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

This study is currently recruiting participants.
Verified April 2013 by University of Iowa
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
John M. Buatti, University of Iowa
ClinicalTrials.gov Identifier:
NCT01752491
First received: December 14, 2012
Last updated: April 16, 2013
Last verified: April 2013
History of Changes
  Purpose

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).


Condition Intervention Phase
Glioblastoma
GBM
Glioblastoma Multiforme
 Drug: Ascorbate
Drug: Temozolomide
Radiation: Radiation therapy
 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme

Resource links provided by NLM:

MedlinePlus related topics: Vitamin C
U.S. FDA Resources

Further study details as provided by University of Iowa:

Primary Outcome Measures:
  • Number of grade 3, 4, & 5 adverse events [ Time Frame: Weekly during therapy for up to 10 months ] [ Designated as safety issue: Yes ]
    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:
  • Time to progression [ Time Frame: monthly up to 5 years post treatment ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    From start of treatment (cycle 1, day 1) until the date of death from any cause.


Estimated Enrollment: 30
Study Start Date: April 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 15g 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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy
Experimental: 25g 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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy
Experimental: 50g arm

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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy
Experimental: 62.5g

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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy
Experimental: 75g 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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy
Experimental: 87.5g 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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy
Experimental: 100g Ascorbate

If the 87.5g arm is tolerated, the study opens the 100g 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: 100 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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy
Experimental: 125g Ascorbate

If the 100g arm is tolerated, the study opens the 125g 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: 125 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.
 Drug: Ascorbate
Intravenous infusion of high-dose ascorbate
Other Names:
  • Ascorbic Acid
  • Vitamin C
Drug: Temozolomide
Oral chemotherapeutic
Other Name: Temodar
Radiation: Radiation therapy
Other Name: External beam radiation therapy

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01752491

Contacts
Contact: Bryan Allen, MD, PhD (319) 356-8538 bryan-allen@uiowa.edu

Locations
United States, Iowa
Holden Comprehensive Cancer Center at the University of Iowa Recruiting
Iowa City, Iowa, United States, 52242
Contact: Sandy Vollstedt, RN, BSN     319-353-7143     sandy-vollstedt@uiowa.edu    
Contact: Jane Hershberger, RN, BSN     (319) 384-7912     jane-hershberger@uiowa.edu    
Principal Investigator: John M Buatti, MD            
Sub-Investigator: Bryan Allen, MD, PhD            
Sub-Investigator: Carryn Anderson, MD            
Sub-Investigator: Daniel Berg, MD            
Sub-Investigator: Sudershan Bhatia, MD, PhD            
Sub-Investigator: Kellie Bodeker, MSHS, CCRC            
Sub-Investigator: Garry Buettner, PhD            
Sub-Investigator: Thomas Carlisle, MD, PhD            
Sub-Investigator: Raymond Hohl, MD, PhD            
Sub-Investigator: William Rockey, MD, PhD            
Sub-Investigator: Mark C Smith, MD            
Sub-Investigator: Wenqing Sun, MD, PhD            
Sub-Investigator: Brett Wagner, MA            
Sponsors and Collaborators
University of Iowa
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Investigators
Principal Investigator: John M. Buatti, MD Department of Radiation Oncology, The University of Iowa
Study Director: Joseph J Cullen, MD Professor of Surgery, The University of Iowa
  More Information

Publications:

Responsible Party: John M. Buatti, Professor and Chair, Department of Radiation Oncology, University of Iowa
ClinicalTrials.gov Identifier: NCT01752491     History of Changes
Other Study ID Numbers: 201211713, P30CA086862, U01CA140206
Study First Received: December 14, 2012
Last Updated: April 16, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Iowa:
Ascorbate
Ascorbic acid
Vitamin C
Radiation
Temozolomide

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Ascorbic Acid
Vitamins
 Temozolomide
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Micronutrients
Growth Substances
Antineoplastic Agents, Alkylating
Alkylating Agents
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on June 17, 2013