Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial Summary
The purpose of this research is to find hidden cancer with an experimental magnetic resonance
imaging (MRI) scan called spectroscopic magnetic resonance imaging (sMRI). That spectroscopic
MRI scan will be used to increase the area of the brain receiving radiation and then the dose
of radiation in attempt to kill more of the cancer. Proton radiotherapy and bevacizumab
(Avastin) are used to minimize the possible side effects of this approach.
Phase
N/A
Funding Agency/Sponsor
Institutional
Disease
Neurological Cancer
Enrollment Eligibility
Inclusion Criteria:
A. Recurrent glioblastoma (or variants such as gliosarcoma) based on one of the following
criteria:
1. An area of MRI enhancement consistent with glioblastoma outside of the initial high
dose radiation field.
2. Biopsy or resection proven recurrent glioblastoma.
3. Progressive glioblastoma based on advanced imaging (brain positron emission tomography
(PET), perfusion MRI, or clinical MR Spectroscopy)
B. Pathology diagnosis of glioblastoma, or variants such as gliosarcoma, on initial and/or
re-resection by 2016 WHO glioblastoma criteria. Prior pathology reports or specimens can be
re-examined and reclassified as glioblastoma based on current criteria.
C. Total area of recurrence on T1 post-contrast MRI (including all nodules of likely tumor)
have a linear maximum measurement of 6 cm or less.
D. Patients must have received prior brain radiation therapy for glioma in conventional
fractionation (1.8 - 2 Gy per fraction, total dose maximum 63 Gy).
E. Patients must have completed prior brain radiation four to six months or more prior to
study treatment for recurrent tumors that are at least half based within the high dose (>
46 Gy) radiation field.
1. For "marginal" or "out of field" radiation failures where at least half of the
enhancing disease is outside of the prior high dose radiation field but there is field
overlap, patients must have completed prior radiation at least four months or more
prior to study treatment.
2. For "in field" radiation failures where at least half of the enhancing disease is
within the prior high dose radiation field, patients must have completed prior
radiation at least six months or more prior to study treatment.
F. A minimum time must be elapsed from the administration of any prior anti-tumor or
investigational agents to initiation of study treatments on this protocol as follows:
1. 28 days or 5 half-lives, whichever is shorter, elapsed from the administration of any
experimental agent prior to initiation of study treatment.
2. 28 days elapsed from the administration of any prior cytotoxic agents except
i. 14 days from vincristine and ≥ 21 days from procarbazine and Temozolomide (TMZ) prior to
initiation of study treatment.
G. Age at least 18.
H. Patients must be able to have MRI scans.
I. Karnofsky performance status 60-100.
J. Life expectancy greater than 12 weeks at the discretion of the enrolling investigator.qa
K. Female subjects should have a negative serum pregnancy test unless they confirm their
menopausal status and/or have undergone previous hysterectomy and/or oophorectomy.
L. Both men and women with childbearing potential should agree to use effective
contraception for the duration of the treatment and for at least 6 months after the last
treatment since medications that will be used can be harmful for the embryo. See
contraception requirements, protocol section 4.16.
M. Complete blood count (CBC)/differential within 21 days prior to registration with
absolute neutrophil count at least 1500 cells/mm2, platelets at least 75,000 cells/mm2, and
hemoglobin at least 9.0 g/dl (transfusion or other intervention to achieve Hgb of 9.0 or
greater is acceptable).
N. Liver function tests must demonstrate total bilirubin 2 mg/dL or less, serum
glutamic-oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST) 2.5 times the
upper limit of normal or less within 21 days prior to registration.
O. Kidney function tests must indicate serum creatinine 1.8 mg/dL or less within 21 days
prior to registration and the following:
a. Urine protein: creatinine (UPC) ratio < 1.0 within 14 days prior to registration OR
urine dipstick for proteinuria ≤ 2+ (patients discovered to have > 2+ proteinuria on
dipstick urinalysis at baseline must have a UPC ratio done that is <1.0 to be eligible. If
the UPC ratio is ≥ 1.0 then the patients should undergo a 24-hour urine collection and must
demonstrate ≤1g of protein in 24 hours to be eligible).
i. Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion; a
UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is
calculated using one of the following formulas:
1. [urine protein]/[urine creatinine]: if both protein and creatinine are reported in
mg/dL
2. [(urine protein) x0.088]/[urine creatinine]: if urine creatinine is reported in mmol/L
P. Patients on full-dose anticoagulants must meet both of the following criteria:
1. No active bleeding or pathological condition that carries a high risk of bleeding
(e.g., tumor involving major vessels or known varices)
2. In-range international normalized ratio (INR) (typically 2-3) on a stable dose of oral
anticoagulant or on a stable dose of low molecular weight heparin, within 21 days
prior to registration
Exclusion Criteria:
A. Brain tumors other than glioblastoma (or variants such as gliosarcoma) by World Health
Organization (WHO) criteria.
B. Glioma that has not previously undergone standard first line therapies including a first
course of radiation therapy.
C. Glioma that has already undergone a second course of radiation therapy.
D. Multi-focal disease (separate enhancing nodules across multiple brain lobes). Note:
Multiple nodules in the same region are allowed as long as the total linear diameter is 6
cm or less.
E. Patients who have had treatment with Bevacizumab in the past.
F. Patients who will receive chemotherapy concurrent with study therapy other than
bevacizumab.
G. Patients with recurrent Glioblastoma (rGBM) based in the following anatomical regions
known to have magnetic susceptibility or poor signal will be excluded: temporal lobe below
the level of the floor of the third ventricle, orbitofrontal cortex, prefrontal cortex,
medial frontal gyrus, brainstem, and cerebellum (these regions have known sMRI artifact).
H. Pregnant or breastfeeding patients.
I. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for
a minimum of 1 year. Non-invasive tumors are permissible (e.g., carcinoma in situ).
J. Severe active co-morbidities as follows:
1. Unstable angina and/or congestive heart failure requiring hospitalization within the
last 6 months prior to registration.
2. Transmural myocardial infarction within the last 6 months prior to registration.
3. History of stroke or transient ischemic attack within 6 months prior to registration.
4. Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or
clinically significant peripheral vascular disease.
5. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
registration.
6. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration.
7. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note,
however, that laboratory tests for liver function other than screening panel (Section
3.1) and coagulation parameters are not required for entry into this protocol.
8. Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease
Control (CDC) definition; note, however, that HIV testing is not required for entry
into this protocol. The need to exclude patients with AIDS from this protocol is
necessary because the treatments involved in this protocol may be significantly
immunosuppressive.
K. Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly teratogenic.
L. Prior allergic reaction to the study drug (Bevacizumab)
M. Prior history of hypertensive crisis or hypertensive encephalopathy.
N. History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior
to registration
O. Gastrointestinal bleeding or any other hemorrhage/bleeding event Common Terminology
Criteria for Adverse Events (CTCAE), v. 4 grade 3 or greater within 30 days prior to
registration
P. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to registration (with the exception of craniotomy)
Q. Concurrent receipt of any other investigational agents