A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme

Glioblastoma Clinical Trial

Official title:

A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01752491
• Other study ID #: 201211713
• Secondary ID: P30CA086862U01CA
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: April 1, 2013
• Est. completion date: December 31, 2024

Study information

• Verified date: October 2023
• Source: University of Iowa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase 1 (first in man) study testing the safety of adding high dose ascorbate (vitamin C) to standard radiation and chemotherapy for initial treatment of glioblastoma multiforme (GBM).

Description:

This phase 1 study will test the safety of adding high dose ascorbate (vitamin C) to standard chemoradiation and, after the radiation is completed, during 6 cycles of temozolomide.

Standard treatment for glioblastoma multiforme (GBM) involves surgery followed by radiation combined with temozolomide (a chemotherapy). After radiation, patients receive cycles of temozolomide (adjuvant chemotherapy)

Participants will:

• receive high doses of intravenous (IV) ascorbate three times a week during chemoradiation

• receive high doses of intravenous (IV) ascorbate twice a week during adjuvant chemotherapy (after radiation)

This is a phase 1 study will evaluate the side effects of adding this drug to the standard therapy. The dose given to a participant will be determined by how well other participants have tolerated the drug.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 13
• Est. completion date: December 31, 2024
• Est. primary completion date: November 30, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have newly diagnosed (i.e., within 5 weeks), histologically or cytologically confirmed glioblastoma multiforme.

• Diagnosis must be made by surgical biopsy or excision.

• Therapy must begin = 5 weeks after surgery.

• Age = 18 years

• ECOG performance status 0-2 (Karnofsky > 50%).

• A complete blood count and differential must be obtained within 21 days prior to the first dose of radiation, with adequate bone marrow functions as defined below:

• Absolute neutrophil count (ANC) = 1500 cells per mm3

• Platelets = 100,000 per mm3

• Hemoglobin = 8 g/dL

• Serum blood chemistries within 21 days before the first day of radiation, as defined below:

• Creatinine = 2.0 mg

• Total bilirubin = 1.5 mg/dL

• ALT (Alanine Aminotransferase)= 3 times the institutional upper limit of normal

• AST (Aspartate Aminotransferase) = 3 times the institutional upper limit of normal

• Tolerate one text dose (15g) of ascorbate

• Not pregnant

• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Recurrent high grade glioma

• G6PD (glucose-6-phosphate dehydrogenase) deficiency

• Patients actively receiving insulin unless approved by the study medical monitor, study sponsor, and the study principal investigator.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide.

• Significant co-morbid central nervous system disease, including but not limited to, multiple sclerosis.

• Patients who are on the following drugs and cannot have a drug substitution:

flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs.

• Prior invasive malignancies (except non-melanomatous skin cancers and carcinoma in situ of the cervix or bladder) unless disease free for = 5 years.

• Patients who have received prior chemotherapy (including Gliadel wafers) for the current glioma.

• Prior radiation therapy to the head or neck, which would result in overlap of radiation therapy fields.

• Patients may not be receiving any other investigational agents.

• 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.

• Pregnant women are excluded from this study because ionizing radiation is a known teratogen, and temozolomide is a Class D agent with the potential for teratogenic or abortifacient effects.

• Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 (an enzyme pathway) inducer, which results in lower serum levels of antiretroviral drugs

Related Conditions & MeSH terms

• GBM
• Glioblastoma
• Glioblastoma Multiforme

Intervention

Drug:
• Ascorbate
Intravenous infusion of high-dose ascorbate
• Temozolomide
Oral chemotherapeutic

Radiation:
• Radiation therapy
External beam radiation therapy

Locations

Country	Name	City	State
United States	Holden Comprehensive Cancer Center at the University of Iowa	Iowa City	Iowa

Sponsors (3)

Lead Sponsor	Collaborator
Joseph J. Cullen, MD, FACS	National Cancer Institute (NCI), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012 Dec;1826(2):443-57. doi: 10.1016/j.bbcan.2012.06.003. Epub 2012 Jun 20. — View Citation

Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, Taghiyev AF, Du C, Knudson CM, Cullen JJ. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010 Jan 15;16(2):509-20. doi: 10.1158/1078-0432.CCR-09-1713. Epub 2010 Jan 12. — View Citation

Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, Sandhu S, Carlisle TL, Smith MC, Abu Hejleh T, Berg DJ, Zhang J, Keech J, Parekh KR, Bhatia S, Monga V, Bodeker KL, Ahmann L, Vollstedt S, Brown H, Shanahan Kauffman EP, Sc — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of grade 3, 4, & 5 adverse events	Assess grade 3 and higher adverse events. Evaluate the frequency and severity against the published literature to determine the likely causality between ascorbate and the adverse event(s).	Weekly during therapy for up to 10 months
Secondary	Time to progression	Time from the start of therapy (day 1, cycle 1) to documented disease progression in MRI imaging as described by MacDonald and colleagues.	monthly up to 5 years post treatment
Secondary	Overall survival	From start of treatment (cycle 1, day 1) until the date of death from any cause.	Up to 5 years