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Bevacizumab and Ascorbic Acid in Patients Treating With Recurrent High Grade Glioma

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ClinicalTrials.gov Identifier: NCT02833701
Recruitment Status : Terminated
First Posted : July 14, 2016
Last Update Posted : July 26, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Nicole Shonka, University of Nebraska

Brief Summary:
This phase I trial studies the side effects and best dose of ascorbic acid when given together with bevacizumab in treating patients with high grade glioma that has come back (recurrent). Monoclonal antibodies, such as bevacizumab may interfere with the ability of tumor cells to grow and spread. Ascorbic acid contains ingredients that may prevent or slow the growth of high grade glioma. Giving bevacizumab and ascorbic acid together may work better in treating patients with high grade glioma.

Condition or disease Intervention/treatment Phase
Glioblastoma Glioma Dietary Supplement: Ascorbic Acid Biological: Bevacizumab Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the toxicities and determine the recommended dose of intravenous ascorbic acid given three times weekly in combination with intravenous bevacizumab every two weeks in patients with recurrent high grade glioma.

SECONDARY OBJECTIVES:

I. To evaluate changes in the levels of serum ascorbic acid (using high performance liquid chromatography [HPLC] with coulometric electrochemical detection) during therapy with ascorbic acid and bevacizumab.

II. Radiographic assessment of disease status after 2 cycles of therapy with ascorbic acid and bevacizumab.

III. To evaluate progression-free and overall survival of patients with recurrent high grade glioma treated with therapy with ascorbic acid and bevacizumab. Patients with stable or responsive disease after every 2 cycles will continue on therapy with ascorbic acid and bevacizumab until intolerance or progressive disease.

IV. To descriptively examine quality of life (QOL) using European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire QLQ-C30 during treatment.

OUTLINE: This is a dose-escalation study of ascorbic acid.

Patients receive ascorbic acid intravenously (IV) over 90-120 minutes three times per week (at least 24 hours apart) and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Bevacizumab and Intravenous Ascorbic Acid for Patients With Recurrent High Grade Glioma
Study Start Date : March 2016
Actual Primary Completion Date : March 2019
Actual Study Completion Date : March 2019


Arm Intervention/treatment
Experimental: Treatment (bevacizumab and ascorbic acid)
Patients receive ascorbic acid IV over 90-120 minutes three times per week (at least 24 hours apart) and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Dietary Supplement: Ascorbic Acid
Given IV
Other Names:
  • 2-(1,2-dihydroxyethyl)-4,5-dihydroxy-furan-3-one
  • Asorbicap
  • C Vitamin
  • C-Long
  • Ce-Vi-Sol
  • Cecon
  • Cenolate
  • Cetane
  • Cevalin
  • L-Ascorbic Acid
  • VIT C
  • Vitamin C
  • Vitamin-C

Biological: Bevacizumab
Given intravenously (IV)
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. Frequency of occurrence of overall toxicity [ Time Frame: Up to 52 weeks ]
    Categorized by toxicity grades.

  2. Incidence of dose limiting toxicities (DLT) [ Time Frame: Up to 56 days ]
    Described by dose level.

  3. Incidence rates of adverse events [ Time Frame: Up to 52 weeks ]
    Described by dose level.

  4. Maximum tolerated dose of ascorbic acid in combination with bevacizumab defined as the highest dose tested which results in DLT in no more than 1 of 6 evaluable patients [ Time Frame: Up to 56 days ]

Secondary Outcome Measures :
  1. Changes in serum levels of ascorbic acid using HPLC with coulometric electrochemical detection [ Time Frame: Week 1 to up to Week 52 ]
    Correlation of intracellular glutathione with ascorbic acid levels during therapy with ascorbic acid and temozolomide will be summarized using descriptive statistics to summarize changes over time.

  2. Disease status by radiologic assessment [ Time Frame: Up to 56 days ]
    Disease status measured by radiologic assessment.

  3. Progression free survival [ Time Frame: First date of therapy until the first notation of clinical progression, relapse or death from any cause, assessed up to 1 year ]
    Will be plotted following the method of Kaplan and Meier.

