Gemcitabine, Ascorbate, Radiation Therapy for Pancreatic Cancer, Phase I

Pancreatic Neoplasms Clinical Trial

Official title:

Gemcitabine, Ascorbate, Radiation Therapy for Pancreatic Cancer, Phase I

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01852890
• Other study ID #: 201310772
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 2014
• Est. completion date: January 2026

Study information

• Verified date: October 2023
• Source: University of Iowa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 treatment of pancreatic cancer.

Description:

This phase 1 study will test the safety of adding high dose ascorbate (vitamin C) to standard chemoradiation. The ascorbate is infused during external beam radiation therapy treatment.

For patients eligible for this trial, standard treatment for their cancer includes radiation therapy combined with weekly gemcitabine (a chemotherapy).

Participants will:

• receive high doses of intravenous (IV) ascorbate during their daily radiation therapy treatments. Radiation treatments are given once a day, Monday through Friday.

• have routine doctor's visits and be asked about any side effects they are experiencing.

This is a phase 1 study that will evaluate the side effects of adding ascorbate to standard therapy. The dose given to a participant will be determined by how well other participants have tolerated ascorbate.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 16
• Est. completion date: January 2026
• Est. primary completion date: January 22, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have histologically or cytologically diagnosed pancreatic adenocarcinoma. Documentation of disease extent by CT scan is required. Radiologically measurable disease is not required.

• Age = 18 years

• ECOG performance status 0, 1, or 2 (Karnofsky > 50%).

• A complete blood count and differential must be obtained within 21 days prior to radiation fraction 1, with adequate bone marrow functions as defined below:

• Absolute neutrophil count (ANC) = 1500 cells per mm3

• Platelets = 100,000 per mm3

• Leukocytes = 3,000 per mm3

• Serum blood chemistries within 21 days of radiation fraction 1, as defined below:

• Creatinine = 1.5 x UIHC upper limit of normal or creatinine clearance of at least 60 ml/min/1.73 m2 for patients with creatinine levels above institutional normal.

• Total bilirubin = 2 x UIHC upper limit of normal

• ALT = 2.5 times the UIHC upper limit of normal

• AST = 2.5 times the UIHC upper limit of normal

• PT/INR within normal limits (UIHC)

• Tolerate one test dose (15g) of ascorbate.

• Not pregnant.

• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• G6PD (glucose-6-phosphate dehydrogenase) deficiency.

• Prior abdominal radiotherapy that would result in overlap of fields. The treating radiation oncologist should review prior RT fields as available.

• Adjuvant therapy (including radiation therapy) within 2 calendar weeks. Toxicities from prior therapy for the malignancy should resolve to grade 1 or less.

• Patients actively receiving insulin are excluded.

• Patients who are on the following drugs and cannot have a drug substitution:

flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbate may affect urine acidification and, as a result, may affect clearance rates of these drugs.

• Second malignancy other than non-melanoma skin cancers within the past 5 years.

• Other investigational agents/therapy with the intention to treat the disease under study (observational or imaging trials are acceptable).

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situations, or any other condition that would limit compliance with study requirements as determined by study team members.

• Pregnant or lactating women: The risks of radiation and chemotherapy to a fetus are well documented.

• Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs. A clinical trial designed to address these interaction issues is more appropriate than this phase 1 study.

Related Conditions & MeSH terms

• Pancreatic Neoplasms

Intervention

Drug:
• Ascorbate
Intravenous infusion of high-dose ascorbate
• Gemcitabine
Intravenous chemotherapeutic

Radiation:
• Radiation therapy

Locations

Country	Name	City	State
United States	The Holden Comprehensive Cancer Center	Iowa City	Iowa

Sponsors (3)

Lead Sponsor	Collaborator
Joseph J. Cullen	Gateway for Cancer Research, Holden Comprehensive Cancer Center

Country where clinical trial is conducted

United States, 

References & Publications (5)

Alexander MS, Wilkes JG, Schroeder SR, Buettner GR, Wagner BA, Du J, Gibson-Corley K, O'Leary BR, Spitz DR, Buatti JM, Berg DJ, Bodeker KL, Vollstedt S, Brown HA, Allen BG, Cullen JJ. Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicit — View Citation

Cullen JJ. Ascorbate induces autophagy in pancreatic cancer. Autophagy. 2010 Apr;6(3):421-2. doi: 10.4161/auto.6.3.11527. Epub 2010 Apr 15. — View Citation

Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012 Dec;1826(2):443-57. doi: 10.1016/j.bbcan.2012.06.003. Epub 2012 Jun 20. — View Citation

Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, Taghiyev AF, Du C, Knudson CM, Cullen JJ. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010 Jan 15;16(2):509-20. doi: 10.1158/1078-0432.CCR-09-1713. Epub 2010 Jan 12. — View Citation

Welsh JL, Wagner BA, van't Erve TJ, Zehr PS, Berg DJ, Halfdanarson TR, Yee NS, Bodeker KL, Du J, Roberts LJ 2nd, Drisko J, Levine M, Buettner GR, Cullen JJ. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013 Mar;71(3):765-75. doi: 10.1007/s00280-013-2070-8. Epub 2013 Feb 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of grade 3, 4, & 5 adverse events during radiation	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).	Weekly during therapy for up to 10 weeks
Secondary	Time to progression	Time from the start of therapy (radiation day 1) to documented disease progression as described by RECIST.	Monthly, up to 10 years post-treatment
Secondary	Overall survival	From start of treatment (radiation day 1) until the date of death from any cause.	Monthly, up to 10 years post-treatment
Secondary	Number of grade 3, 4, & 5 adverse events post-treatment	Beginning one month after completing radiation therapy, grade 3 and higher adverse events will be assessed. Evaluate the frequency and severity against the published literature to determine the likely causality between ascorbate and the adverse event(s).	every 3 months for 2 years