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

• Sponsor: University of Nebraska (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02168270
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 4
• Location: 1
• Arm: 1
• Duration (Months): 14
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma; Glioblastoma; Gliosarcoma	Dietary Supplement: ascorbic acid; Drug: temozolomide; Other: quality-of-life assessment; Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

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

3. To evaluate progression-free and overall survival of patients with recurrent high grade glioma treated with therapy with ascorbic acid and temozolomide.

4. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of Metronomic Temozolomide and Intravenous Ascorbic Acid for Patients With Recurrent High Grade Glioma
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Dietary Supplement: ascorbic acid; Given IV; Other Names: C-Long Ce-Vi-Sol Cecon Cenolate Cetane ; Drug: temozolomide; Given PO; Other Names: SCH 52365 Temodal Temodar TMZ ; Other: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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 [56 days]

   Graded by the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 4.0. DLT incidence will be described by dose level.

2. 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 Outcome Measures

1. Changes in Serum Levels of Ascorbic Acid (Using 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.

2. Using Radiologic Measurements for Tumor Response [Up to 52 weeks]

   The measurement of effect will be based on the Macdonald criteria

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198

Sponsors and Collaborators

• University of Nebraska
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Nicole Shonka, University of Nebraska

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nicole Shonka, Principal Investigator, University of Nebraska
• ClinicalTrials.gov Identifier: NCT02168270
• Other Study ID Numbers: 735-13; NCI-2014-01061; 735-13; P30CA036727
• First Posted: Jun 20, 2014
• Last Update Posted: Feb 23, 2018
• Last Verified: Jan 1, 2018

• 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
• Additional relevant MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Ascorbic Acid; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Treatment (Ascorbic Acid, Temozolomide)
Arm/Group 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. ascorbic acid: Given IV temozolomide: Given PO quality-of-life assessment: Ancillary studies laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	4
COMPLETED	0
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Treatment (Ascorbic Acid, Temozolomide)
Arm/Group 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. ascorbic acid: Given IV temozolomide: Given PO quality-of-life assessment: Ancillary studies laboratory biomarker analysis: Correlative studies
Overall Participants	4
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	42
Sex: Female, Male (Count of Participants)
Female	2 50%
Male	2 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	4 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This study was terminated as subjects had disease progression so no subjects were evalable.

Arm/Group Title	Treatment (Ascorbic Acid, Temozolomide)
Arm/Group 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. ascorbic acid: Given IV temozolomide: Given PO quality-of-life assessment: Ancillary studies laboratory biomarker analysis: Correlative studies
Measure Participants	0

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This study was terminated after only 4 patients enrolled. Incidence rates of adverse event could not be describe by dose level.

Arm/Group Title	Treatment (Ascorbic Acid, Temozolomide)
Arm/Group 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. ascorbic acid: Given IV temozolomide: Given PO quality-of-life assessment: Ancillary studies laboratory biomarker analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No patients were analyzed as all experienced progressive disease after 2 cycles of treatment.

Arm/Group Title	Treatment (Ascorbic Acid, Temozolomide)
Arm/Group 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. ascorbic acid: Given IV temozolomide: Given PO quality-of-life assessment: Ancillary studies laboratory biomarker analysis: Correlative studies
Measure Participants	0

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

This outcome measure was not analyzed as all patients had progressive disease by 2 cycles of treatment.

Arm/Group Title	Treatment (Ascorbic Acid, Temozolomide)
Arm/Group 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. ascorbic acid: Given IV temozolomide: Given PO quality-of-life assessment: Ancillary studies laboratory biomarker analysis: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Adverse event data was collected from the time the first patient consented (6-30-14) until July 2015 when all subjects were off study.
Arm/Group Title	Treatment (Ascorbic Acid, Temozolomide)
Arm/Group 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. ascorbic acid: Given IV temozolomide: Given PO quality-of-life assessment: Ancillary studies laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Ascorbic Acid, Temozolomide)
	Affected / at Risk (%)	# Events
Total	0/4 (0%)
Serious Adverse Events
	Treatment (Ascorbic Acid, Temozolomide)
	Affected / at Risk (%)	# Events
Total	2/4 (50%)
Gastrointestinal disorders
Vomiting	1/4 (25%)	1
General disorders
Headache	1/4 (25%)	3
Weakness	1/4 (25%)	1
Metabolism and nutrition disorders
Hyponatremia	1/4 (25%)	2
Musculoskeletal and connective tissue disorders
Pain, Hip, back	1/4 (25%)	1
Nervous system disorders
Seizure	1/4 (25%)	2
Renal and urinary disorders
Urinary retention	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Ascorbic Acid, Temozolomide)
	Affected / at Risk (%)	# Events
Total	1/4 (25%)
Blood and lymphatic system disorders
Lymphopenia	1/4 (25%)	2
Metabolism and nutrition disorders
Hyponatremia	1/4 (25%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.