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

Study Overview
=================
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.

Official Title
-----------------
Gemcitabine, Ascorbate, Radiation Therapy for Pancreatic Cancer, Phase I

Conditions
-----------------
Pancreatic Neoplasms

Intervention / Treatment
-----------------
* Drug: Ascorbate
* Drug: Gemcitabine
* Radiation: Radiation therapy


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Gemcitabine<br>* Intravenous chemotherapeutic<br>* Other names: Gemzar;Radiation: Radiation therapy<br> <br> * Other names: IMRT;|
| Experimental: 75g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Gemcitabine<br>* Intravenous chemotherapeutic<br>* Other names: Gemzar;Radiation: Radiation therapy<br> <br> * Other names: IMRT;|
| Experimental: 100g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Gemcitabine<br>* Intravenous chemotherapeutic<br>* Other names: Gemzar;Radiation: Radiation therapy<br> <br> * Other names: IMRT;|
| Experimental: 25g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Gemcitabine<br>* Intravenous chemotherapeutic<br>* Other names: Gemzar;Radiation: Radiation therapy<br> <br> * Other names: IMRT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Overall survival | From start of treatment (radiation day 1) until the date of death from any cause. | Monthly, up to 10 years post-treatment | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ascorbate, Vitamin C, Radiation, Gemcitabine, Ascorbic Acid