Primary Objective: To achieve a 20-fold MDSC reduction in the concentration of circulating
MDSCs after treatment with low dose capecitabine.
Secondary Objectives:
1. To determine the concentration of circulating MDSCs in patients with recurrent
glioblastoma after treatment with low dose capecitabine
2. To determine the concentration of tissue MDSCs and T-regulatory cells in resected
glioblastoma after treatment with low dose capecitabine
3. To determine the safety and toxicity of continuous low dose capecitabine with and
without standard dose bevacizumab.
Exploratory Objective:
To obtain a signal for efficacy as measured by progression-free survival rate at 6 months
Inclusion Criteria:
- Subjects must have histologically or cytologically confirmed WHO grade 4 glioma for
which a clinically indicated tumor resection is planned.
- Subjects must not have received capecitabine or bevacizumab for this disease.
- Performance status: Karnofsky Performance status ≥ 60%
- Subjects must have adequate organ function and laboratory parameters within 21 days of
study entry as defined below:
- Hemoglobin ≥ 8 g/dl
- Absolute neutrophil count ≥ 1,500/mcL
- Platelet count ≥ 100,000/mcL
- Total bilirubin < 1.5 x institutional upper limit of normal (ULN)
- AST (SGOT) ≤ 3 X institutional ULN
- ALT (SGPT) ≤ 3 X institutional ULN
- Calculated creatinine clearance ≥ 50 mL/min
- Urine protein screened by urine analysis for urine protein creatinine (UPC)
ratio. For UPC ratio > 0.5, 24-hour urine protein must be obtained and must be <
1000 mg.
- Prothrombin time/international normalized ratio (PT/INR) < 1.4 for patients not
on warfarin
- Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet
both of the following criteria:
- No active bleeding or pathological condition that carries a high risk of
bleeding (e.g., tumor involving major vessels or known varices)
- In-range international normalized ratio (between 2 and 3) on a stable dose
of oral anticoagulant or on a stable dose of low molecular weight heparin
- Subjects must have the ability to understand and the willingness to sign a written
informed consent document.
- Women of childbearing potential must have a negative pregnancy test within 21 days of
study entry. Women of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation, and through 30 days after the last
dose of study drug. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and through 30 days after
the last dose of study drug.
- Patients must be able to swallow whole tablets.
- Systolic blood pressure ≤ 160 mg Hg or diastolic pressure ≤ 90 mg Hg within 14 days
prior to study registration
- Electrocardiogram without evidence of acute cardiac ischemia within 14 days prior
study registration
- Patients must have the following minimum intervals from prior treatments:
- surgery - 4 weeks
- nitrosoureas - 6 weeks
- cytotoxic chemotherapy - standard intervals depending on the most recent regimen.
i.e., for temozolomide 5 of 28, 23 days after most recent temozolomide; for
temozolomide 21 of 28 days, 7 days after most recent dose; etoposide 14 of 21
days, 7 days after last dose. For drugs not listed, the research nurse, treating
investigator, and principal investigator will determine the appropriate interval.
- Investigational therapy or non cytotoxic therapy - 2 weeks
Exclusion Criteria:
- Prior treatment toxicities not resolved to ≤ Grade 1 according to NCI CTCAE Version
4.0 except alopecia and neuropathy.
- Subjects receiving any other investigational agents.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to capecitabine or bevacizumab.
- Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.
- HIV-positive subjects on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with capecitabine and/or bevacizumab.
In addition, these subjects are at increased risk of lethal infections when treated
with marrow suppressive therapy.
- Other malignancy within the past 2 years with the exception of a) adequately treated
basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in
situ of the cervix or vulva; c) prostate cancer of Gleason Score 6 or less with stable
prostate-specific antigen levels; or d) cancer considered cured by surgical resection
or unlikely to impact survival during the duration of the study, such as localized
transitional cell carcinoma of the bladder, or benign tumors of the adrenal or
pancreas.
- Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g.,
Crohn's disease, malabsorption, or Grade ≥2 (National Cancer Institute [NCI] Common
Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any
etiology at screening).
- Active infection with hepatitis B or hepatitis C virus.
- Pregnant or breastfeeding.
- Known dihydropyrimidine dehydrogenase deficiency.
- Known hypersensitivity to 5-fluorouracil, capecitabine, bevacizumab or to any
component of the investigational products or compounds of similar chemical
composition.
- Unable or unwilling to swallow tablets.
- Evidence of significant medical illness, abnormal laboratory finding, or psychiatric
illness/social situations that would, in the Investigator's judgment, make the patient
inappropriate for this study.
- Arterial ischemic event (e.g., unstable angina, myocardial infarction, stroke) within
6 months of study entry
