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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme
• Intervention / Treatment: Radiation: Radiation therapy; Drug: Temozolomide; Drug: Bevacizumab; Drug: Bevacizumab; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Huntsville, Alabama, United States, 35805
      • Clearview Cancer Institute
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Consultants in Blood Disorders and Cancer
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center For Cancer And Blood Disorders
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Grand Rapids Clinical Oncology Program
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • St. Louis Cancer Care
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Cancer Center
  • South Carolina
    • Columbia, South Carolina, United States, 29210
      • South Carolina Oncology Associates, PA
  • Tennessee
    • Nashville, Tennessee, United States, 37023
      • Tennessee Oncology, PLLC
  • Virginia
    • Newport News, Virginia, United States, 23601
      • Peninsula Cancer Institute
    • Richmond, Virginia, United States, 23235
      • Virginia Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: 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 Names: Combined Modality Treatment; Drug: Bevacizumab; Bevacizumab 10mg/kg IV, every 2 weeks, beginning day 1 of radiation therapy; Other Names: Combined Modality Treatment; Drug: Bevacizumab; Bevacizumab 10mg/kg IV, every 2 weeks, beginning Week 11; Other Names: Systemic Therapy; Drug: Everolimus; Everolimus 10mg by mouth daily, beginning Week 11; Other Names: Systemic Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever comes first.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Toxicity After This Novel Multimodality Regimen	The toxicity assessments were made according to the common terminology criteria for adverse events (CTCAE version 3.0) of the National Cancer Institute. Number of participants with Grade 1 to 5 adverse events are reported here.	18 months
Overall Survival of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen	Overall survival was defined as the interval from the first day of study treatment until the date of death.	18 months
Objective Response Rate of Patients With Glioblastoma Multiforme Following Treatment With This Novel Multimodality Regimen	Response to treatment was assessed by MRI using the MacDonald criteria based on the assessment of the MRI scan for measurable, evaluable, and new lesions. The objective response rate is defined as the proportion of patients with improvement and or decreased extent of lesions compared to baseline.	18 months

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Novartis; Genentech, Inc.

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (ACTUAL): October 1, 2009
• Study Completion (ACTUAL): May 1, 2013

Study Registration Dates

• First Submitted: December 9, 2008
• First Submitted That Met QC Criteria: December 9, 2008
• First Posted (ESTIMATE): December 10, 2008

Study Record Updates

• Last Update Posted (ACTUAL): December 8, 2021
• Last Update Submitted That Met QC Criteria: November 8, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Temozolomide; Glioblastoma Multiforme; Bevacizumab; Everolimus; Radiation Therapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Temozolomide; Bevacizumab; Everolimus
• Other Study ID Numbers: SCRI CNS 10