Clinical trial NCT01752491: A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme
Official title: A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioblastoma
GBM
Glioblastoma Multiforme
Keywords: Ascorbate
Ascorbic acid
Vitamin C
Radiation
Temozolomide
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Cancer Institute (NCI)
First posted: 2012-12-19
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of grade 3, 4, & 5 adverse events
timeFrame: Weekly during therapy for up to 10 months
Secondary outcomes:
measure: Time to progression
timeFrame: monthly up to 5 years post treatment
measure: Overall survival
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at the University of Iowa
state: Iowa
Study officials:
affiliation: Department of Radiation Oncology, The University of Iowa
name: John M. Buatti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Professor of Surgery, The University of Iowa
name: Joseph J Cullen, MD
role: STUDY_DIRECTOR
References:
citation: 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.
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.
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, Schall ME, Hohl RJ, Clamon GH, Greenlee JD, Howard MA, Schultz MK, Smith BJ, Riley DP, Domann FE, Cullen JJ, Buettner GR, Buatti JM, Spitz DR, Allen BG. O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 2017 Apr 10;31(4):487-500.e8. doi: 10.1016/j.ccell.2017.02.018. Epub 2017 Mar 30.