Clinical trial NCT01852890: Gemcitabine, Ascorbate, Radiation Therapy for Pancreatic Cancer, Phase I
Official title: Gemcitabine, Ascorbate, Radiation Therapy for Pancreatic Cancer, Phase I
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Pancreatic Neoplasms
Keywords: Ascorbate
Vitamin C
Radiation
Gemcitabine
Ascorbic Acid
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: Holden Comprehensive Cancer Center
name: Gateway for Cancer Research
First posted: 2013-05-14
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of grade 3, 4, & 5 adverse events during radiation
timeFrame: Weekly during therapy for up to 10 weeks
Secondary outcomes:
measure: Time to progression
timeFrame: Monthly, up to 10 years post-treatment
measure: Overall survival
timeFrame: Monthly, up to 10 years post-treatment
measure: Number of grade 3, 4, & 5 adverse events post-treatment
timeFrame: every 3 months for 2 years
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: The Holden Comprehensive Cancer Center
state: Iowa
Study officials:
affiliation: The University of Iowa Hospitals & Clinics
name: Joseph J Cullen, MD, FACS
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
citation: Mezey E, Potter JJ, French SW, Tamura T, Halsted CH. Effect of chronic ethanol feeding on hepatic collagen in the monkey. Hepatology. 1983 Jan-Feb;3(1):41-4. doi: 10.1002/hep.1840030106.