Hypofractionated Stereotactic Radiotherapy With Bevacizumab in the Treatment of Recurrent Malignant Glioma

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT01392209

Collaborator

Genentech, Inc. (Industry), Columbia University (Other), University of California, San Francisco (Other)

Enrollment

Locations

Arm

100.3

Actual Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The best dose of radiation to be given with bevacizumab is currently unknown. This study will use higher doses of radiation with bevacizumab than have been used before. This study will test the safety of radiation given at different doses with bevacizumab to find out what effects, good and/or bad, it has on the patient and the malignant glioma or related brain cancers.

Condition or Disease	Intervention/Treatment	Phase
Brain Cancer MALIGNANT GLIOMA Glioblastoma Anaplastic Astrocytoma (AA) Anaplastic Oligodendroglioma (AO) Anaplastic Oligo-astrocytoma (AOA) Anaplastic Mixed Gliomas Malignant Glioma NOS	Other: Bevacizumab & Stereotactic Radiotherapy	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A PHASE I DOSE ESCALATION STUDY OF HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY WITH BEVACIZUMAB IN THE TREATMENT OF RECURRENT MALIGNANT GLIOMA

Actual Study Start Date :

Jul 8, 2011

Actual Primary Completion Date :

Nov 15, 2019

Actual Study Completion Date :

Nov 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab & Stereotactic Radiotherapy This will be a multicenter (MSKCC and UCSF) phase I dose escalation study to determine the maximum tolerated dose (MTD) of hypofractionated stereotactic radiotherapy when administered in combination with a fixed dose of bevacizumab.	Other: Bevacizumab & Stereotactic Radiotherapy Treatment: (until treatment failure): bevacizumab 10 mg/kg IV once every two weeks on days 1 (+/- 3 days) and 15 (+/- 3 days) of every cycle (Cycle defined as 28 days). On day 28 (or up to 2 days before) of cycles 1 and 2 (and for every other cycle thereafter) patients will undergo a physical and radiological re-evaluation (MRI). Patients will begin stereotactic radiotherapy beginning anywhere from day 7 to day 10 of cycle 2 with escalating fraction sizes (interpatient - there is no intrapatient escalation). Assessment of response will be performed following cycles 1 and 2 then following every two cycles.

Arm

Intervention/Treatment

Experimental: Bevacizumab & Stereotactic Radiotherapy

This will be a multicenter (MSKCC and UCSF) phase I dose escalation study to determine the maximum tolerated dose (MTD) of hypofractionated stereotactic radiotherapy when administered in combination with a fixed dose of bevacizumab.

Other: Bevacizumab & Stereotactic Radiotherapy

Treatment: (until treatment failure): bevacizumab 10 mg/kg IV once every two weeks on days 1 (+/- 3 days) and 15 (+/- 3 days) of every cycle (Cycle defined as 28 days). On day 28 (or up to 2 days before) of cycles 1 and 2 (and for every other cycle thereafter) patients will undergo a physical and radiological re-evaluation (MRI). Patients will begin stereotactic radiotherapy beginning anywhere from day 7 to day 10 of cycle 2 with escalating fraction sizes (interpatient - there is no intrapatient escalation). Assessment of response will be performed following cycles 1 and 2 then following every two cycles.

Outcome Measures

Primary Outcome Measures

To establish the maximum tolerated dose (MTD) [1 year]
of hypofractionated stereotactic re-irradiation delivered with concomitant bevacizumab in recurrent malignant gliomas (using a standard 3+3 design).

Secondary Outcome Measures

Response rate [1 year]
Median overall survival and progression-free survival, along with the estimated survival and PFS rates at specified time points will be estimated using Kaplan-Meier method. Confidence intervals will be included with all point estimates. Response rate will be estimated using an exact binomial distribution together with 95% confidence interval.
Median progression free survival [1 year]
Median overall survival and progression-free survival, along with the estimated survival and PFS rates at specified time points will be estimated using Kaplan-Meier method. Confidence intervals will be included with all point estimates. Response rate will be estimated using an exact binomial distribution together with 95% confidence interval.
6 month progression-free survival rate [1 year]
Median overall survival and progression-free survival, along with the estimated survival and PFS rates at specified time points will be estimated using Kaplan-Meier method. Confidence intervals will be included with all point estimates. Response rate will be estimated using an exact binomial distribution together with 95% confidence interval.
Median overall survival [1 year]
Median overall survival and progression-free survival, along with the estimated survival and PFS rates at specified time points will be estimated using Kaplan-Meier method. Confidence intervals will be included with all point estimates. Response rate will be estimated using an exact binomial distribution together with 95% confidence interval.
Use of tractography to predict routes of progression in gliomas (MSKCC only) [1 year]
DTI will be acquired at the time of the patient's routinely scheduled brain MRIs but at least on the baseline scan and the MRI 1 month after cycle 2. DTI parameters: A spin-echo echo-planar sequence using 25 gradient directions, TR/TE 11000/100 msec; matrix 128 × 128; in-plane resolution 1.88 × 1.88 mm; slice thickness 3 mm; b-value 1000 sec/mm2; NEX 1 and maximum diffusion gradient strength 22mTm-1.
Correlation of VEGF and VEGFR IHC and related pathways (MSKCC only) and MGMT promoter methylation with efficacy [1 year]
Exploratory analyses related to VEGFR signaling including IHC for VEGF and VEGFR on pre-treatment tissue and post-treatment tissue and the analysis of biological correlate data has the overall goal of providing increased understanding of the nature of the response to bevacizumab but the amount of data available for the various measures is uncertain. Information may also be limited by the impact of intervening treatment between the most recent surgery and initiation of study treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have EITHER
Histologically confirmed intracranial malignant glioma of the following types: Glioblastoma, Anaplastic astrocytoma (AA), Anaplastic oligodendroglioma (AO), Anaplastic oligo-astrocytoma (AOA) also called anaplastic mixed gliomas, Malignant glioma NOS (not otherwise specified). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a high grade (malignant) glioma is made.

Histologically confirmed low grade (WHO grade II) gliomas (such as low grade astrocytoma, low grade oligodendroglioma, low grade oligo-astrocytoma (mixed gliomas), or low grade glioma NOS) IF there is radiographic evidence by MRI of malignant transformation but histologic confirmation of high grade (malignant) transformation would not be otherwise undertaken for routine clinical care. Inclusion of patients in this group will allow increased accrual rapidity by enrolling patients who are otherwise ineligible for almost all malignant glioma trials yet whom are treated presumptively for malignant glioma. The primary aim of the phase I study is not determination of efficacy. Therefore, inclusion of such patients will not affect efficacy analyses.

Participating site confirmation is adequate.

Able to undergo brain MRI scans.
MRI scan with gadolinium contrast showing geographically-circumscribed tumor ≤40 cc incorporating both enhancing and non-enhancing volume. This is calculated by the product of maximum measurements in 3 dimensions divided by 2. Tumors exceeding this limit may be eligible and any question should be directed to a Radiation Oncology Investigator and the MSK PI. (The MRI must be performed on a steroid dosage that has been stable or decreasing for at least 5 days. Patients on no steroids are eligible. If the steroid dose is increased between date of imaging and registration, a new baseline MRI is required).
Prior treatment with approximately 60 Gy of radiotherapy.
Patients must have recovered from the toxic effects of prior therapy including but not limited to:
An interval of ≥ 4 weeks (28 days) from prior cytotoxic therapy except 6 weeks from nitrosoureas
An interval of ≥ 1 week (7 days) from any non-cytotoxic agents
An interval of ≥ 3 months from the completion of radiation therapy
Absolute neutrophil count ≥ 1,500/mm3.
Platelet count ≥ 100,000/mm3.
Hemoglobin ≥ 10 g/dl.
Serum creatinine ≤ 2 times upper limit of normal.
Total bilirubin ≤ 2 times upper limit of normal.
SGOT and SGPT both ≤ 3 times upper limit of normal.
≥18 years of age.
Karnofsky Performance Score ≥ 60
Life expectancy ≥ 12 weeks
Men and women with reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.
Written informed consent prior to registration on study.

Exclusion Criteria:

Prior treatment with radiosurgery
Prior disease progression/recurrence during or immediately following treatment with bevacizumab. Any question should be directed to the PI.
Multicentric glioma
Other malignancy (with the exception of cervical carcinoma in situ or basal cell carcinoma of the skin) for which there has been treatment within the last 3 years
Serious medical or psychiatric illness that would in the opinion of the investigator interferes with the prescribed treatment.
Pregnant or breast feeding women
Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)
Any prior history of hypertensive crisis or hypertensive encephalopathy
Grade 2 or greater congestive heart failure
History of myocardial infarction, unstable angina, stroke, or transient ischemic attack within 12 months prior to Day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
History of hemoptysis ≥1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
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 Day 1 of treatment or anticipation of need for major surgical procedure during the course of the study
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
Serious, non-healing wound, active ulcer, or untreated bone fracture
Proteinuria as demonstrated by a UPC ratio ≥ 1.0 at screening
Known hypersensitivity to any component of bevacizumab
History of peptic ulcer within the last 6 months
Clinically significant peripheral vascular disease
Craniotomy wound that has not sufficiently healed
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
Glioma showing prior spontaneous hemorrhage as determined from the clinical history or from any preoperative CT or MRI scan (excluding grade 1 punctate, incidentally found).
Longest uni-dimensional measurement of contrast enhancing tumor ≥ 4cm. Tumors exceeding this limit may be eligible and any question should be directed to a Radiation Oncology Investigator and the MSK PI.
Tumor must not invade the corpus callosum
Tumor must not invade the brainstem
Suspected or documented radionecrosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco	San Francisco	California	United States	94143
2	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey	United States	07920
3	Memorial Sloan Kettering Commack	Commack	New York	United States	11725
4	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
5	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065