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

Sponsor

Joseph J. Cullen (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01852890

Collaborator

Holden Comprehensive Cancer Center (Other), Gateway for Cancer Research (Other)

Enrollment

Location

Arms

120

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Neoplasms	Drug: Ascorbate Drug: Gemcitabine Radiation: Radiation therapy	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 1, 2014

Actual Primary Completion Date :

Jan 22, 2019

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 50g Ascorbate This arm is the initial starting dose. The first study participant will be assigned the 50g ascorbate arm. Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based on tumor. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 50 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Gemcitabine Intravenous chemotherapeutic Other Names: Gemzar Radiation: Radiation therapy Other Names: External beam radiation therapy Intensity modulated radiation therapy IMRT
Experimental: 75g Ascorbate If the 50g arm is tolerated, the study opens the 75g arm. Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based on tumor. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 75 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Gemcitabine Intravenous chemotherapeutic Other Names: Gemzar Radiation: Radiation therapy Other Names: External beam radiation therapy Intensity modulated radiation therapy IMRT
Experimental: 100g Ascorbate If the 75g arm is tolerated, the study opens the 100g arm. Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based on tumor. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 100 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Gemcitabine Intravenous chemotherapeutic Other Names: Gemzar Radiation: Radiation therapy Other Names: External beam radiation therapy Intensity modulated radiation therapy IMRT
Experimental: 25g Ascorbate This study arm will only be used if participants cannot tolerate the 50g arm. If participants cannot tolerate 50 grams of Ascorbate, the 25g arm is opened. Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based on tumor. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 25 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Gemcitabine Intravenous chemotherapeutic Other Names: Gemzar Radiation: Radiation therapy Other Names: External beam radiation therapy Intensity modulated radiation therapy IMRT

Outcome Measures

Primary Outcome Measures

Number of grade 3, 4, & 5 adverse events during radiation [Weekly during therapy for up to 10 weeks]
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).

Secondary Outcome Measures

Time to progression [Monthly, up to 10 years post-treatment]
Time from the start of therapy (radiation day 1) to documented disease progression as described by RECIST.
Overall survival [Monthly, up to 10 years post-treatment]
From start of treatment (radiation day 1) until the date of death from any cause.
Number of grade 3, 4, & 5 adverse events post-treatment [every 3 months for 2 years]
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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.