Targeting Myeloid Derived Suppressor Cells in Recurrent Glioblastoma: Phase 0/1 Trial of Low Dose Capecitabine + Bevacizumab in Patients With Recurrent Glioblastoma
Overview
- Phase
- Phase 1
- Intervention
- Capecitabine
- Conditions
- Glioblastoma
- Sponsor
- Case Comprehensive Cancer Center
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Change of concentration in circulating MDSCs after treatment with low dose capecitabine
- Status
- Completed
- Last Updated
- 2 months ago
Overview
Brief Summary
This study involves participants with recurrent glioblastoma brain tumors (GBM). This means that a participant's brain tumor has either returned after being treated by a previous therapy, or has continued to progress despite being treated.
The purpose of this study is to provide proof of concept that suppression of MDSCs (myeloid-derived suppressor cells) is feasible in patients with GBM. Rather than targeting tumor cells or immune checkpoints, which has been the focus of recent therapeutic efforts, direct targeting of MDSCs with low dose capecitabine has the potential to reverse the immunosuppressed microenvironment of GBM and thereby reduce tumors
Detailed Description
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
Investigators
Eligibility Criteria
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
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.
Arms & Interventions
Treatment: Capecitabine + Bevacizumab
Capecitabine, PO dose to be determined by phase 1 dose escalation, cycle length 28 days. Treated with Bevacizumab, IV, 10 mg/kg days 1, 15 every 28 days, until progression.
Intervention: Capecitabine
Treatment: Capecitabine + Bevacizumab
Capecitabine, PO dose to be determined by phase 1 dose escalation, cycle length 28 days. Treated with Bevacizumab, IV, 10 mg/kg days 1, 15 every 28 days, until progression.
Intervention: Bevacizumab
Outcomes
Primary Outcomes
Change of concentration in circulating MDSCs after treatment with low dose capecitabine
Time Frame: baseline to eight months after
Secondary Outcomes
- Concentration of MDSCs in resected glioblastoma after treatment with low dose capecitabine(Eight months)
- Concentration of T-regulatory cells after treatment with low dose capecitabine(Eight months)
- Number of participants with adverse events relating to treatment with low-dose capecitabine alone as assessed by CTCAE v4.0(Nine months)
- Number of participants with adverse events relating to treatment with low-dose capecitabine combined with bevacizumab as assessed by CTCAE v4.0(Nine months)