  4. QOL using EORTC QLQ-C30 [ Time Frame: Up to 52 weeks ]
    Will be descriptively summarized using means and standard deviations.

  5. Survival [ Time Frame: First date of therapy until the date of death from any cause, assessed up to 1 year ]
    Will be plotted following the method of Kaplan and Meier.



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have pathologically proven diagnosis of high grade glioma
  • Patients must have received prior radiation therapy and standard temozolomide; patients who have received additional therapies for previous progressions will be considered eligible
  • Patients must be three or more months from the end of chemoradiotherapy or have biopsy or imaging consistent with disease progression
  • Patients must have recovered from toxicity of prior therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 or better
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Hemoglobin >= 8 g/dL
  • Platelet count >= 100,000/mm^3
  • Serum creatinine that is at or below 2.0 mg/dL
  • Serum aspartate transaminase (AST) and alanine transaminase (ALT) less than 1.5 times the upper limits of normal
  • Serum alkaline phosphatase less than 2.5 times the upper limits of normal
  • The patient must be aware of the neoplastic nature of his/her disease and willingly provide written, informed consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts
  • Women of reproductive potential must be non-pregnant and non-nursing and must agree to employ an effective barrier method of birth control throughout the study and for up to 6 months following treatment
  • Women of child-bearing potential must have a negative pregnancy test within 7 days of initiating study; (no childbearing potential is defined as age 55 years or older and no menses for two years or any age with surgical removal of the uterus and/or both ovaries)

Exclusion Criteria:

  • History of uncontrollable allergic reactions to bevacizumab or ascorbic acid
  • Known human immunodeficiency virus (HIV)-positivity AND actively being treated with highly active antiretroviral therapy (HAART)
  • History of glucose-6-phosphate dehydrogenase deficiency
  • History of oxalate nephrolithiasis or urine oxalate >60 mg/dL
  • Anuria, dehydration, severe pulmonary congestion or pulmonary edema or fixed low cardiac input
  • Prior hypersensitivity to bevacizumab or toxicity requiring discontinuation of bevacizumab
  • Clinically significant cardiovascular disease defined as follows:

    • Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] > 160 mm Hg and/or diastolic pressure [DBP] > 90 mm Hg despite antihypertensive therapy)
    • History of cerebrovascular accident (CVA) within 6 months
    • Myocardial infarction or unstable angina within 6 months
  • Evidence or history of bleeding diathesis (greater than normal risk of bleeding, i.e., Hereditary Hemorrhagic Telangiectasia type I or HHT-1) or coagulopathy in the absence of therapeutic anti-coagulation or any hemorrhage/bleeding event > grade 3 within 4 weeks prior to registration; note: patients with full-dose anticoagulants are eligible provided the patient has been on a stable dose for at least 2 weeks of low molecular weight heparin; therapeutic Coumadin and aspirin doses > 325 mg daily are not allowed
  • Active wound, a serious or non-healing wound, an active ulcer or untreated bone fracture
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess =< 6 months prior to registration
  • Major surgical procedure, open biopsy or significant traumatic injury =< 28 days prior to registration
  • Any other clinically significant medical disease or condition laboratory abnormality or psychiatric illness that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
  • Patients who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, and chlorpropamide; Note: high dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs
  • Simultaneous participation in other therapeutic clinical trials will not be allowed
  • Inability to co-operate with the requirements of the protocol
  • Pregnant and nursing women are excluded from this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02833701


Locations
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United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198
Sponsors and Collaborators
University of Nebraska
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Nicole Shonka University of Nebraska

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Responsible Party: Nicole Shonka, Principal Investigator, University of Nebraska
ClinicalTrials.gov Identifier: NCT02833701     History of Changes
Other Study ID Numbers: 769-15
NCI-2016-00239 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
769-15-FB
769-15 ( Other Identifier: University of Nebraska Medical Center )
P30CA036727 ( U.S. NIH Grant/Contract )
First Posted: July 14, 2016    Key Record Dates
Last Update Posted: July 26, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Vitamins
Ascorbic Acid
Bevacizumab
Antineoplastic Agents, Immunological
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Inhibitors
Immunologic Factors
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents