Clinical trial NCT00805961: RT, Temozolomide, and Bevacizumab Followed by Bevacizumab/Everolimus in First-line Treatment of GBM
Official title: A Phase II Study of Concurrent Radiation Therapy, Temozolomide, and Bevacizumab Followed by Bevacizumab/Everolimus in the First-line of Treatment of Patients With Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioblastoma Multiforme
Keywords: Glioblastoma Multiforme
Radiation Therapy
Temozolomide
Bevacizumab
Everolimus
Lead sponsor: SCRI Development Innovations, LLC
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: Novartis
First posted: 2008-12-10
Enrollment: 68
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: In this phase II trial the investigators plan to incorporate two targeted agents, bevacizumab and everolimus, into the first-line multimodality therapy of glioblastoma. In the first portion of the treatment, bevacizumab will be added to standard concurrent radiation therapy plus temozolomide. After completing radiation therapy, patients will continue treatment with the combination of bevacizumab and everolimus.

Detailed description: Although this maintenance regimen departs from the standard treatment with single agent temozolomide, we feel this approach may add to the overall efficacy of treatment for the following reasons: 1) results with bevacizumab/everolimus in renal cell carcinoma suggest there is at least an additive efficacy when these drugs are used in combination; 2) the efficacy of single agent temozolomide following standard concurrent radiation therapy/temozolomide has not been proven, 3) the use of the three-drug maintenance program (i.e., bevacizumab/everolimus/temozolomide) would probably not be tolerated well on a chronic basis in this patient population; and 4) the bevacizumab/everolimus combination has potential advantages as a maintenance therapy, since it has been well tolerated for many months in patients with other malignancies.

Eligibility criteria: Inclusion Criteria:

* Age \>=18 years.
* Histologically confirmed intracranial glioblastoma multiforme (WHO grade 4).
* Patients who have had partial or complete surgical debulking are eligible, as are those with inoperable glioblastoma.
* No previous treatment with radiotherapy or systemic therapy. Local therapy with a Gliadel wafer placed at the time of surgical debulking is permitted.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate bone marrow function
* Adequate liver function:
* Serum creatinine \<=1.5 x institutional ULN.
* Ability to swallow whole pills.
* Women of child-bearing potential must have a negative serum pregnancy test performed within 7 days prior to start of treatment. Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control) while receiving study treatment and for 6 months after the last study treatment. Hormonal contraceptives are not acceptable as a sole method of contraception. Female patients must not breast feed.
* INR \<1.3 or PT/PTT within normal limits in patients not receiving anticoagulation. However, patients receiving anticoagulation treatment with an agent such as warfarin or heparin are also eligible. For patients on warfarin, the INR should be measured prior to initiation of everolimus and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
* Fasting serum cholesterol \<=300 mg/dL OR \<=7.75 mmol/L AND fasting triglycerides \<= 2.5 x institutional ULN.

Exclusion Criteria:

* New York Heart Association (NYHA) grade II or greater congestive heart failure (see Appendix B) or symptomatic congestive heart failure.
* Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg).
* History of myocardial infarction or unstable angina within 6 months prior to beginning study treatment.
* History of stroke or transient ischemic attack within 6 months prior to beginning study treatment.
* Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to beginning study treatment.
* Prior history of hypertensive crisis or hypertensive encephalopathy.
* History of hemoptysis (\>=1/2 teaspoon of bright red blood per episode) within 1 month prior to beginning study treatment.
* Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
* History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1.
* Serious, non-healing wound, active ulcer, or untreated bone fracture.
* Proteinuria as demonstrated by urine dipstick for proteinuria \>=2+. For patients with \>=2+ proteinuria on dipstick urinalysis, a urine protein: creatinine (UPC) ratio will be determined or a 24-hour urine collection will be done. Patients with a UPC ratio \<1 or a 24-hour urine protein \<1 gram are eligible.
* Minor surgical procedures (excluding placement of a vascular access device), fine-needle aspirations, or core biopsies within 7 days prior to starting treatment.
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting protocol treatment or anticipation of need for major surgical procedure during the course of study treatment. Patients who have not recovered from the side effects of any major surgery are not eligible.
* Treatment with any investigational agents within 4 weeks of study entry.
* Chronic, systemic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled steroids are allowed.
* Other malignancies within the past 3 years except for adequately treated carcinoma in situ of the cervix or basal cell or superficial squamous (skin cell) carcinomas.

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: 18 months
Secondary outcomes:
measure: Number of Participants Experiencing Toxicity After This Novel Multimodality Regimen
timeFrame: 18 months
measure: Overall Survival of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen
timeFrame: 18 months
measure: Objective Response Rate of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen
timeFrame: 18 months
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Clearview Cancer Institute
state: Alabama
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Louisville
country: United States
facility: Consultants in Blood Disorders and Cancer
state: Kentucky
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Grand Rapids
country: United States
facility: Grand Rapids Clinical Oncology Program
state: Michigan
city: Chesterfield
country: United States
facility: St. Louis Cancer Care
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Omaha
country: United States
facility: Methodist Cancer Center
state: Nebraska
city: Columbia
country: United States
facility: South Carolina Oncology Associates, PA
state: South Carolina
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Newport News
country: United States
facility: Peninsula Cancer Institute
state: Virginia
city: Richmond
country: United States
facility: Virginia Cancer Institute
state: Virginia
Study officials:
affiliation: SCRI Development Innovations, LLC
name: John D Hainsworth, M.D.
role: STUDY_CHAIR
References:
citation: Hainsworth JD, Shih KC, Shepard GC, Tillinghast GW, Brinker BT, Spigel DR. Phase II study of concurrent radiation therapy, temozolomide, and bevacizumab followed by bevacizumab/everolimus as first-line treatment for patients with glioblastoma. Clin Adv Hematol Oncol. 2012 Apr;10(4):240-6.