Pancreatic Cancer, Pancreatic Neoplasms
Conditions
Keywords
Vitamins, Complementary medicine, Pancreatic cancer, Ascorbate, Ascorbic Acid, Antioxidants, Gemcitabine, Pharmacologic actions
Brief summary
This is a phase II study. It is designed to provide information about if high-dose ascorbate (vitamin C) increases survival for pancreatic cancer patients. The hypothesis is that vitamin C is well tolerated and increases cancer treatment effectiveness, lengthening survival time for patients with advanced pancreatic cancer.
Detailed description
Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence; the prognosis remains dismal. We propose to investigate an entirely new approach, using pharmacological ascorbate, combined with Gemcitabine, to treat this cancer. Intravenous ascorbate (i.e., ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations, which are in the range that can be cytotoxic to tumor cells. Though ascorbate has been utilized in cancer therapy, few studies have investigated intravenous deliver of ascorbate. Preliminary studies from our group have demonstrated that ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We hypothesize that production of H2O2 mediates the increased susceptibility of pancreatic cancer cells to ascorbate-induced metabolic oxidative stress. Gemcitabine is the standard chemotherapy drug used to treat pancreatic cancer.
Interventions
Gemcitabine 1000 mg/m2 weekly for 3 weeks with one week off (this is 1 cycle) Ascorbate dose is targeted to achieve plasma level of 350 mg/dL. Infusions are given twice weekly, each week of a cycle (4 weeks to a cycle)
Sponsors
Susan L Bader Foundation of Hope
Holden Comprehensive Cancer Center
National Cancer Institute (NCI)
Joseph J. Cullen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a cytological or histological diagnosis of adenocarcinoma arising in the pancreas. Diagnosis from metastatic sampling is acceptable. * Disease must be measured radiologically. * Failed initial therapy or ineligible for definitive curative therapy. * If prior treatment included radiation therapy, recurrent disease must be outside of the targeted volume. * Age ≥ 18 years * ECOG performance status 0-2 (Karnofsky \> 50%, see Appendix A). * Patients must have normal organ and marrow function as defined below: * leukocytes ≥ 3,000/mm3 * absolute neutrophil count ≥ 1,500/mm3 * platelets ≥ 100,000/mm3 * total bilirubin \< 2x institutional upper limit of normal * AST(SGOT) \< 3x institutional upper limit of normal OR \< 5x institutional upper limit of normal for patients presenting with liver metastases * ALT (SGPT) \< 3x institutional upper limit of normal OR \< 5x institutional upper limit of normal for patients presenting with liver metastases * PT/INR within normal institutional limits, unless patient is on warfarin or other antithrombotic agents * creatinine \< 1.5 X institutional upper limit of normal OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. * Not pregnant. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Prior chemotherapy to treat metastatic disease. * Adjuvant therapy (including radiation therapy) within 4 calendar weeks. * Unresolved toxicities from prior therapy for the malignancy. * G6PD (glucose-6-phosphate dehydrogenase) deficiency. * Second malignancy other than non-melanoma skin cancers within the past 5 years. * Excess consumption of alcohol where an excess of alcohol is defined as more than four of any one of the following per day: 30 mL distilled spirits, 340 mL beer, or 120 mL wine. * 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 chemotherapy to a fetus/infant are well documented.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | up to 5 years | Time to event outcome measure (death), measured in days from cycle 1 day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | up to 5 years | Time-to-event outcome measure (initial disease progression) measured in days from cycle 1 day 1 to day of first progression as defined by RECIST criteria from NCI. |
| Number of Drug-related Adverse Events Per Cycle | every 28 days up to 5 years | Adverse events linked to ascorbate will be categorized and quantified using CTCAE v4 at the bottom of each cycle. Incidence and frequency will be compared to scientific literature |
| F2-isoprostane Levels | Once every 28 days for up to 5 years | F2-isoprostane is a marker of systemic oxidative stress. |
| Ascorbate Levels | Once every 28 days up to 5 years | Ascorbate levels will be taken at the bottom of each cycle to assess therapeutic dose window. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine With Escalating IV Ascorbate Gemcitabine (1000 mg/m2) weekly for three weeks and then one week off. Ascorbic Gemcitabine (1000 mg/m2) weekly for three weeks and then one week off.
Ascorbate (vitamin C) given twice weekly, escalating doses weekly. Week 1: 15 grams ascorbate / infusion for two infusions. Doses are then escalated in 25 gram increments until therapeutic window is achieved (350 mg/dL or above). Dose is then held at that level for the full cycle.
Gemcitabine with escalating ascorbic acid: Gemcitabine 1000 mg/m2 weekly for 3 weeks with one week off (this is 1 cycle)
Ascorbate dose is targeted to achieve plasma level of 350 mg/dL. Infusions are given twice weekly, each week of a cycle (4 weeks to a cycle) | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Gemcitabine With Escalating IV Ascorbate |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 1 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Overall Survival
Time to event outcome measure (death), measured in days from cycle 1 day 1.
Time frame: up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gemcitabine With Escalating IV Ascorbate | Overall Survival | 268 days |
Secondary
Ascorbate Levels
Ascorbate levels will be taken at the bottom of each cycle to assess therapeutic dose window.
Time frame: Once every 28 days up to 5 years
Secondary
F2-isoprostane Levels
F2-isoprostane is a marker of systemic oxidative stress.
Time frame: Once every 28 days for up to 5 years
Population: Due to n=1 and study termination, the data were not analyzed.
Secondary
Number of Drug-related Adverse Events Per Cycle
Adverse events linked to ascorbate will be categorized and quantified using CTCAE v4 at the bottom of each cycle. Incidence and frequency will be compared to scientific literature
Time frame: every 28 days up to 5 years
Population: Due to n=1 and study termination, the data were not analyzed.
| Arm | Measure | Value |
|---|---|---|
| Gemcitabine With Escalating IV Ascorbate | Number of Drug-related Adverse Events Per Cycle | 0 |
Secondary
Progression Free Survival
Time-to-event outcome measure (initial disease progression) measured in days from cycle 1 day 1 to day of first progression as defined by RECIST criteria from NCI.
Time frame: up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gemcitabine With Escalating IV Ascorbate | Progression Free Survival | 80 days |