Anaplastic Astrocytoma, Anaplastic Oligoastrocytoma, Anaplastic Oligodendroglioma, Glioblastoma, Gliosarcoma
Conditions
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.
Interventions
DIETARY_SUPPLEMENTascorbic acid
Given IV
DRUGtemozolomide
Given PO
OTHERquality-of-life assessment
Ancillary studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
University of Nebraska
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Ascorbic Acid in Combination With Temozolomide | 56 days | 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 | Up to 30 days after last administration of study medication | 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
| Measure | Time frame | Description |
|---|---|---|
| Changes in Serum Levels of Ascorbic Acid Using High-performance Liquid Chromatography (HPLC) With Coulometric Electrochemical Detection) | Baseline to up to 52 weeks | 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 | Up to 52 weeks | The measurement of effect will be based on the Macdonald criteria |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Ascorbic Acid, Temozolomide) 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.
ascorbic acid: Given IV
temozolomide: Given PO
quality-of-life assessment: Ancillary studies
laboratory biomarker analysis: Correlative studies | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 4 |
Baseline characteristics
| Characteristic | Treatment (Ascorbic Acid, Temozolomide) |
|---|---|
| Age, Continuous | 42 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 1 / 4 |
| serious Total, serious adverse events | 2 / 4 |
Outcome results
Primary
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.
Time frame: Up to 30 days after last administration of study medication
Population: This study was terminated after only 4 patients enrolled. Incidence rates of adverse event could not be describe by dose level.
Primary
Maximum Tolerated Dose of Ascorbic Acid in Combination With Temozolomide
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.
Time frame: 56 days
Population: This study was terminated as subjects had disease progression so no subjects were evaluable.
Secondary
Changes in Serum Levels of Ascorbic Acid Using High-performance Liquid Chromatography (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.
Time frame: Baseline to up to 52 weeks
Population: No patients were analyzed as all experienced progressive disease after 2 cycles of treatment.
Secondary
Using Radiologic Measurements for Tumor Response
The measurement of effect will be based on the Macdonald criteria
Time frame: Up to 52 weeks
Population: This outcome measure was not analyzed as all patients had progressive disease by 2 cycles of treatment.