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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Glioblastoma Multiforme	Drug: Temozolomide; Radiation: radiation therapy; Drug: Ascorbic Acid	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	90 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pharmacological Ascorbate Combined With Radiation and Temozolomide in Glioblastoma Multiforme: A Phase 2 Trial
Actual Study Start Date :	March 13, 2017
Estimated Primary Completion Date :	April 2020
Estimated Study Completion Date :	December 2023

Arms and Interventions

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Arm

Intervention/treatment

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

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

Outcome Measures

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Primary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: monthly up to 5 years post treatment ]
   From radiation day 1 until date of death from any cause.

Secondary Outcome Measures :

1. 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
2. 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.

Other Outcome Measures:

1. 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Contacts

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

Locations

United States, Iowa
Holden Comprehensive Cancer Center	Recruiting
Iowa City, Iowa, United States, 52242
Contact: Sandy Vollstedt, RN, BSN 319-353-7143 sandy-vollstedt@uiowa.edu
Contact: Heather Brown, RN, BAN 319-384-7912 heather-brown@uiowa.edu
Sub-Investigator: John M. Buatti, MD
Sub-Investigator: Joseph J. Cullen, MD
Sub-Investigator: Daniel Berg, MD
Sub-Investigator: Matthew Howard, MD
Sub-Investigator: Jeremy Greenlee, MD
Sub-Investigator: David Hasan, MD
Sub-Investigator: Patrick Hitchon, MD
Sub-Investigator: Varun Monga, MD
Sub-Investigator: Mark C. Smith, MD
Sub-Investigator: Carryn M. Anderson, MD
Sub-Investigator: Wenqing Sun, MD, PhD
Sub-Investigator: Douglas Spitz, PhD
Sub-Investigator: Mohammed Milhem, MBBA
Sub-Investigator: Garry R. Buettner, PhD

Sponsors and Collaborators

Bryan Allen

Holden Comprehensive Cancer Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Bryan G. Allen, MD, PhD	Assistant Professor, Department of Radiation Oncology, The University of Iowa

More Information

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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.

Responsible Party:	Bryan Allen, Assistant Professor, Radiation Oncology, University of Iowa
ClinicalTrials.gov Identifier:	NCT02344355 History of Changes
Other Study ID Numbers:	201504786
First Posted:	January 22, 2015
Last Update Posted:	May 28, 2018
Last Verified:	May 2018
Individual Participant Data (IPD) Sharing Statement:
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; Statistical Analysis Plan (SAP); 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.

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Bryan Allen, University of Iowa:

Ascorbic Acid; temozolomide; radiation

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; Temozolomide; Dacarbazine	Ascorbic Acid; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antioxidants; Protective Agents; Physiological Effects of Drugs; Vitamins; Micronutrients; Growth Substances