Clinical trial NCT00720356: Bevacizumab and Erlotinib After Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Brain and Central Nervous System Tumors
Keywords: adult glioblastoma
adult gliosarcoma
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: M.D. Anderson Cancer Center
First posted: 2008-07-22
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

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

Primary outcomes:
measure: Overall Survival
timeFrame: 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:
measure: Progression-free Survival at 12 Months
timeFrame: At 12 months from start of treatment
measure: Response Rate (RR)
timeFrame: From the start of treatment, every 2 cycles (1 cycle = 28 days) during treatment until progressive disease
measure: Safety of the Combination of Erlotinib and Bevacizumab in This Patient Population
timeFrame: 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.
measure: Progression Free Survival at 18 Months
timeFrame: At 18 months from start of treatment
Other outcomes:
measure: Changes in Tumor Blood Flow Based on MR Perfusion
timeFrame: 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.
measure: Gene Methylation Studies (Optional)
timeFrame: At baseline and then plasma only will be collected every odd cycle (1 cycle = 28 days) during treatment for a maximum of 49 cycles.
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Orlando
country: United States
facility: M.D. Anderson Cancer Center at Orlando
state: Florida
city: Chicago
country: United States
facility: Northwestern University, Northwestern Medical Faculty Foundation
state: Illinois
city: Evanston
country: United States
facility: Evanston Hospital
state: Illinois
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Neuro-Oncology Associates at Baylor University Medical Center, Dallas
state: Texas
city: Houston
country: United States
facility: M.D. Anderson Cancer Center at University of Texas
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital Neurological Institute
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Robert H. Lurie Cancer Center
name: Jeffrey J. Raizer, MD
role: PRINCIPAL_INVESTIGATOR
References: