Hypofractionated Intensity-Modulated Radiation Therapy With Temozolomide and Bevacizumab for Glioblastoma Multiforme

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01209442
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 30
• Location: 1
• Arm: 1
• Actual Duration (Months): 76.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to find out whether Hypofractionated Intensity-Modulated Radiation Therapy (Hypo-IMRT) combining with temozolomide chemotherapy can be safely given with a targeted agent, bevacizumab, and how effective this study treatment will be in controlling your brain tumor.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Drug: Bevacizumab; Drug: Temozolomide; Radiation: RT (Radiation Therapy)	Phase 2

Detailed Description

This is a pilot phase II trial of the combination of concurrent hypofractionated IMRT (60 Gy/2 weeks), temozolomide and bevacizumab followed by 6 cycles of adjuvant bevacizumab and temozolomide in patients with grade IV malignant gliomas (glioblastoma and gliosarcoma). The study will have survival and toxicity endpoints.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Phase II Trial of Hypofractionated Intensity-Modulated Radiation Therapy (Hypo-IMRT) Combining With Temozolomide (TMZ) and Bevacizumab for Patients With Newly Diagnosed Glioblastoma Multiforme (GBM)
• Actual Study Start Date: Sep 16, 2010
• Actual Primary Completion Date: Sep 7, 2014
• Actual Study Completion Date: Feb 3, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: RT with Temozolomide and Bevacizumab Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx) and daily TMZ at 75 mg/m2 qd concurrent with IMRT (including weekends and holidays). Bevacizumab will be administered at 10 mg/kg on day 1 and day 15. Day 1 and the 1st Fx of IMRT must start on the same day. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab therapy, patients will have a brain MRI and if there is no evidence of disease progression, patients will receive 6 cycles of Bevacizumab and TMZ. Beginning a minimum of 28 days after the last radiation treatment the bevacizumab will be dosed at 10 mg/kg on day 1 and day 15 of each cycle. TMZ will be given at 150-200 mg/m2 qd on days 1-5 of each cycle. Each cycle is 28 days.

Drug: Bevacizumab; Bevacizumab will be administered at 10 mg/kg on day 1 and day 15. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab, patients will receive 6 cycles of Bevacizumab.; Other Names: Avastin ; Drug: Temozolomide; Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx) and daily temozolomide at 75 mg/m2 qd concurrent with IMRT. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab, temozolomide will be given at 150-200 mg/m2 qd on days 1-5 of each cycle.; Other Names: Temodar ; Radiation: RT (Radiation Therapy); Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx)

Outcome Measures

Primary Outcome Measures

1. 6-month Progression-free Survival [6 months]

   To use 6-month progression-free survival to assess the efficacy of the combination of hypofractionated IMRT delivering 60 Gy over 2 weeks with concurrent bevacizumab and temozolomide followed by 6 cycles of adjuvant bevacizumab and temozolomide.

Secondary Outcome Measures

1. Overall Survival, Measured From the Day of Initial Diagnosis (Biopsy or Surgery) to the Time of Death From Any Cause. [follow up for life]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed diagnosis of WHO grade IV primary malignant glioma (GBM or gliosarcoma).

• Age ≥ 18 years at the time of study registration

• Karnofsky Performance Scale ≥ 60%

• Absolute Neutrophil Count (ANC) ≥ 1,500 cells/mm3, hemoglobin ≥ 9.0 g/dl, platelets ≥ 100,000 cells/ mm3

• Serum creatinine ≤ 1.5 mg/dl, serum glutamate oxaloacetate transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal

• Signed informed consent approved by the Institutional Review Board

• Craniotomy or intracranial biopsy site must be adequately healed, free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of study entry. Study treatment should be initiated > 28 days following the last surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity)

Exclusion Criteria:

• Life expectancy of less than 12 weeks

• Prior treatment, including radiation therapy or chemotherapy, for GBM with the exception of surgery (Gliadel Wafers are allowed at the time of surgery)

• Active malignancy, with the exception of superficial basal cell and/or superficial squamous (skin) cell, or carcinoma in situ of the cervix

• Active infection requiring IV antibiotics

• Pregnant or breast feeding

• International normalized ratio (INR) > 1.5 and activated partial thromboplastin time (aPTT) > 1.5 × the upper limit of normal (ULN) (except for subjects receiving anticoagulation therapy) in the absence of therapeutic intent to anticoagulate the subject. Therapeutic anticoagulation is permitted

• Evidence of ≥ Common Toxicity Criteria for Adverse Effects (CTCAE) v.3 grade 2 CNS hemorrhage (CNS hemorrhage when medical intervention indicated), but grade 1 CNS hemorrhage (asymptomatic radiographic findings on the baseline brain CT or MRI only) is allowed. Punctate hemorrhage or the presence of hemosiderin is not considered a Grade 1 event for the purpose of this study. )

• Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)

• Prior history of hypertensive crisis or hypertensive encephalopathy

• Current New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of myocardial infarction or unstable angina within 6 months prior to enrollment

• History of stroke or transient ischemic attack within 6 months prior to enrollment

• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to enrollment

• History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to enrollment

• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment or anticipation of need for major surgical procedure during the course of the study

• Core needle biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to enrollment

• History of abdominal fistula or gastrointestinal perforation within 6 months prior to enrollment

• Serious, non-healing wound, active ulcer, or untreated bone fracture

• Proteinuria as demonstrated by a Urine protein-creatinine ratios (UPC) ratio ≥ 1.0 at screening (Appendix A).

• Known hypersensitivity to any component of bevacizumab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Denver, University of Colorado Cancer Center	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• Genentech, Inc.

Investigators

• Principal Investigator: Douglas Ney, M.D, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01209442
• Other Study ID Numbers: 10-0274.cc; AVF4733s
• First Posted: Sep 27, 2010
• Last Update Posted: Apr 12, 2019
• Last Verified: Apr 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Colorado, Denver: Glioblastoma; Multiforme
• Additional relevant MeSH terms: Glioblastoma; Bevacizumab; Temozolomide

Study Results

Participant Flow

Arm/Group Title	RT With Temozolomide and Bevacizumab
Arm/Group Description	Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx) and daily TMZ at 75 mg/m2 qd concurrent with IMRT (including weekends and holidays). Bevacizumab will be administered at 10 mg/kg on day 1 and day 15. Day 1 and the 1st Fx of IMRT must start on the same day. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab therapy, patients will have a brain MRI and if there is no evidence of disease progression, patients will receive 6 cycles of Bevacizumab and TMZ. Beginning a minimum of 28 days after the last radiation treatment the bevacizumab will be dosed at 10 mg/kg on day 1 and day 15 of each cycle. TMZ will be given at 150-200 mg/m2 qd on days 1-5 of each cycle. Each cycle is 28 days.
Period Title: Overall Study
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	RT With Temozolomide and Bevacizumab
Arm/Group Description	Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx) and daily TMZ at 75 mg/m2 qd concurrent with IMRT (including weekends and holidays). Bevacizumab will be administered at 10 mg/kg on day 1 and day 15. Day 1 and the 1st Fx of IMRT must start on the same day. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab therapy, patients will have a brain MRI and if there is no evidence of disease progression, patients will receive 6 cycles of Bevacizumab and TMZ. Beginning a minimum of 28 days after the last radiation treatment the bevacizumab will be dosed at 10 mg/kg on day 1 and day 15 of each cycle. TMZ will be given at 150-200 mg/m2 qd on days 1-5 of each cycle. Each cycle is 28 days.
Overall Participants	30
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	57
Sex: Female, Male (Count of Participants)
Female	13 43.3%
Male	17 56.7%
Region of Enrollment (participants) [Number]
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	6-month Progression-free Survival
Description	To use 6-month progression-free survival to assess the efficacy of the combination of hypofractionated IMRT delivering 60 Gy over 2 weeks with concurrent bevacizumab and temozolomide followed by 6 cycles of adjuvant bevacizumab and temozolomide.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RT With Temozolomide and Bevacizumab
Arm/Group Description	Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx) and daily TMZ at 75 mg/m2 qd concurrent with IMRT (including weekends and holidays). Bevacizumab will be administered at 10 mg/kg on day 1 and day 15. Day 1 and the 1st Fx of IMRT must start on the same day. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab therapy, patients will have a brain MRI and if there is no evidence of disease progression, patients will receive 6 cycles of Bevacizumab and TMZ. Beginning a minimum of 28 days after the last radiation treatment the bevacizumab will be dosed at 10 mg/kg on day 1 and day 15 of each cycle. TMZ will be given at 150-200 mg/m2 qd on days 1-5 of each cycle. Each cycle is 28 days.
Measure Participants	30
Median (95% Confidence Interval) [months]	90

2. Secondary Outcome

Title	Overall Survival, Measured From the Day of Initial Diagnosis (Biopsy or Surgery) to the Time of Death From Any Cause.
Time Frame	follow up for life

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RT With Temozolomide and Bevacizumab
Arm/Group Description	Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx) and daily TMZ at 75 mg/m2 qd concurrent with IMRT (including weekends and holidays). Bevacizumab will be administered at 10 mg/kg on day 1 and day 15. Day 1 and the 1st Fx of IMRT must start on the same day. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab therapy, patients will have a brain MRI and if there is no evidence of disease progression, patients will receive 6 cycles of Bevacizumab and TMZ. Beginning a minimum of 28 days after the last radiation treatment the bevacizumab will be dosed at 10 mg/kg on day 1 and day 15 of each cycle. TMZ will be given at 150-200 mg/m2 qd on days 1-5 of each cycle. Each cycle is 28 days.
Measure Participants	30
Median (95% Confidence Interval) [months]	16.3

Adverse Events

Arm/Group Title	RT With Temozolomide and Bevacizumab
Arm/Group Description	Patients will be treated with hypofractionated IMRT (60 Gy in 10 Fx) and daily TMZ at 75 mg/m2 qd concurrent with IMRT (including weekends and holidays). Bevacizumab will be administered at 10 mg/kg on day 1 and day 15. Day 1 and the 1st Fx of IMRT must start on the same day. Four to six weeks following completion of concurrent IMRT, TMZ and bevacizumab therapy, patients will have a brain MRI and if there is no evidence of disease progression, patients will receive 6 cycles of Bevacizumab and TMZ. Beginning a minimum of 28 days after the last radiation treatment the bevacizumab will be dosed at 10 mg/kg on day 1 and day 15 of each cycle. TMZ will be given at 150-200 mg/m2 qd on days 1-5 of each cycle. Each cycle is 28 days.
All Cause Mortality
	RT With Temozolomide and Bevacizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	RT With Temozolomide and Bevacizumab
	Affected / at Risk (%)	# Events
Total	3/30 (10%)
Infections and infestations
sepsis	1/30 (3.3%)	1
cranial dehiscence/wound infection	1/30 (3.3%)	1
Nervous system disorders
seizure	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	RT With Temozolomide and Bevacizumab
	Affected / at Risk (%)	# Events
Total	10/30 (33.3%)
Blood and lymphatic system disorders
myelosuppression	10/30 (33.3%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.