RT, Temozolomide, and Bevacizumab Followed by Bevacizumab/Everolimus in First-line Treatment of GBM

• ClinicalTrials.gov Identifier: NCT00805961
• Recruitment Status: Completed
• First Posted: December 10, 2008
• Results First Posted: September 21, 2012
• Last Update Posted: August 28, 2013
• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Genentech, Inc.; Novartis
• Information provided by (Responsible Party): SCRI Development Innovations, LLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Glioblastoma Multiforme	Radiation: Radiation therapy; Drug: Temozolomide; Drug: Bevacizumab; Drug: Everolimus	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 68 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: January 2009
• Actual Primary Completion Date: October 2009
• Actual Study Completion Date: May 2013

Arms and Interventions

Arm

Intervention/treatment

Experimental: Intervention; Combined Modality Treatment and Systemic Therapy Combined Modality Therapy - Radiation Therapy: 2 Gy/fraction, single daily fractions Monday-Friday, to total of 60 Gy Temozolomide: 75 mg/m2 by mouth daily Bevacizumab: 10 mg/kg IV every 2 weeks (Weeks 1, 3, 5, and 7) After the last dose of radiation, patients exhibiting an objective response, stable disease on MRI scan, or have stable/improved tumor-related symptoms will begin systemic therapy Systemic Therapy - Bevacizumab: 10 mg/kg IV every 2 weeks Everolimus: 10 mg by mouth daily

Radiation: Radiation therapy; Radiation therapy, 2.0 Gy daily, 5 days per week by single daily dose, to a total of 60 Gy over 6 weeks; Other Name: Combined Modality Treatment; Drug: Temozolomide; Temozolomide 75mg/m2 by mouth daily, beginning day 1 of radiation therapy and continuing through the last day of radiation therapy; Other Name: Combined Modality Treatment; Drug: Bevacizumab; Bevacizumab 10mg/kg IV, every 2 weeks, beginning day 1 of radiation therapy; Other Name: Combined Modality Treatment; Drug: Bevacizumab; Bevacizumab 10mg/kg IV, every 2 weeks, beginning Week 11; Other Name: Systemic Therapy; Drug: Everolimus; Everolimus 10mg by mouth daily, beginning Week 11; Other Name: Systemic Therapy

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: 18 months ]

Secondary Outcome Measures :

1. To Assess the Toxicity of This Novel Multimodality Regimen [ Time Frame: 18 months ]
2. To Assess the Overall Survival of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen [ Time Frame: 18 months ]
3. To Assess the Complete Response Rate of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen [ Time Frame: 18 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

Clearview Cancer Institute

Huntsville, Alabama, United States, 35805

United States, Florida

Florida Cancer Specialists

Fort Myers, Florida, United States, 33901

United States, Georgia

Northeast Georgia Medical Center

Gainesville, Georgia, United States, 30501

United States, Kentucky

Consultants in Blood Disorders and Cancer

Louisville, Kentucky, United States, 40207

United States, Maryland

Center for Cancer and Blood Disorders

Bethesda, Maryland, United States, 20817

United States, Michigan

Grand Rapids Clinical Oncology Program

Grand Rapids, Michigan, United States, 49503

United States, Missouri

St. Louis Cancer Care

Chesterfield, Missouri, United States, 63017

Research Medical Center

Kansas City, Missouri, United States, 64132

United States, Nebraska

Methodist Cancer Center

Omaha, Nebraska, United States, 68114

United States, South Carolina

South Carolina Oncology Associates, PA

Columbia, South Carolina, United States, 29210

United States, Tennessee

Tennessee Oncology, PLLC

Nashville, Tennessee, United States, 37023

United States, Virginia

Peninsula Cancer Institute

Newport News, Virginia, United States, 23601

Virginia Cancer Institute

Richmond, Virginia, United States, 23235

Sponsors and Collaborators

SCRI Development Innovations, LLC

Genentech, Inc.

Novartis

Investigators

• Study Chair: John D Hainsworth, M.D.; SCRI Development Innovations, LLC

More Information

Publications:

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.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT00805961 History of Changes
• Other Study ID Numbers: SCRI CNS 10
• First Posted: December 10, 2008
• Results First Posted: September 21, 2012
• Last Update Posted: August 28, 2013
• Last Verified: August 2012

Keywords provided by SCRI Development Innovations, LLC:

Glioblastoma Multiforme; Radiation Therapy; Temozolomide; Bevacizumab; Everolimus

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Sirolimus; Bevacizumab; Everolimus; Temozolomide; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action