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

Phase 1

Completed

• Conditions: Glioblastoma Multiforme; GBM; Glioblastoma
• Interventions: Drug: Ascorbate; Drug: Temozolomide; Radiation: Radiation therapy

• Registration Number: NCT01752491
• Lead Sponsor: Joseph J. Cullen, MD, FACS

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.

Study Timeline

• Study First Submitted: 2012-12-14
• Study First Submitted QC: 2012-12-14
• Study First Posted: 2012-12-19
• Study Start: 2013-04-01
• Primary Completion: 2015-11-30
• Study Completion: 2019-11-15
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-17
• Last Update Posted: 2024-12-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 13

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
62.5g	Radiation therapy	If the 50g arm is tolerated, the study opens the 62.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
50g arm	Radiation therapy	If the 25g arm is tolerated, the study opens the 50g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
15g Ascorbate	Radiation therapy	During radiation therapy: * Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed. * Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
25g Ascorbate	Radiation therapy	If the 15g arm is tolerated, the study opens the 25g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
87.5g Ascorbate	Radiation therapy	If the 75g arm is tolerated, the study opens the 87.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
75g Ascorbate	Radiation therapy	If the 62.5g arm is tolerated, the study opens the 75g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
15g Ascorbate	Ascorbate	During radiation therapy: * Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed. * Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
15g Ascorbate	Temozolomide	During radiation therapy: * Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed. * Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
25g Ascorbate	Ascorbate	If the 15g arm is tolerated, the study opens the 25g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
25g Ascorbate	Temozolomide	If the 15g arm is tolerated, the study opens the 25g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
50g arm	Temozolomide	If the 25g arm is tolerated, the study opens the 50g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
50g arm	Ascorbate	If the 25g arm is tolerated, the study opens the 50g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
62.5g	Ascorbate	If the 50g arm is tolerated, the study opens the 62.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
62.5g	Temozolomide	If the 50g arm is tolerated, the study opens the 62.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
75g Ascorbate	Ascorbate	If the 62.5g arm is tolerated, the study opens the 75g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
75g Ascorbate	Temozolomide	If the 62.5g arm is tolerated, the study opens the 75g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
87.5g Ascorbate	Ascorbate	If the 75g arm is tolerated, the study opens the 87.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
87.5g Ascorbate	Temozolomide	If the 75g arm is tolerated, the study opens the 87.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Primary Outcome Measures

Name	Time	Method
Number of grade 3, 4, & 5 adverse events	Weekly during therapy for up to 10 months	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).

Secondary Outcome Measures

Name	Time	Method
Time to progression	monthly up to 5 years post treatment	Time from the start of therapy (day 1, cycle 1) to documented disease progression in MRI imaging as described by MacDonald and colleagues.
Overall survival	Up to 5 years	From start of treatment (cycle 1, day 1) until the date of death from any cause.

Trial Locations

Locations (1)

Holden Comprehensive Cancer Center at the University of Iowa; 🇺🇸 Iowa City, Iowa, United States