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A Phase 2 Trial of High-Dose Ascorbate in Glioblastoma Multiforme

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02344355
Recruitment Status : Recruiting
First Posted : January 22, 2015
Last Update Posted : April 7, 2020
Sponsor:
Collaborators:
Holden Comprehensive Cancer Center
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Bryan Allen, University of Iowa

Tracking Information
First Submitted Date  ICMJE January 16, 2015
First Posted Date  ICMJE January 22, 2015
Last Update Posted Date April 7, 2020
Actual Study Start Date  ICMJE March 13, 2017
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 3, 2016)
Overall Survival (OS) [ Time Frame: monthly up to 5 years post treatment ]
From radiation day 1 until date of death from any cause.
Original Primary Outcome Measures  ICMJE
 (submitted: January 16, 2015)
Progression Free Survival (PFS) [ Time Frame: monthly up to 5 years post treatment ]
From radiation day 1 to documented disease progression in MRI imaging as described by MacDonald and colleagues
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 3, 2016)
  • Progression Free Survival (PFS) [ Time Frame: monthly up to 5 years post treatment ]
    From radiation day 1 to documented disease progression in MRI imaging as described by the RANO criteria
  • Adverse Event Frequency [ Time Frame: monthly through 7 months post-radiation ]
    Categorize and quantify using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4 from radiation day 1 through 7 months post-radiation.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 16, 2015)
  • Overall Survival (OS) [ Time Frame: monthly up to 5 years post treatment ]
    From radiation day 1 until date of death from any cause.
  • Adverse Event Frequency [ Time Frame: monthly through 7 months post-radiation ]
    Categorize and quantify using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4 from radiation day 1 through 7 months post-radiation.
Current Other Pre-specified Outcome Measures
 (submitted: January 16, 2015)
Health-related Quality of Life (HRQOL) [ Time Frame: monthly for 3 months, then every 3 months up to 5 years post treatment ]
Measure health-related outcomes using the validated EORTC (European Organization for Research and Treatment of Cancer) questionnaires QLQ-C30 and BN-20.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Phase 2 Trial of High-Dose Ascorbate in Glioblastoma Multiforme
Official Title  ICMJE Pharmacological Ascorbate Combined With Radiation and Temozolomide in Glioblastoma Multiforme: A Phase 2 Trial
Brief Summary This clinical trial evaluates adding high-dose ascorbate (vitamin C) to standard of care treatment of glioblastoma multiforme (a type of brain tumor) in adults. All subjects will receive high-dose ascorbate in addition to the standard treatment.
Detailed Description

Standard treatment for glioblastoma multiforme (GBM) involves maximum safe surgical resection followed by radiation combined with temozolomide (a chemotherapy pill you take by mouth). After radiation, patients receive additional cycles of temozolomide (adjuvant chemotherapy).

Participants will:

  • receive high doses of intravenous (IV) ascorbate three times a week during the combined radiation and chemotherapy phase
  • receive high doses of intravenous (IV) ascorbate twice a week during adjuvant chemotherapy (after radiation)
  • complete health-related quality of life questionnaires pre-radiation, 4 weeks into radiation, 4 weeks after radiation, and then every 3 months. In addition, patients will complete neurocognitive testing pre-radiation, 4 weeks into radiation, 4 weeks after radiation, and approximately 9 months after initiating radiation therapy.

The adjuvant chemotherapy portion of this study lasts for 6 months. After that is completed, participants will go back to standard therapy for their cancer. Participants will continue to have life-long follow-up for this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme
Intervention  ICMJE
  • Drug: Temozolomide

    oral temozolomide (75 mg/m2), given 7 days per week, for a maximum of 49 days during radiation therapy.

    Starting 1 month after radiation therapy, additional temozolomide will be given as chemotherapy cycles. Each cycle is 28 days.

    For the first cycle, temozolomide will be administered (150 mg/m2) once per day for 5 days.

    If the subject tolerates the first cycle well, temozolomide will be prescribed at 200 mg/m2 for cycles 2 through 6. Each cycle is 28 days.

    Other Names:
    • Temodar
    • Temodal
  • Radiation: radiation therapy
    Conformal radiation administered daily, M-F, to a total dose of 61.2 Gray in 34 fractions.
    Other Names:
    • EBRT
    • XRT
    • external beam radiation therapy
  • Drug: Ascorbic Acid

    Intravenous infusions of 87.5g of ascorbate administered three times weekly during radiation.

    After radiation, ascorbate is administered twice weekly through the end of cycle 6 of temozolomide.

    Other Names:
    • Vitamin C
    • Ascorbate
    • Pharmacological Ascorbate
    • 67457-118-50
Study Arms  ICMJE Experimental: ascorbate, radiation, temozolomide

Concomitant therapy:

Radiation therapy, oral temozolomide, and pharmacological ascorbate (ascorbic acid) infusions

Adjuvant therapy:

Oral temozolomide and pharmacological ascorbate (ascorbic acid) infusions

Interventions:
  • Drug: Temozolomide
  • Radiation: radiation therapy
  • Drug: Ascorbic Acid
Publications * 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. O(2)(⋅-) and H(2)O(2)-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. Erratum in: Cancer Cell. 2017 Aug 14;32(2):268.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 16, 2015)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Ability to understand and willingness to sign informed consent (power of attorney and/or legally authorized representatives cannot sign on behalf of the patient)
  • 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 or biopsy
  • Age ≥ 18 years
  • ECOG performance status 0-2. (KPS > 50)
  • Absolute neutrophil count (ANC) ≥ 1500 cells per mm3
  • Platelets ≥ 100,000 per mm3
  • Hemoglobin ≥ 8 g/dL
  • Creatinine ≤ 2.0 mg
  • Total bilirubin ≤ 1.5 mg/dL
  • ALT ≤ 3 times the institutional upper limit of normal
  • AST ≤ 3 times the institutional upper limit of normal
  • Tolerate one test dose (15g) of ascorbate.
  • Not pregnant.

Exclusion Criteria:

  • Recurrent high grade glioma
  • G6PD (glucose-6-phosphate dehydrogenase) deficiency.
  • Patients actively receiving insulin or using a finger-stick glucometer daily for blood glucose measurements
  • 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: warfarin, flecainide, methadone, amphetamines, quinidine, and chlorpropamide.
  • Known active concurrent malignancy, as determined by treating physicians.
  • Patients who have received prior chemotherapy (including Gliadel wafers) for the current glioma.
  • Prior radiation therapy to the head or neck resulting in overlap of RT fields.
  • Patients receiving any other investigational agents (imaging agents are acceptable)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection that would result in a hospital stay or delay of treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or impact patient safety.
  • Pregnant women.
  • Breastfeeding women.
  • Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bryan G. Allen, MD, PhD 319-353-8836 bryan-allen@uiowa.edu
Contact: Joseph J Cullen, MD 319-356-1616 joseph-cullen@uiowa.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02344355
Other Study ID Numbers  ICMJE 201504786
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be released publicly as per participant consent and IRB approval. Individual researchers should contact the research team for data sharing.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Study protocol and informed consent will be shared after primary completion. Statistical analysis plan will be shared with results reporting.
Access Criteria: An IRB-stamped signed usage agreement will be required in addition to a data sharing agreement between the academic centers.
Responsible Party Bryan Allen, University of Iowa
Study Sponsor  ICMJE Bryan Allen
Collaborators  ICMJE
  • Holden Comprehensive Cancer Center
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Bryan G. Allen, MD, PhD Assistant Professor, Department of Radiation Oncology, The University of Iowa
PRS Account University of Iowa
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP