Clinical Trials /

Capecitabine + Bevacizumab in Patients With Recurrent Glioblastoma

NCT02669173

Description:

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

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Capecitabine + Bevacizumab in Patients With Recurrent Glioblastoma
  • Official Title: Targeting Myeloid Derived Suppressor Cells in Recurrent Glioblastoma: Phase 0/1 Trial of Low Dose Capecitabine + Bevacizumab in Patients With Recurrent Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: CASE7315
  • NCT ID: NCT02669173

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
CapecitabineTreatment: Capecitabine + Bevacizumab
BevacizumabTreatment: Capecitabine + Bevacizumab

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
Treatment: Capecitabine + BevacizumabExperimentalCapecitabine, 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.
  • Capecitabine
  • Bevacizumab

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

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change of concentration in circulating MDSCs after treatment with low dose capecitabine
Time Frame:baseline to eight months after
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Concentration of MDSCs in resected glioblastoma after treatment with low dose capecitabine
Time Frame:Eight months
Safety Issue:
Description:
Measure:Concentration of T-regulatory cells after treatment with low dose capecitabine
Time Frame:Eight months
Safety Issue:
Description:
Measure:Number of participants with adverse events relating to treatment with low-dose capecitabine alone as assessed by CTCAE v4.0
Time Frame:Nine months
Safety Issue:
Description:
Measure:Number of participants with adverse events relating to treatment with low-dose capecitabine combined with bevacizumab as assessed by CTCAE v4.0
Time Frame:Nine months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Myeloid derived suppressor cells
  • brain tumor
  • MDSC
  • GBM
  • recurrent

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