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Temozolomide and Ascorbic Acid in Treating Patients With Recurrent High-Grade Glioma

Primary Purpose

Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ascorbic acid
temozolomide
quality-of-life assessment
laboratory biomarker analysis
Sponsored by
University of Nebraska
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anaplastic Astrocytoma

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have pathologically proven diagnosis of high grade glioma
  • Patients must have received prior radiation therapy and standard temozolomide
  • 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) count >= 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 aminotransferase (AST) and alanine aminotransferase (ALT) less than 1.5 times the upper limits of normal; note: if hepatic function is abnormal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient
  • Serum alkaline phosphatase less than 2.5 times the upper limits of normal; note: if hepatic function is abnormal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient
  • 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 temozolomide or ascorbic acid or to antiemetics appropriate for administration in conjunction with protocol-directed chemotherapy
  • Known human immunodeficiency virus (HIV)-positivity AND actively being treated with highly active anti-retroviral 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 since all are conditions for which osmotic diuresis are contraindicated and ascorbic acid has high osmolarity
  • 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

Sites / Locations

  • University of Nebraska Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ascorbic acid, temozolomide)

Arm Description

Patients receive ascorbic acid IV over 90-120 minutes three times per week and temozolomide orally days 1-28. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose of Ascorbic Acid in Combination With Temozolomide, Defined as the Highest Dose Tested Which Results in Dose Limiting Toxicity (DLT) in no More Than One of Six Evaluable Patients
Graded by the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 4.0. DLT incidence will be described by dose level.
Incidence Rates of Adverse Events, Graded According to the NCI Common Toxicity Criteria for Adverse Events Version 4.0
The incidence rates of adverse events will be described by dose level. The frequency of occurrence of overall toxicity, categorized by toxicity grades, will be described.

Secondary Outcome Measures

Changes in Serum Levels of Ascorbic Acid (Using HPLC With Coulometric Electrochemical Detection)
Correlation of intracellular glutathione (in peripheral blood mononuclear cells) with ascorbic acid levels during therapy with ascorbic acid and temozolomide will be summarized using descriptive statistics to summarize changes over time.
Using Radiologic Measurements for Tumor Response
The measurement of effect will be based on the Macdonald criteria

Full Information

First Posted
May 29, 2014
Last Updated
January 25, 2018
Sponsor
University of Nebraska
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02168270
Brief Title
Temozolomide and Ascorbic Acid in Treating Patients With Recurrent High-Grade Glioma
Official Title
A Phase I Study of Metronomic Temozolomide and Intravenous Ascorbic Acid for Patients With Recurrent High Grade Glioma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Terminated
Study Start Date
June 2014 (undefined)
Primary Completion Date
August 2015 (Actual)
Study Completion Date
August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Nebraska
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial studies the side effects and best dose of ascorbic acid when given together with temozolomide in treating patients with high-grade glioma that has come back. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ascorbic acid contains ingredients that may prevent or slow the growth of high-grade gliomas. Giving temozolomide with ascorbic acid may kill more tumor cells.
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 temozolomide 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 temozolomide. II. Radiographic assessment of disease status after 2 cycles of therapy with ascorbic acid and temozolomide. III. To evaluate progression-free and overall survival of patients with recurrent high grade glioma treated with therapy with ascorbic acid and temozolomide. IV. To descriptively examine quality of life (QOL) using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (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 and temozolomide orally days 1-28. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 2 months for 1 year and then periodically thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma, Glioblastoma, Gliosarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (ascorbic acid, temozolomide)
Arm Type
Experimental
Arm Description
Patients receive ascorbic acid IV over 90-120 minutes three times per week and temozolomide orally days 1-28. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Dietary Supplement
Intervention Name(s)
ascorbic acid
Other Intervention Name(s)
C-Long, Ce-Vi-Sol, Cecon, Cenolate, Cetane
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
temozolomide
Other Intervention Name(s)
SCH 52365, Temodal, Temodar, TMZ
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
quality-of-life assessment
Other Intervention Name(s)
quality of life assessment
Intervention Description
Ancillary studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose of Ascorbic Acid in Combination With Temozolomide, Defined as the Highest Dose Tested Which Results in Dose Limiting Toxicity (DLT) in no More Than One of Six Evaluable Patients
Description
Graded by the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 4.0. DLT incidence will be described by dose level.
Time Frame
56 days
Title
Incidence Rates of Adverse Events, Graded According to the NCI Common Toxicity Criteria for Adverse Events Version 4.0
Description
The incidence rates of adverse events will be described by dose level. The frequency of occurrence of overall toxicity, categorized by toxicity grades, will be described.
Time Frame
Up to 30 days after last administration of study medication
Secondary Outcome Measure Information:
Title
Changes in Serum Levels of Ascorbic Acid (Using HPLC With Coulometric Electrochemical Detection)
Description
Correlation of intracellular glutathione (in peripheral blood mononuclear cells) with ascorbic acid levels during therapy with ascorbic acid and temozolomide will be summarized using descriptive statistics to summarize changes over time.
Time Frame
Baseline to up to 52 weeks
Title
Using Radiologic Measurements for Tumor Response
Description
The measurement of effect will be based on the Macdonald criteria
Time Frame
Up to 52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have pathologically proven diagnosis of high grade glioma Patients must have received prior radiation therapy and standard temozolomide 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) count >= 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 aminotransferase (AST) and alanine aminotransferase (ALT) less than 1.5 times the upper limits of normal; note: if hepatic function is abnormal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient Serum alkaline phosphatase less than 2.5 times the upper limits of normal; note: if hepatic function is abnormal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient 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 temozolomide or ascorbic acid or to antiemetics appropriate for administration in conjunction with protocol-directed chemotherapy Known human immunodeficiency virus (HIV)-positivity AND actively being treated with highly active anti-retroviral 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 since all are conditions for which osmotic diuresis are contraindicated and ascorbic acid has high osmolarity 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicole Shonka
Organizational Affiliation
University of Nebraska
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States

12. IPD Sharing Statement

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Temozolomide and Ascorbic Acid in Treating Patients With Recurrent High-Grade Glioma

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