants)	Treatment
United States	115

Methylated/unmethylated MGMT promoter
Methylated/unmethylated MGMT promoter(Participants)	Treatment
Methylated MGMT promoter	67
Unmethylated MGMT promoter	48

Study locations

9 sites

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

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Oct 26, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT00720356
Lead sponsor: Northwestern University
Collaborators: M.D. Anderson Cancer Center
Responsible party: Jeffrey Raizer (Principal Investigator, Northwestern University) — Principal investigator
First posted: Jul 22, 2008
Start date: Jul 7, 2009
Primary completion: Jun 24, 2014
Completion: Jul 5, 2018
Results posted: Oct 26, 2018
Last update: Oct 26, 2018

Study contacts

Jeffrey J. Raizer, MD

principal investigator · Robert H. Lurie Cancer Center

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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