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

Primary Purpose

Glioblastoma Multiforme

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Temozolomide

radiation therapy

Ascorbic Acid

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring Ascorbic Acid, temozolomide, radiation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Holden Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ascorbate, radiation, temozolomide

Arm Description

Concomitant therapy: Radiation therapy, oral temozolomide, and pharmacological ascorbate (ascorbic acid) infusions Adjuvant therapy: Oral temozolomide and pharmacological ascorbate (ascorbic acid) infusions

Outcomes

Primary Outcome Measures

Overall Survival (OS)

From radiation day 1 until date of death from any cause.

Secondary Outcome Measures

Progression Free Survival (PFS)

From radiation day 1 to documented disease progression in MRI imaging as described by the RANO criteria

Adverse Event Frequency

Categorize and quantify using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4 from radiation day 1 through 7 months post-radiation.

Full Information

NCT ID

NCT02344355

First Posted

January 16, 2015

Last Updated

August 8, 2023

Sponsor

Bryan Allen

Collaborators

Holden Comprehensive Cancer Center, National Cancer Institute (NCI), Gateway for Cancer Research

1. Study Identification

Unique Protocol Identification Number

NCT02344355

Brief Title

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

Official Title

Pharmacological Ascorbate Combined With Radiation and Temozolomide in Glioblastoma Multiforme: A Phase 2 Trial

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

March 13, 2017 (Actual)

Primary Completion Date

December 31, 2025 (Anticipated)

Study Completion Date

December 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Bryan Allen

Collaborators

Holden Comprehensive Cancer Center, National Cancer Institute (NCI), Gateway for Cancer Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastoma Multiforme

Keywords

Ascorbic Acid, temozolomide, radiation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

ascorbate, radiation, temozolomide

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Temozolomide

Other Intervention Name(s)

Temodar, Temodal

Intervention Description

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.

Intervention Type

Radiation

Intervention Name(s)

radiation therapy

Other Intervention Name(s)

EBRT, XRT, external beam radiation therapy

Intervention Description

Conformal radiation administered daily, M-F, to a total dose of 61.2 Gray in 34 fractions.

Intervention Type

Drug

Intervention Name(s)

Ascorbic Acid

Other Intervention Name(s)

Vitamin C, Ascorbate, Pharmacological Ascorbate, 67457-118-50

Intervention Description

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.

Primary Outcome Measure Information:

Title

Overall Survival (OS)

Description

From radiation day 1 until date of death from any cause.

Time Frame

monthly up to 5 years post treatment

Secondary Outcome Measure Information:

Title

Progression Free Survival (PFS)

Description

From radiation day 1 to documented disease progression in MRI imaging as described by the RANO criteria

Time Frame

monthly up to 5 years post treatment

Title

Adverse Event Frequency

Description

Categorize and quantify using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4 from radiation day 1 through 7 months post-radiation.

Time Frame

monthly through 7 months post-radiation

Other Pre-specified Outcome Measures:

Title

Health-related Quality of Life (HRQOL)

Description

Measure health-related outcomes using the validated EORTC (European Organization for Research and Treatment of Cancer) questionnaires QLQ-C30 and BN-20.

Time Frame

monthly for 3 months, then every 3 months up to 5 years post treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bryan G. Allen, MD, PhD

Organizational Affiliation

Assistant Professor, Department of Radiation Oncology, The University of Iowa

Official's Role

Principal Investigator

Facility Information:

Facility Name

Holden Comprehensive Cancer Center

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52242

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Data will be released publicly as per participant consent and IRB approval. Individual researchers should contact the research team for data sharing.

IPD Sharing Time Frame

Study protocol and informed consent will be shared after primary completion. Statistical analysis plan will be shared with results reporting.

IPD Sharing Access Criteria

An IRB-stamped signed usage agreement will be required in addition to a data sharing agreement between the academic centers.

Citations:

PubMed Identifier

28366679

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. Erratum In: Cancer Cell. 2017 Aug 14;32(2):268.

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

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