Clinical trial NCT02896907
Conditions: Pancreatic Adenocarcinoma Recurrent Pancreatic Carcinoma Stage III Pancreatic Cancer Stage IV Pancreatic Cancer Unresectable Pancreatic Carcinoma
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
Start date: 2016-10-18; Completion date: 2019-03-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies the side effects of ascorbic acid and combination chemotherapy in treating patients with pancreatic cancer that has spread to other places in the body, has come back, or cannot be removed by surgery. Nutrients found in food and dietary supplements, such as ascorbic acid, may improve the tolerability of chemotherapy regimens. Drugs used in chemotherapy, such as fluorouracil, irinotecan hydrochloride, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ascorbic acid and combination chemotherapy may work better in treating patients with pancreatic cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine safety of intravenous ascorbic acid in combination with fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin (FOLFIRINOX) as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 in patients with advanced pancreatic cancer.

SECONDARY OBJECTIVES:

I. To test feasibility of collecting quality of life (QOL), patient reported outcomes (PRO) data and correlative studies on patients with advanced pancreatic cancer.

Arms: arm 1: Patients receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46 hours on day 1. Patients then receive ascorbic acid IV over 2 hours on days 3, 5, 8, 10 and 12. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Oxaliplatin intervention 2: Irinotecan Hydrochloride intervention 3: Leucovorin Calcium intervention 4: Fluorouracil intervention 5: Ascorbic Acid
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
THOMAS JEFFERSON UNIVERSITY 
Sidney Kimmel Cancer Center 
 
 
A PILOT STUDY OF INTRAVENOUS ASCORBIC 
ACID AND FIRINOX IN THE TREATMENT OF 
ADVANCED PANCREATIC CANCER 
Principal Investigator: 
James Posey III, MD  
Assistant Professor  of Medical Oncology 
Thomas Jefferson University  
Sidney Kimmel Cancer Center  
1025 Walnut Street, Suite 700, Philadelphia, PA 19107 
215-955-8874 
Co-Investigator(s): 
Daniel Monti, MD, MBA (Co-Principal Investigator) 
Professor/Director, Myrna Brind Center for Integrative Medicine 
Thomas Jefferson University 
925 Chestnut Street, Suite 120, Philadelphia, PA 19107 
215-955-4410 
 
Andrew Newberg, MD 
Professor Myrna Brind Center for Integrative Medicine 
Thomas Jefferson University 
925 Chestnut St, Suite 120, Philadelphia, PA 19107 
215-503-3422 
 
Edith Mitchell, MD 
Professor of Medical Oncology 
Thomas Jefferson University 
Sidney Kimmel Cancer Center 
233 South 10th Street, Room 502, Philadelphia, PA 19107 
215-955-8874 
 
Ashwin Sama, MD, MS 
Professor of Medical Oncology 
Thomas Jefferson University 
Sidney Kimmel Cancer Center 
1025 Walnut Street #700, Philadelphia, PA 
215-955-8874 
 
Daniel Lin, MD 
Professor of Medical Oncology 
Thomas Jefferson University 
Sidney Kimmel Cancer Center 
1025 Walnut Street #700, Philadelphia, PA 
215-955-8874 
 
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Steven Cohen, MD 
Professor of Medical Oncology 
Thomas Jefferson University 
Sidney Kimmel Cancer Center 
1025 Walnut Street #700, Philadelphia, PA 
215-955-8874 
 
Atrayee Basu-Mallick, MD 
Assistant Professor of Medical Oncology 
Thomas Jefferson University 
Sidney Kimmel Cancer Center 
1025 Walnut Street #700, Philadelphia, PA 
215-955-8874 
 
Avnish Bhatia, MD 
Assistant Professor of Medical Oncology 
Thomas Jefferson University 
Sidney Kimmel Cancer Center 
925 Chestnut St, 4th Floor, Philadelphia, PA 
215-955-8874 
 
Theresa P. Yeo, PhD, MPH, MSN, CRNP 
Associate Director, Jefferson Pancreas Tumor Registry 
Thomas Jefferson University Hospital 
Department of Surgery 
Adjunct Professor at Jefferson School of Nursing 
1025 Walnut Street, Suite 605B, College Building Philadelphia, 
PA 19107 
 
Consultant: 
Mark Levine, M.D., Ph.D 
Chief, Molecular and Clinical Nutrition Section Senior Staff 
Physician 
Building 10, Room 4D52 MSC 1372 National Institutes of 
Health Bethesda, MD 20892-1372 
 
Statistician: 
Scott Keith, Ph.D 
Assistant Professor, Division of Biostatistics 
Department of Pharmacology and Experimental Therapeutics 
1015 Chestnut St, Suite M100, Philadelphia, PA 19107 
215-955-4083 
Funding Sponsor: 
Sidney Kimmel Cancer Center, Department of Medical 
Oncology and Myrna Brind Center of Integrative Medicine 
IND/IDE Holder: 
Daniel Monti, MD 
IND/IDE Number: 
77486 
Study Product: 
Intravenous Ascorbic Acid 
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Protocol IDs: 
JeffTrial # 8223 
PRC # 2015-098 
IRB Control # 16D.347 
 
 
Version Number: 
Version Date: 
4.1  
2016-03-21 
4.2.1 
2016-10-18 
5.0 
2017-01-27 
6.0 
2017-02-13 
6.1 
2017-06-05 
6.2 
2017-08-28 
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CONFIDENTIAL 
 
This document is confidential and the property of THOMAS JEFFERSON 
UNIVERSITY.  No part of it may be transmitted, reproduced, published, or used 
by other persons without prior written authorization from the study sponsor. 
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Table of Contents 
STUDY SUMMARY ....................................................................................................................................... 7 
1.0 INTRODUCTION  .................................................................................................................................. 10 
1.1 
SPECIFIC AIMS AND HYPOTHESIS  ................................................................................................... 10 
1.2 BACKGROUND AND RATIONALE  ............................................................................................................ 10 
1.3 STUDY THERAPY  ................................................................................................................................ 13 
1.4 PRECLINICAL DATA  ............................................................................................................................. 14 
1.5 CLINICAL DATA TO DATE  ..................................................................................................................... 14 
1.6 DOSE RATIONALE AND RISK/BENEFITS  ................................................................................................. 19 
2.0 STUDY OBJECTIVES  ......................................................................................................................... 20 
3.0 STUDY DESIGN  .................................................................................................................................. 20 
3.1 GENERAL DESIGN  ............................................................................................................................... 20 
3.2 PRIMARY STUDY ENDPOINTS  ............................................................................................................... 20 
3.3 SECONDARY STUDY ENDPOINTS  .......................................................................................................... 20 
4.0 SUBJECT SELECTION AND WITHDRAWAL  .................................................................................... 21 
4.1 INCLUSION CRITERIA  ........................................................................................................................... 21 
4.2 EXCLUSION CRITERIA  .......................................................................................................................... 21 
4.4 SUBJECT RECRUITMENT AND SCREENING  ............................................................................................ 22 
4.5 EARLY WITHDRAWAL OF SUBJECTS  ..................................................................................................... 22 
4.5.1 When and How to Withdraw Subjects  ....................................................................................... 22 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects  ............................................................. 22 
5.0 STUDY DRUG/THERAPY  ................................................................................................................... 22 
5.2 TREATMENT REGIMEN  ......................................................................................................................... 28 
FOLFIRINOX  .......................................................................................................................................... 29 
LIKELY: (OCCURRING IN 30% OR MORE PEOPLE)  ....................................................................................... 29 
5.4 METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS  ............................................................... 31 
5.5 PREPARATION AND ADMINISTRATION OF STUDY DRUG/THERAPY  ........................................................... 31 
5.6 SUBJECT COMPLIANCE MONITORING .................................................................................................... 32 
5.7 PRIOR AND CONCOMITANT THERAPY .................................................................................................... 32 
5.8 PACKAGING  ........................................................................................................................................ 33 
5.9 BLINDING OF STUDY DRUG  .................................................................................................................. 33 
5.10 RECEIVING, STORAGE, DISPENSING AND RETURN  ............................................................................... 33 
5.10.1Receipt of Drug Supplies  ......................................................................................................... 33 
5.10.2Storage  .................................................................................................................................... 33 
5.10.3Dispensing of Study Drug  ........................................................................................................ 33 
5.10.4Return or Destruction of Study Drug  ........................................................................................ 33 
6.0 STUDY PROCEDURES  ....................................................................................................................... 33 
7.1 STATISTICAL PLAN  ........................................................................................................................ 40 
7.2 SAMPLE SIZE DETERMINATION  ............................................................................................................. 40 
7.3 STATISTICAL METHODS  ....................................................................................................................... 40 
7.4 SUBJECT POPULATION(S) FOR ANALYSIS  .............................................................................................. 41 
8.0 SAFETY AND ADVERSE EVENTS  ..................................................................................................... 41 
8.1 DEFINITIONS  ....................................................................................................................................... 41 
8.2 RECORDING OF ADVERSE EVENTS  ....................................................................................................... 43 
8.3 UNBLINDING PROCEDURES  .................................................................................................................. 44 
8.4 STOPPING RULES  ............................................................................................................................... 44 
8.5 DATA AND SAFETY MONITORING PLAN  ................................................................................................. 44 
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9.0 DATA HANDLING AND RECORD KEEPING  ..................................................................................... 47 
9.1 CONFIDENTIALITY  ............................................................................................................................... 47 
9.2 SOURCE DOCUMENTS  ......................................................................................................................... 48 
9.3 CASE REPORT FORMS  ........................................................................................................................ 48 
9.4 RECORDS RETENTION  ......................................................................................................................... 48 
10.0 STUDY MONITORING, AUDITING, AND INSPECTING  ................................................................... 49 
10.1 STUDY MONITORING PLAN  ................................................................................................................ 49 
THE INVESTIGATOR WILL ALLOCATE ADEQUATE TIME FOR MONITORING ACTIVITIES. THE INVESTIGATOR WILL 
ALSO ENSURE THAT THE MEDICAL MONITOR OR OTHER COMPLIANCE OR QUALITY ASSURANCE REVIEWER IS 
GIVEN ACCESS TO ALL THE ABOVE NOTED STUDY-RELATED DOCUMENTS AND STUDY RELATED FACILITIES (E.G. 
PHARMACY, DIAGNOSTIC LABORATORY, ETC.), AND HAS ADEQUATE SPACE TO CONDUCT THE MONITORING 
VISIT. 
................................................................................................................................................................ 49 
10.2 AUDITING AND INSPECTING  ................................................................................................................ 50 
11.0 ETHICAL CONSIDERATIONS  .......................................................................................................... 51 
12.0 STUDY FINANCES  ............................................................................................................................ 51 
12.1 FUNDING SOURCE  ............................................................................................................................ 51 
12.2 CONFLICT OF INTEREST  ..................................................................................................................... 51 
12.3 SUBJECT STIPENDS OR PAYMENTS  .................................................................................................... 51 
13.0 PUBLICATION PLAN  ........................................................................................................................ 52 
14.0 REFERENCES  ................................................................................................................................... 52 
15.1 APPENDICES  .................................................................................................................................... 53 
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List of Abbreviations 
5FU  
 
5 Flourouracil  
AA 
 
 
Ascorbic acid 
ANC  
 
Absolute Neutrophil Count 
ASCO 
 
American Society of Clinical Oncology  
BSA  
 
Body Surface Area 
CHF  
 
Congestive Heart Failure 
CIPN  
 
Chemotherapy Induced Peripheral Neuropathy  
CKD  
 
Chronic Kidney Disease 
CNS  
 
Central Nervous System  
CrCL  
 
Creatinine Clearance 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
DLT  
 
Dose Limiting Toxicity 
ECOG 
 
Eastern Cooperative Oncology Group  
EKG  
 
Electrocardiogram 
EORTC 
 
European Organization for Research and Treatment of Cancer  
FACIT 
 
Functional Assessment of Chronic Illness Therapy 
FDA  
 
Food and Drug Administration 
FIRINOX 
Combination of infusional 5 fluorouracil, oxaliplatin and irinotecan  
FOLFIRINOX 
Combination of folinic acid, bolus and infusional 5 fluorouracil, 
oxaliplatin and irinotecan 
G6PD 
 
Glucose 6 Phosphatase deficiency 
GCSF 
 
Granulocyte Colony Stimulating Factor GI: Gastrointestinal 
IV 
 
 
Intravenous  
M2 
 
 
Meter Squared  
MG  
 
MilliGrams 
NCCN 
 
National Comprehensive Cancer Network  
NCI  
 
National Cancer Institute 
ORR  
 
Overall Response Rate  
OS  
 
Overall Survival 
PFS  
 
Progression Free Survival  
PI 
 
 
Principal Investigator 
PRO  
 
Patient Reported Outcomes 
PS 
 
 
Performance Status  
PT 
 
 
Prothrombin Time 
PTT  
 
Partial Thromboplatin Time  
QLQ  
 
Quality of Life Questionnaire  
QOL  
 
Quality of Life 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
SC 
 
 
Sub-Cutaneous 
SGA  
 
Subjective Global Assessment 
TITE-CRM  
Time to event continual reassessment method  
ULN  
 
Upper Limit of Normal 
WBC  
 
White Blood Cells 
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Study Summary 
Title 
A Pilot Study of Intravenous Ascorbic Acid and FIRINOX in the 
Treatment of Advanced Pancreatic Cancer 
Short Title 
IV Ascorbic acid + FIRINOX in pancreatic cancer. 
Phase 
Pilot 
Methodology/Study 
Design 
Time-to-event continual reassessment method, open label, single 
arm 
Study Duration 
1 year 
Study Center(s) 
Thomas Jefferson University 
Objectives 
1) Safety of Ascorbic acid + FIRINOX. 
2) Feasibility of collecting QOL questionnaires in advanced 
pancreatic cancer. 
Number of 
Subjects 
8 
Diagnosis and 
Main Inclusion 
Criteria 
• Age 18-75 
• Histological diagnosis of 
adenocarcinoma of the pancreas 
Stage IV or recurrent pancreatic 
cancer 
• Locally advanced unresectable pancreatic cancer 
• ECOG 0-1 
• First line treatment (Neo-adjuvant or adjuvant 
chemotherapy or chemoradiation allowed) 
• Adequate hematologic and chemistry parameters 
• No clinical ascites (mild ascites on scans permissible) 
• No known CHF, ventricular arrhythmias, 
cirrhosis, uncontrolled diabetes  
• No preexisting peripheral neuropathy 
Study Therapy, 
Dose, Route, 
Regimen 
Ascorbic acid 100 grams IV 2-3 times a week 
Duration of 
administration and 
follow-up 
Till progression (RECIST 1.1), intolerance, withdrawal, 
noncompliance or death Follow up 30 days 
Reference therapy 
Modified FOLFIRINOX 
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Statistical 
Methodology 
The study will follow a Phase I design for toxicities called the 
time-to-event continual reassessment method. We will enroll 8 
patients and monitor toxicities for 28 days. The expected 
accrual rate is one patient a month. The first patient will be 
started at the highest dose. Change in quality of life over three 
measurement times will be modeled using mixed effects linear 
regression to account for correlation among repeated 
measurements from the same subjects. 
Schema 
 
 
Ascorbic acid infusions can be adjusted by up to 72 hours to 
account for weekends, holidays, clinic schedules and patient 
convenience. Treatment delays more than 72 hours may be 
allowed after discussion with PI. 
Example schema: 
Monday 
D1 - FIRINOX 
D8 - Ascorbic acid 
Tuesday 
D2 - 5FU 
D9  
Wednesday 
D3 - 5FU disconnect + 
Ascorbic acid 
D10 - Ascorbic acid 
Thursday 
D4  
D11  
Friday 
D5 Ascorbic acid 
D12 - Ascorbic acid 
Saturday 
D6 
D13 
Sunday 
D7 
D14 
 
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Brief Rationale: 
Combination of infusional 5 fluorouracil, leucovorin, oxaliplatin and irinotecan 
(FOLFIRINOX) is the most active regimen in the treatment of metastatic pancreatic 
cancer. Its widespread use is limited by a higher number of side effects compared to 
gemcitabine.(Conroy et al., 2011) However, FOLFIRINOX significantly improves 
Quality of Life (QOL) compared to gemcitabine in spite of the reported higher side 
effects.(Gourgou-Bourgade et al., 2013) High dose parenteral ascorbic acid has been 
shown to enhance chemosensitivity and decrease toxicity associated with 
chemotherapy in ovarian cancer patients in a small randomized trial.(Ma et al., 2014) 
Newer agents are unlikely to be added to FOLFIRINOX due to perceived toxicity and 
lack of a clear path to Food and Drug Administration (FDA) approval. FOLFIRINOX 
regimen is routinely modified by removing the bolus 5FU to decrease risk of 
neutropenia and other side effects. Folinic acid which modulates the action of bolus 
5FU is not needed when the bolus 5FU is eliminated. If FIRINOX regimen (without 
the bolus 5FU and leucovorin, also referred to as modified FOLFIRINOX) can be 
made more tolerable, it may have a greater impact on metastatic pancreatic cancer 
patients, than trying to improve survival marginally with less active regimens. 
 
Dose Limiting Toxicity (DLT): 
• Any Grade 5 event attributable to the regimen 
• Any Grade 4 non-hematological toxicity that is attributable to regimen 
• Nausea, vomiting or diarrhea ≥ Grade 3 that persists for greater than 72 hours 
despite optimal antiemetic or anti-diarrheal therapy and IV hydration 
• Any Grade 3 or higher non-hematological toxicity that is study drug related that 
results in delay in FIRINOX chemotherapy by greater than 2 weeks 
 
QOL Management: 
• Eastern Cooperative Oncology Group (ECOG) Performance Status every 2 
weeks (Appendix 2) 
• European Organization for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire (QLQ) 30 every 2 weeks (appendix 3) 
• EORTC Chemotherapy-Induced Peripheral Neuropathy (CIPN) 20 every 
month (appendix 4) 
• Oxaliplatin neuropathy scale every month (appendix 5) 
• Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale every 
2 months (appendix 6) 
• Subjective Global Assessment (SGA) every 2 months (appendix 7) 
 
 
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1.0 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 
part 312 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures. 
 
1.1 
Background and Rationale 
Pancreatic Cancer 
There were an estimated 48,960 new cases of pancreatic cancer and 40,560 estimated 
deaths from pancreatic cancer in the United States in 2015.(Siegel, Miller, & Jemal, 
2015) 5 years survival of newly diagnosed pancreatic cancer patients is only 6 to 
7%.(Siegel et al., 2015). Pancreas cancer is the 4th leading cause of cancer death and 
is expected to be the 2nd leading cause of cancer death by 2020.(Rahib et al., 2014) 
Surgery is currently the only effective curative treatment; however only 10-20% of 
patients diagnosed with pancreas cancer can actually have a curative 
resection.(Conlon, Klimstra, & Brennan, 1996; Shaib, Davila, Naumann, & El-Serag, 
2007)  Of the patients who undergo resection, tumor recurrence occurs in over 80 % of 
patients over time. Therefore 5 year survival of resected pancreatic cancer is only 
about 20 %. (Mayo et al., 2012; Winter et al., 2006) Patients who present with 
metastatic pancreatic cancer have a dismal survival with a 1 year survival of only 20% 
and have a median survival of about 6 months with gemcitabine. (Burris et al., 1997) 
 
Treatment of Pancreatic Cancer: 
Adjuvant therapy with gemcitabine improves disease free survival, overall survival and 
doubles 5 year survival compared to observation alone. (Oettle et al., 2013) The role of 
radiation after surgery is controversial with some studies showing a benefit and others 
showing no benefit and potential harm. (Kalser & Ellenberg, 1985; Klinkenbijl et al., 
1999; Neoptolemos et al., 2004) In the United States, adjuvant gemcitabine and 
chemoradiation is commonly used. For patients with unresectable disease, treatment is 
palliative and chemotherapy is recommended to prolong survival and improve quality of 
life. (Yip, Karapetis, Strickland, Steer, & Goldstein, 2006) Gemcitabine was initially 
approved based on improvement in clinical benefit rate, a composite of pain control, 
weight gain and survival. (Burris et al., 1997) Combining gemcitabine with other 
cytotoxic chemotherapy agents has been largely unsuccessful until recently. The 
National Cancer Institute Canada PA3 trial demonstrated that the combination of 
gemcitabine with erotinib resulted in a statistically significant improvement in overall 
survival when compared to gemcitabine and placebo (hazard ration 0.81, p=0.025). 
(Moore et al., 2007) Median survival in the gemcitabine plus erlotinib arm was 6.4 
months compared to 5.9 months in the gemcitabine plus placebo arm questioning 
whether this improvement in survival is clinically significant. More recently multi- agent 
chemotherapy with FOLFIRINOX and gemcitabine + nab-paclitaxel has shown 
encouraging results. (Conroy et al., 2011; Von Hoff et al., 2011) 
 
A recent phase III clinical trial of nab-paclitaxel in combination with gemcitabine in 
treatment-naïve patients with metastatic pancreatic cancer demonstrated a statistically 
significant improvement in overall survival compared to patients receiving gemcitabine 
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alone [(median of 8.5 vs. 6.7 months) (HR 0.72, P=0.000015)]. (Von Hoff et al., 2011) 
In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, nab-
paclitaxel plus gemcitabine demonstrated a 59% increase in one-year survival (35% vs. 
22%, p=0.0002) and demonstrated double the rate of survival at two years (9% vs. 4%, 
p=0.02) as compared to gemcitabine alone. Nab-paclitaxel plus gemcitabine also 
demonstrated a statistically significant improvement in key secondary endpoints 
compared to gemcitabine alone, including a 31% reduction in the risk of progression or 
death with a median progression-free survival (PFS) of 5.5 vs. 3.7 months (HR 0.69, 
P=0.000024) and an overall response rate (ORR) of 23% compared to 7% (response 
rate ratio of 3.19, p=1.1 x 10-10). The most common grade ≥ 3 treatment-related 
adverse events in the study for nab-paclitaxel plus gemcitabine vs. gemcitabine alone 
were neutropenia (38% vs. 27%), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). 
In the nab-paclitaxel plus gemcitabine arm, the median time to neuropathy 
improvement was 29 days. There was no difference in serious life threatening toxicity 
(4% in each arm). 
 
FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 
180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 
mg per square meter given as a bolus followed by 2400 mg per square meter given as 
a 46-hour continuous infusion, every 2 weeks) was compared to standard gemcitabine 
monotherapy in 342 patients with an ECOG PS=0 or 1 in the PRODIGE/ACCORD 
French trial.(Conroy et al., 2011) The primary endpoint was overall survival (OS), with 
a median OS of 11.1 months in the FOLFIRINOX group vs 6.8 months in the 
gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 
0.73; P<0.001). Median progression-free survival (PFS) was 6.4 months in the 
FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease 
progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate (RR) 
was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group 
(P<0.001). Despite more adverse events in the FOLFIRINOX group, including a 
neutropenia, febrile neutropenia, diarrhea, neuropathy and LFT abnormalities, at 6 
months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of 
the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 
0.30 to 0.70; P<0.001). There was also improvement in global health status in the 
FOLFIRINOX arm. (Conroy et al., 2011; Gourgou-Bourgade et al., 2013) FOLFIRINOX 
regimen is routinely modified by removing the bolus 5FU or decrease the irinotecan 
dose to decrease the risk of side effects and make it more tolerable. (Mahaseth et al., 
2013; Chllamma et al.,2016; Gunturu et al.,2013) Folinic acid which modulates the 
action of bolus 5FU is not needed when the bolus 5FU is eliminated. 
 
FOLFIRINOX has been adopted as a standard of care for newly diagnosed metastatic 
or unresectable pancreatic cancer patients with a good performance status. Patients 
treated with FOLFIRINOX have a 9% incidence of grade 3 or 4 sensory neuropathy 
and many patients discontinue treatment due to neuropathy. (Conroy et al., 2011) If 
FOLFIRINOX can be made more tolerable with lesser side effects, more patients can 
get treatment shown to have the best efficacy data in metastatic pancreatic cancer. 
Pancreatic cancer has a high symptom burden with short survival and the goals of 
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treatment are palliative.(Gourgou-Bourgade et al., 2013) QOL is as important as 
prolonging survival in incurable patients and ways to improve QOL are needed. 
 
EORTC QLQ C 30 is a validated tool to objectively measure quality of life in cancer 
patients.(Aaronson et al., 1993) It was used in the pivotal trial of FOLFIRINOX to 
prospectively collect longitudional QOL as a secondary endpoint.(Conroy et al., 2011; 
Gourgou-Bourgade et al., 2013) QLQ CIPN 20 is a validated tool to objectively 
measure peripheral neuropathy in patients.(Postma et al., 2005) A scale to specifically 
measure oxalipalatin induced neuropathy has been developed.(Leonard et al., 2005) 
Since oxaliplatin causes both acute neurosensory complex which develops soon after 
infusion and also cumulative sensory neuropathy. The acute neuropathy manifests as 
discomfort swallowing cold foods, sensitivity to touch cold items and paresthesisas of 
the perioral region. Symptoms usually resolve in 1-4 days. Fatigue is the most common 
complaint in patients undergoing chemotherapy. (Yeo et al., 2012) FACIT-F scale is a 
very brief, but reliable and valid measure of fatigue in cancer patients.(Yellen, Cella, 
Webster, Blendowski, & Kaplan, 1997) Pancreatic cancer patients with a higher FACIT-
F score had a lower median overall survival in a randomized, placebo controlled phase 
2 study collecting PRO.(Robinson et al., 2008) Pancreatic cancer patients frequently 
also manifest with cachexia and weight loss. The patient generated subjective global 
assessment questionnaires can be used as a nutrition assessment tool that identifies 
malnutrition in ambulatory oncology patients. (Isenring, Bauer, & Capra, 2003) 
Feasibility of collecting QOL and PRO data will enable design of future clinical trials. 
 
1.2 
Study Therapy 
Intravenous, high dose ascorbic acid is a widely used alternative cancer treatment, 
although its use as such has not been appropriately tested in randomized controlled 
studies. Linus Pauling reported prolonged survival in terminal cancer patients in an 
open labelled study using oral and intravenous ascorbic acid.(Cameron & Campbell, 
1974; Cameron & Pauling, 1976, 1978) Ascorbic acid as a cancer therapy was largely 
discarded when two randomized trials of oral ascorbic acid therapy done at the Mayo 
Clinic failed to demonstrate therapeutic benefit. (Creagan et al., 1979; Moertel et al., 
1985) However, pharmacokinetic modelling indicates that intravenous administration 
of Ascorbic acid produces a 25-fold or greater plasma concentration than the same 
dose given orally.(Padayatty et al., 2004; Verrax & Calderon, 2009)  Chen and 
associates have reported that ascorbic acid levels achievable in vivo by intravenous 
infusion are selectively cytotoxic in vitro to various cancer cell lines but not to normal 
cells by a mechanism involving formation of hydrogen peroxide.(Chen et al., 2005; Du 
et al., 2010) This mechanism is dependent on pro-oxidant actions, as a consequence 
of ascorbic acid concentrations achieved only by intravenous administration. Ascorbic 
acid is generally a chemically reducing agent (anti-oxidant), or electron donor. 
However, at pharmacologic concentrations, ascorbic acid electron donation sets in 
motion a series of chemical reactions whose end result is formation of hydrogen 
peroxide and subsequent pro-oxidant compounds, with selective toxicity to cancer but 
not normal cells. Thus, while ascorbic acid action is always as an electron donor, its 
actions at pharmacologic concentrations produce pro-oxidant consequences. The 
mechanism of action of Ascorbic acid as a prodrug for hydrogen peroxide formation in 
the extravascular space has been confirmed by the laboratory of study consultant 
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Mark Levine, M.D., Ph.D. (Chen et al., 2007; Sestili, Brandi, 
Brambilla, Cattabeni, & Cantoni, 1996; Verrax & Calderon, 2009) This action of IV 
Ascorbic acid is consistent with a growing literature that reactive oxygen species play 
an important role in the mechanism of action of proven cancer treatments and that 
impaired oxygen-reduction balance in cancer cells might cause induced reactive 
oxygen species to selectively kill cancer cell.(Chen et al., 2007; Du et al., 2010) Since 
FDA does not approve vitamins, ascorbic acid has not been approved by the FDA 
although it is widely used to treat different medical conditions including cancer. High 
dose intravenous ascorbic acid therefore should be given only in the context of clinical 
trial to evaluate its true efficacy. (Parrow, Leshin, & Levine, 2013; Welsh et al., 2013) 
 
1.3 
Preclinical Data 
Studies on tumor xenographs in mice confirming ascorbic acid as a prooxidant showed 
decreased growth of three aggressive tumor types: Pancreatic, glioblastoma, and 
ovarian (Chen, 2008). To test this action in vivo, the investigators bypassed normal oral 
tight control with parenteral ascorbic acid administration. Real-time microdialysis 
sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic 
dose of ascorbic acid produced sustained ascorbic acid radical and hydrogen peroxide 
formation selectively within interstitial ﬂuids of tumors but not in blood. Moreover, a 
regimen of daily pharmacologic ascorbic acid treatment signiﬁcantly decreased growth 
rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) 
tumors established in mice. Also in this study, similar pharmacologic concentrations 
were readily achieved in humans given ascorbic acid intravenously. These data 
suggest that ascorbic acid as a prodrug may have beneﬁts for some cancers. Overall, 
recent in vitro biological evidence, limited human case data, clinical pharmacokinetic 
data, and recent in vivo data confer biological plausibility to the notion that ascorbic 
acid could affect cancer biology and that there is reason to explore the therapeutic 
concept. (Du et al., 2010; Welsh et al., 2013) More research data is needed to guide 
the current wide use of high dose intravenous ascorbic acid. (Hoffer et al., 2015; Ohno, 
Ohno, Suzuki, Soma, & Inoue, 2009) 
 
1.4 
Clinical Data to Date 
Thousands of patients are treated every year with intravenous ascorbic acid for 
infection, cancer and fatigue by integrative medicine practitioners. A large survey 
showed that most practitioners report no serious adverse event even at high doses. 
Side effects are minor and include lethargy, fatigue, phlebitis and dizziness. (Padayatty 
et al., 2010) 
 
A phase 1 dose escalation clinical trial in 24 advanced cancer patients showed that 
Maximum Tolerated Dose (MTD) was not reached at 1.5/kg of intravenous ascorbic 
acid as single agent. (Hoffer et al., 2008) The only grade 2 Adverse Events (AE) noted 
was dizziness, flushing, vomiting and headache. No abnormal hematologic or 
biochemical parameters were noted. Unfortunately no objective tumor responses were 
noted either with single agent intravenous ascorbic acid. (Hoffer et al., 2008)  A dose of 
1.5g/Kg was the recommended phase 2 dose (RP2D) for future studies. Another 
phase 1 study using intravenous ascorbic acid for 4 days a week also did not reach 
MTD and a dose of 70-80g/m2. (Stephenson, Levin, Spector, & Lis, 2013) A phase 1 
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study with concurrent gemcitabine showed that treatment with intravenous ascorbic 
acid 15-125 grams twice weekly was well tolerated.(Welsh et al., 2013) We completed 
a phase 1 study of intravenous ascorbic acid in combination with gemcitabine and 
erlotinib and the results are presented below.(Monti et al., 2012) 
 
Data from Phase 1 Intravenous Ascorbic Acid in Combination with Gemcitabine 
and Erlotinib in the Treatment of Metastatic Pancreatic Cancer . TJU IRB# 09D.99: 
We attempted to determine the initial safety and efficacy of high dose intravenous 
ascorbic acid in combination with gemcitabine and erlotinib chemotherapy in patients 
with metastatic pancreatic cancer. A phase 1 study of Intravenous (IV) ascorbic acid 
was completed at Thomas Jefferson University. Fourteen subjects (4 male and 10 
female) with pancreatic cancer metastatic to the liver and other organs were recruited 
to receive an 8 week cycle of intravenous AA given three times per  week in addition to 
standard treatment with gemcitabine (1000mg/m2/wk) and daily erlotinib, using a 
standard 3+3 dose escalating design (50grams, 75grams, and 100grams). Data were 
obtained regarding laboratory values and adverse events throughout the treatment 
period. In addition, subjects received either Computerized Tomography (CT) of the 
chest, abdomen, and pelvis, or a whole body Positron Emission Tomography PET-CT 
scans to evaluate for response to treatment using Response Evaluation Criteria In 
Solid Tumors (RECIST) criteria. 
 
Patient Cohort: 
Overall, 14 patients were recruited with 4 males and 10 females and a mean age of 
64.4 (±10.0) (range 47-81). All patients had pancreatic adenocarcinoma that was either 
metastatic or locally advanced. Nine patients received the full cycle of ascorbic acid 
plus gemicitabine/erlotinib treatments. The full cycle was defined as at least 24 (±6) 
treatments for 8 (±1) weeks. Five patients did not complete the study. Two subjects 
(003 and 007) chose not to continue. Three subjects died from progression of disease 
(subjects 009 after only 5 weeks of treatment, 011 after only 3 weeks of treatment, and 
014 after only 1 week of treatment) and could not be evaluated using imaging. The 
other nine subjects were included in the CT evaluation for response to therapy. 
 
Safety Evaluation:  
The most common reported adverse event was mild light headedness when patients 
are receiving the intravenous ascorbic acid usually resolving with eating and drinking. 
For the total cohort of 14 patients, there were 23 total adverse events with 8 being 
serious adverse events. The adverse events are shown in Table 2. All of these adverse 
events were most likely attributable to progression of disease or concomitant treatment 
with gemcitabine/erlotinib. One male subject was hospitalized with low hemoglobin due 
to an internal bleed and then was subsequently placed on hospice care. Two subjects 
were found to have a pulmonary embolism most likely related to the underlying 
pancreatic cancer that has a reported rate of Pulmonary Embolism (PE) between 20-
50%. Three subjects died from progression of the underlying cancer. One patient was 
hospitalized twice, once for anemia symptoms and once for a UTI Urinary Tract 
Infection (UTI) which both resolved. A male subject was hospitalized with abdominal 
pain and ileus which he actually had at the study onset, and he received Total Parental 
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Nutrition (TPN) and Nasogastric tube feeds, but was finally put on hospice before dying 
of the underlying cancer. None of these subjects received the full treatment with the IV 
ascorbic acid. None of these adverse events appear to be specifically related to the 
Ascorbic acid treatment since each of these events is frequently observed in the 
normal progression of pancreatic cancer patients and/or gemcitibine and erlotinib 
treatment. 
 
Response to Treatment Based on CT Results: 
With regard to efficacy, 9 patients underwent pre and post treatment CT scans. Scans 
were evaluated for the change in size of the primary tumor as well as by using RECIST 
criteria (see Table 3). The results showed that all patients had a reduction in size of the 
primary tumor (with one patient having no change in size). By RECIST criteria, 6 
patients had stable disease and 3 patients had progressive disease. However, two 
patients in the highest dose range (100g per infusion) actually had a reduction in size of 
the primary tumor and a reduction in the metastatic sites. However, the reduction in the 
target lesion size was not sufficient to be reported as a partial response by RECIST 1.0 
criteria which require a 30% reduction in size in the target lesions. 
 
The three dosage levels were generally well tolerated with similar AE profiles for 
each with no AE’s other than what might be expected for progression of 
pancreatic cancer and/or treatment with gemcitabine and erlotinib. Thus, there 
were no dose-limiting toxicities and the target dose of 100 grams was not 
associated with increased adverse events. 
 
Table 1: Patient Demographics and Disease Status 
ID 
Age/ 
Gender 
Time Dx 
to Rx 
Dx (in addition to 
pancreatic 
primary mass)* 
Dose Level 
(g/infusion) 
Doses Weeks 
001 
60 M 
3 wks 
Liver/lung/media 
50 
24 
8 
002 
75  F 
5 wks 
Liver/retroper 
50 
24 
8 
003 
81  F 
5 wks 
Locally adv 
50 
3 
1 
004 
64  F 
4 wks 
Liver 
50 
18 
7 
005 
69 M 
6 mon 
Locally adv 
75 
23 
8 
006 
66  F 
2 wks 
Media/retroper 
75 
22 
8 
007 
47  F 
6 wks 
Liver/peritoneal 
75 
3 
1 
008 
75  F 
3 wks 
Liver 
75 
21 
7 
009 
51 M 
3 mon 
Liver/peritoneal 
75 
14 
5 
010 
48  F 
3 wks 
Liver 
100 
21 
8 
011 
67  F 
4 wks 
Liver/peritoneal 
100 
9 
3 
012 
67 F 
4 mon 
Locally adv/bone 
100 
24 
8 
013 
66 F 
3 wks 
Liver 
100 
24 
8 
014 
65 M 
4 mon 
Liver/peritoneal 
100 
3 
1 
Bone=bone metastases, Liver=liver metastases, Locally adv=locally advanced spread of cancer, 
Lung=lung metastases, Media=mediastinal metastases Peritoneal=peritoneal metastases, 
Retroper=retroperitoneal nodes or metastases 
 
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Table 3. Response to ascorbic acid plus gemcitabine based on CT findings in 
patients with scans pre and post the 8 week ascorbic acid treatment cycle plus 
gemcitabine/erlotnib. 
Patient 
(Dose) 
Pancreatic Mass 
Pre (mm) 
Pancreatic Mass 
Post (mm) 
% Change 
Primary Mass 
Non-Target 
Lesions 
RECIST Criteria 
Response 
001 (50g) 
32 x 20 
28 x 22 
-13% 
Progressed 
PD 
002 (50g) 
31 x 18 
18 x 16 
-42% 
Stable 
SD 
004 (50g) 
43 x 39 
33 x 39 
-23% 
Stable 
SD 
005 (75g) 
43 x 19 
38 x 21 
-12% 
Stable 
SD 
006 (75g) 
92 x 42 
82 x 36 
-11% 
Progressed 
PD 
008 (75g) 
41 x 38 
41 x 38 
0% 
Progressed 
PD 
010 (100g) 42 x 22 
36 x 17 
-14% 
Improved 
SD 
012 (100g) 59 x 38 
48 x 37 
-19% 
Stable 
SD 
013 (100g) 49 x 49 
44 x 42 
-10% 
Improved 
SD 
 
 
These findings suggest that IV Ascorbic Acid (AA) is relatively safe in pancreatic cancer 
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patients receiving gemcitabine and erlotinib, which is consistent with previous studies on 
the safety of AA in cancer populations. The results also suggest the need for the further 
studies to assess the use of IV AA in patients with metastatic pancreatic cancer. As 
more effective chemotherapy backbones like FOLFIRINOX are now available, 
gemcitabine+erlotinib is no longer considered an acceptable first line regimen for fit 
patients. 
 
A recent study of ascorbic acid in advanced ovarian cancer showed cytotoxic effects on 
cancer cells in vivo, synergizing with chemotherapy and decrease in tumors in a mouse 
xenograft model. (Ma et al., 2014) In a pilot study of 27 patients, patients were 
randomized to standard first line carboplatin and paclitaxel chemotherapy with or 
without ascorbic acid. Patient who received intravenous ascorbic acid had decreased 
frequency of grade 1 and 2 adverse events and longer time to disease progression. 
The study however was not powered to show a difference in survival. (Ma et al., 2014) 
 
1.5 
Dose Rationale and Risk/Benefits 
Ascorbic acid has been shown to be well tolerated even when administered 
intravenously, and phase I human data from a group of 24 mixed cancer patients 
confirm it to be relatively safe and non-toxic, even at doses as high as 1.5 grams/Kg 
(Hoffer et al., 2008; Hoffer et al., 2015; Stephenson et al., 2013). This study reported 
only mild adverse effects associated with such doses of ascorbic acid. Two cases of 
acute oxalate nephropathy were reported in patients with pre- existing renal 
insufficiency given massive intravenous doses of vitamin; (Wong, Thomson, Bailey, 
McDiarmid, & Gardner, 1994) therefore, patients with renal insufficiency or renal failure, 
or who are undergoing dialysis, should not receive high doses of ascorbic acid. There 
are two reports of intravascular hemolysis in people infused with more than 50 g 
ascorbic acid and one that describes cases of hemolysis in persons who received at 
least 6 g of ascorbic acid as a single oral dose. All of the cases were in persons with 
the rare congenital metabolic disease, glucose-6-phosphate dehydrogenase (G6PD) 
deficiency, which renders red blood cells susceptible to oxidative stress. (Riordan et al., 
2004) G6PD status will be evaluated prior to start of therapy for all potential subjects. 
Our phase 1 study showed no Dose Limiting Toxicities (DLT) with 100 grams of 
ascorbic acid. (Monti et al., 2012) Since the toxicities of ascorbic acid and FIRINOX are 
not overlapping, we do not feel a dose escalation study is warranted. FIRINOX is 
standard chemotherapy and has reported the longest survival reported in a randomized 
trial in pancreatic cancer and therefore ascorbic acid is being added to this regimen to 
evaluate safety of the combination. As part of this study, patients will receive a modified 
FOLFIRINOX called FIRINOX as they will not be receiving the folinic acid (FOL). 
 
Special Risk Factors: 
Due to the frequency of the study regimen in combination with disease progression and 
standard treatment patients may experience fatigue and psychological distress about 
their diagnosis and prognosis which will be captured in QOL questionnaires. 
 
Risks of venous cannulation or Port access for ascorbic acid infusion: 
Venous cannulation and port accessing are routine clinical procedures that carry 
minimal risks when performed by trained personnel. It is possible that bruising/bleeding 
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could occur in some subjects. There is a risk of phlebitis or infection which is very low. 
 
Teratogenic Effects: Pregnancy Category C: 
Animal reproduction studies have not been conducted with ascorbic acid injection. It is 
not known whether ascorbic acid injection can cause fetal harm when administered to 
a pregnant woman or can affect reproduction capacity. Therefore, ascorbic acid 
injections should not be administered to a pregnant woman unless the potential benefit 
justifies the potential risk to the fetus and therefore pregnant women are excluded and 
women of child bearing age are encouraged to use contraception. 
 
Nursing Mothers: 
Ascorbic acid is excreted into human breast milk, but its effects on an infant are 
unknown. Thus, nursing women will be excluded from this study. 
 
2.0 
STUDY OBJECTIVES 
Primary Objective: 
The primary objective is to determine safety of intravenous ascorbic acid in combination 
with FIRINOX as defined by CTCAE version 4.03 in patients with advanced pancreatic 
cancer. 
 
Secondary Objective: 
The secondary objective is to test feasibility of collecting QOL, PRO data and correlative 
studies on patients with advanced pancreatic cancer. 
 
3.0 
STUDY DESIGN 
3.1 
General Design 
This is a pilot study of 8 patients with pancreatic cancer. It is a single arm, non- 
randomized, open label study. Patients will continue on treatment till progression, death 
or withdrawal from the study. Patients who progress or are withdrawn from study will be 
followed for 30 days. 
 
3.2 
Primary Endpoint 
Safety of the regimen as determined by CTCAE version 4.03. 
 
3.3  
Secondary Study Endpoint 
Change in QOL as defined by EORTC QLQ C-30. 
 
3.4 
Exploratory End Points 
Feasibility of collection of all QOL and PRO questionnaires. 
 
4.0 
SUBJECT SELECTION AND WITHDRAWAL 
4.1 Inclusion and Exclusion Criteria 
Inclusion Criteria:  
• Age 18-75 capable of giving informed consent 
• Histological diagnosis of adenocarcinoma of the pancreas 
• Stage IV or recurrent pancreatic cancer by imaging 
• Locally advanced unresectable pancreatic cancer by NCCN criteria 
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• ECOG PS 0-1 
• No prior treatment for metastatic disease (Prior neo-adjuvant or adjuvant 
chemotherapy, except FOLFIRINOX, chemoradiation or radiation allowed)  
• White Blood Count >/= 3000, Platelets >/= 100,000 
• Total bilirubin </= 1.5mg/dl, AST and ALT </= 5 X 
ULN Creatinine <1.5 mg/dL 
•  G6PD level of 5-14 units/g Hgb or within institutional standard parameters 
• All subjects of child producing potential must agree to use contraception or 
avoidance of pregnancy measures while enrolled on study.  
 
Exclusion Criteria 
• Other pancreatic cancer histology. (islet cell, acinar, neuroendocrine tumors).  
• Resectable pancreatic cancer 
• Prior neoadjuvant FOLFIRINOX  
• Pregnant or lactating females 
• No clinical ascites (mild ascites on scans permissible)  
• Central Nervous System (CNS) metastasis 
• Known Congestive Heart Failure, significant ventricular arrhythmias, cirrhosis, 
grade 4/5 Chronic Kidney Disease, uncontrolled diabetes 
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic 
therapy. 
• Peripheral neuropathy grade 2 or greater 
• Any condition, psychiatric or otherwise, that would preclude informed 
consent, consistent follow-up or compliance with any aspect of the study 
(e.g., untreated schizophrenia or other significant cognitive impairment, etc.). 
 
4.2 
Gender/Minority Inclusion for Research 
The ratio of men to women in pancreatic cancer is almost equal with slight male 
predominance. Participation of women and minorities is especially encouraged. 
 
4.3  
Subject Recruitment and Screening 
8 patients, 18-75 years of age with a good performance status (ECOG 0 or 1) will be 
enrolled. Patients will be identified from the medical oncology practice at Thomas 
Jefferson University or referred from integrative medicine, surgery or other providers 
within and outside of Thomas Jefferson University. No advertisements are planned for 
the pilot study. 
 
4.4  
Early Withdrawal of Subjects 
When and How to Withdraw Subjects: 
Patients are withdrawn from the study of they have progression, intolerance, non- 
compliance, death or withdraw consent or continuing on the study is not in the patient’s 
best interest as determined by the treating physician in collaboration with the principal 
investigator. 
 
Data Collection and Follow-Up for Withdrawn Subjects: 
Even though subjects may be withdrawn prematurely from the study, we will make all 
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efforts to collect at least survival data on all subjects every 6 months by phone call 
throughout the protocol defined follow-up period. Such data is important to the integrity 
of the final study analysis since early withdrawal could be related to the safety profile of 
the study drug. 
 
If a subject withdraws consent or the treating investigator withdraws the patient from the 
study, every attempt will be made to obtain permission to record at least survival data 
every 6 months by phone call up to the protocol-described end of subject follow-up 
period using phone calls to next-of-kin if possible, certified letters or querying Social 
Security Administration's Death Index and obituaries. 
 
5.0 
STUDY DRUG/THERAPY 
5.1 
Ascorbic Acid 
Ascorbic acid is a 6-carbon ketolactone structurally related to glucose and other 
hexoses. Its formal chemical structure is 3-oxo-L-gulofuranolactone, C6H8O6© 40.9%, 
H 4.6% O 54.5%), molecular weight 176.13. 
 
Investigational Formulation and Supplier: 
Ascorbic Acid Injection USP is ordered through the Thomas Jefferson University 
pharmacy and is provided free of charge to the study patients. It will be reconstituted 
and infused by the Myrna Brind Center. It is a clear, colorless to slightly yellow sterile 
solution of ascorbic acid in water for injection, for intravenous, intramuscular, or 
subcutaneous use. Each mL contains ascorbic acid 500 mg (2.84 mmol), edetate 
disodium 0.025%, and water for injection q.s. with the pH (range 5.5 to 7.0) adjusted 
with sodium bicarbonate, hence providing ~ 2.84 mmol sodium. The product is supplied 
in sterile 50 mL single use glass ampules containing 500 mg/mL of ascorbic acid USP. 
The stock solution contains 2.84 mmol of ascorbic acid per mL and 2.84 mmol of 
sodium per mL for a theoretical osmolality of 2.84 + 2.84 = 5.7 mOsm/mL. 
 
5.2 
Oxaliplatin 
Chemistry: 
Oxaliplatin is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the 
chemical name of cis-[(1 R,2 R)-1,2- cyclohexanediamine-N,N'] [oxalato(2-)- O,O'] 
platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is 
complexed with 1, 2 - diaminocyclohexane(DACH) and with an oxalate ligand as a 
leaving group. 
 
Mechanism of Action: 
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active 
derivatives via displacement of the labile oxalate ligand. Several transient reactive 
species are formed, including monoaquo and diaquo DACH platinum, which covalently 
bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. 
Crosslinks are formed between the N7 positions of two adjacent guanines (GG), 
adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide 
(GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-
cycle nonspecific. 
 
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In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In 
combination with 5-fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative 
activity greater than either compound alone in several tumor models [HT29 (colon), GR 
(mammary), and L1210 (leukemia)]. 
 
Pharmacokinetics: 
The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in 
plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin 
administration is triphasic, characterized by two relatively short distribution phases 
(t1/2α; 0.43 hours and t1/2β; 16.8 hours) and a long terminal elimination phase (t1/2γ; 
391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous 
infusion of ELOXATIN at a dose of 85 mg/m2 expressed as ultrafilterable platinum were 
Cmax of 0.814 mcg/mL and volume of distribution of 440 L. 
 
Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0–48hr) 
assessed over 3 cycles was moderate to low (23% and 6%, respectively). A 
pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety 
and effectiveness has not been established. 
 
Known Side Effects and Toxicities: 
Most common adverse reactions (incidence ≥ 40%) were peripheral sensory 
neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in 
transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. 
Other adverse reactions, including serious adverse reactions, have been reported. 
 
Pharmaceutical Data: 
Powder for solution for infusion: Oxaliplatin is supplied in clear, glass, single-use vials 
with gray elastomeric stoppers and aluminum flip-off seals containing 50 mg or 100 mg 
of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Lactose 
monohydrate is also present as an inactive ingredient. Store under normal lighting 
conditions at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). Concentrate for 
solution for infusion: Oxaliplatin is supplied in clear, glass, single-use vials with gray 
elastomeric stoppers and aluminum flip-off seals containing 50 mg, 100 mg or 200 mg 
of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 
mg/ml. Water for Injection, USP is present as an inactive ingredient. Store at 25°C 
(77°F); excursions permitted to 15- 30°C (59-86°F). Do not freeze and protect from light 
(keep in original outer carton). 
 
Supply: 
Commercially available. 
 
5.3 
Irinotecan 
Chemistry: 
Irinotecan hydrochloride injection is an antineoplastic agent of the topoisomerase I 
inhibitor class. Irinotecan hydrochloride was clinically investigated as CPT-11. Irinotecan 
hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from 
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plants such as Mappia foetida and Camptotheca acuminata. The chemical name is (S)-
4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy- 3,14-dioxo-1H - pyrano[3',4':6,7] - 
indolizino[1,2 - b]quinolin - 9 - yl - [1,4'bipiperidine] - 1' - carboxylate, 
monohydrochloride, trihydrate. 
 
Mechanism of Action: 
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the 
enzyme topoisomerase I which relieves torsional strain in DNA by inducing reversible 
singlestrand breaks. Irinotecan and its active metabolite SN-38 bind to the 
topoisomerase I-DNA complex and prevent religation of these singlestrand breaks. 
Current research suggests that the cytotoxicity of Irinotecan is due to double-strand 
DNA damage produced during DNA synthesis when replication enzymes interact with 
the ternary complex formed by topoisomerase I, DNA, and either Irinotecan or SN-38. 
Mammalian cells cannot efficiently repair these double-strand breaks.  
 
Pharmacokinetics: 
After intravenous infusion of Irinotecan in humans, Irinotecan plasma concentrations 
decline in a multiexponential manner, with a mean terminal elimination half-life of about 
6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is 
about 10 to 20 hours. The half-lives of the lactone (active) forms of Irinotecan and SN-
38 are similar to those of total Irinotecan and SN-38, as the lactone and hydroxy acid 
forms are in equilibrium. Over the recommended dose range of 50 to 350 mg/m2, the 
AUC of Irinotecan increases linearly with dose; the AUC of SN-38 increases less than 
proportionally with dose. Maximum concentrations of the active metabolite SN-38 are 
generally seen within 1 hour following the end of a 90-minute infusion of Irinotecan. 
Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is 
highly bound to human plasma proteins (approximately 95% bound). The plasma 
protein to which Irinotecan and SN-38 predominantly binds is albumin. 
 
Known Side Effects and Toxicities: 
Irinotecan can induce both early and late forms of diarrhea. Both forms of diarrhea may 
be severe. Early diarrhea (occurring during or shortly after infusion of irinotecan) may be 
accompanied by cholingergic symptoms of rhinitis, increased salivation, miosis, 
lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis than can cause 
abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented 
or ameliorated by atropine. Late diarrhea (generally occurring more than 24 hours after 
irinotecan) can be life threatening since it may be prolonged and may lead to 
dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly 
with loperamide. Severe myelosuppression may also occur with irinotecan. 
 
Pharmaceutical Data: 
Each mL of Irinotecan hydrochloride injection contains 20 mg Irinotecan (on the basis of 
the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic acid. When necessary, pH has 
been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. 
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). 
Protect from light. Do not freeze. It is recommended that the vial should remain in the 
22 
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carton until the time of use. 
 
Supply: 
Commercially available. 
 
5.5 
Fluorouracil (5-FU) 
Chemistry: 
Fluorouracil or 5-Fluorouracil (5-FU) is a fluorinated pyrimidine differing from the normal 
RNA substrate, uracil, by a fluorinated number 5 carbon. The chemical has a pH of 8.1, 
and the commercially available solution is buffered with NaOH to obtain an alkaline 
solution with a pH of around 9.0. The drug is both light sensitive and will precipitate at 
low temperatures or, occasionally, after a prolonged period at room temperature. 
Melting range of the solid is 280-284°C. At 25°C the solubility is 1.2 m g/m l in 
chloroform. The sodium content is 8.24 mg/ml and molecular weight 130.08. 
 
Mechanism of Action: 
The metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of 
deoxyuridilic acid to thymidilic acid. In this fashion, 5-FU interferes with the synthesis of 
DNA. This creates a thymidine deficiency that provides unbalanced growth and cell 
death. Prolonged administration of 5-FU continuous infusion may favor 5-FU 
incorporation into RNA. 
 
Pharmacokinetics: 
5-FU is rapidly absorbed by the tissues. Studies with radioactively labeled 5-FU 
administered IV, have indicated passage of the drug through the blood-brain barrier. 
Intravenous administration gives a half-life of 5 – 7.5 minutes at a 15 mg/kg dose. 
Following the i.v. administration of a single 15 mg/kg dose of radioactively labeled drug, 
levels of 28 mcg/ml, 2-8 mcg/ml, and 0.72 mcg/ml in plasma were observed at 10 
minutes, 2 hours, and 24 hours, respectively. The drug is largely catabolized in the liver 
and excreted in the form of nontoxic metabolites. Eighty percent of the drug is excreted 
as CO2 from the lungs, and approximately 15% is excreted intact in the urine in 6 hours. 
Of this, 90% is excreted in the first hour. 
 
Known Side Effects and Toxicities: 
Mild nausea and vomiting, stomatitis, anorexia, diarrhea, alopecia, hand/foot syndrome, 
myelosuppression, cerebellar ataxia, skin, and cardiac toxicity have been observed. The 
most common toxicities with continuous infusion 5-FU are mucositis and hand/foot 
syndrome. 
 
Pharmaceutical Data: 
Each 10 ml ampule contains 500 mg of the drug (50 mg/ml), adjusted to a pH of 
approximately 9 with sodium hydroxide. 5-FU is stored at room temperature and given 
over 46 hours infusion as per standard of care. 
 
Supply: 
Commercially available. 
23 
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5.6 Treatment Regimen 
FIRINOX REGIMEN 
Given every 14 days: 
• Oxaliplatin 85 mg/m2 IV over 2 hours 
• Irinotecan 180 mg/m2 IV over 90 minutes 
• Fluorouracil 2400 mg/m2 IV infusion over approximately 46 hours (NO BOLUS) 
 
Based on the patient's baseline BSA, recommended 5-FU and oxaliplatin or irinotecan 
doses will be calculated. If the patient has a 10% or greater weight change (+/-) from 
baseline or from the last weight used to calculate BSA and drug doses, dose will be 
recalculated. Rounding the doses of 5-FU, oxaliplatin, and irinotecan is allowed as per 
institutional guidelines. Pre-medications and supportive medications are as per 
institutional practice. 
 
Ascorbic Acid 
Ascorbic acid 100 grams IV over approximately 2 hours, 2 or 3 times a week as 
described below. Test dose/doses of ascorbic acid will be given prior to the first cycle as 
per routine integrative medicine department policy once patients sign informed consent. 
The test dose will be ascorbic acid 50 grams IV to be given during the screening visit.  
 
5.7 
Prior and Concomitant Therapy 
Prior therapy with FOLFIRINOX will exclude the patient from participation in the study. 
 
Throughout the study, investigators may prescribe concomitant medications or 
treatments deemed necessary to provide adequate supportive care. 
 
The following therapies and treatment should not be administered while on study 
protocol: any investigational agent or other anti-tumor treatment (both standard and 
investigational) outside of protocol described therapy. Elective major surgeries during 
the study through 30 days after the last dose of the protocol specified treatment. 
 
Prophylactic growth factor use is permitted as per ASCO, NCCN or institutional 
guidelines. 
 
5.8 
Side Effects 
5.8.1 Ascorbic Acid 
Possible (occurring in 10-29% of people) 
• Gastrointestinal: Nausea, vomiting, abdominal cramps and diarrhea have been 
reported during infusion of ascorbic acid. 
• Neurologic: Lightheadedness, flushing and shivering during infusion, headaches, 
weakness. 
 
Rare <1%: 
• Oxalate Nephropathy 
• Acute Renal Failure 
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• Intravascular hemolysis seen in G6PD deficiency patients 
 
5.8.2 FIRINOX: 
Likely (occurring in 30% or more people): 
• Anemia (low number of red blood cells) 
• Bruising or bleeding 
• Neutropenia 
• Delayed or persistent diarrhea 
• Neuropathy 
• Nausea and vomiting 
• Mucositis 
• Cholinergic reaction (stomach cramps, diarrhea, sweats, dizziness, excess 
saliva, watery eyes, tiredness, and problems with vision) 
• Palmar plantar erythemia 
• Skin hyperpigmentation 
• Increased sensitivity to sun 
• Fatigue and lack of energy 
• Hair thinning/loss 
 
Possible (occurring in 10-29% of people): 
• Watery eyes 
• Infusion reactions 
• Extravasation 
 
Rare, but could be serious (occurring in less than 10%): 
• Allergic reaction 
• Chest pain or stroke 
 
There can be treatment delays or interruptions, if needed, to make the treatment safer 
or more tolerable or if there are side effects as described in dose modifications. 
 
5.9 
Supportive Therapy 
Antidiarrheal medications: 
• Patients should be instructed to begin taking loperamide (2mg) at the earliest 
sign of poorly-formed or loss stools. Oral loperamide 2mg every two hours should 
continue until 12 hours after the last liquid stool 
• Aggressive supportive care should be provided for patients with Grade 4 ANC 
and ≥ Grade 3 diarrhea until neutropenia and diarrhea resolve. Hospitalization for 
evaluation and management of complicated diarrhea, is strongly recommended. 
 
Irinotecan-Related Cholinergic Syndrome 
• Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal 
cramping, diarrhea, or other symptoms of early cholinergic syndrome may occur 
during or shortly after receiving irinotecan. Atropine, 0.25-1.0mg IV or SC should 
be used to treat these symptoms and should be used prophylactically. 
• Combination anticholinergic medications containing barbiturates or other agents 
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(e.g. Donnatal®) should not be used because these may affect irinotecan 
metabolism. Anticholinergics should be used with caution in patients with 
potential contraindications (e.g., obstructive uropathy, glaucoma, tachycardia, 
etc). 
• Diarrhea developing more than 24 hours after the irinotecan dose should be 
managed with loperamide as described above. 
 
Antiemetic Therapy: 
• Antiemetic therapy should be administered at the physician’s discretion. A 
combination of a 5-HT# antagonist and dexamethasone is strongly 
recommended. Additionally, for delayed nausea, a combination of 
dexamethasone 4mg and ondansetron 8mg twice a day orally for three days, and 
prochlorperazine 10mg orally four times daily on an as needed basis for nausea 
are recommended. 
 
Growth Factor Supply: 
• Use of growth factor support as primary prophylaxis to prevent neutropenia is not 
prohibited. An ANC <1500 on day 1 of any cycle will require the use of growth 
factor for all remaining cycles as per NCCN/ASCO guidelines for prophylaxis of 
febrile neutropenia unless otherwise not indicated. 
• Choice of growth factor is at the investigator’s discretion 
• Use of an erythropoiesis-stimulating agent is to be used at the investigator’s 
discretion 
 
Fever: 
• Because of the risk of sepsis with FOLFIRINOX, especially in those patients who 
have biliary stents due to biliary obstruction, patients should call their treating 
physician and be evaluated as soon as possible. 
 
Management of Laryngopharyngeal Dysesthesias: 
• Oxaliplatin may cause discomfort in the larynx or pharynx associated with the 
sensation of dyspnea, anxiety, and swallowing difficulty.  
• Exposure to cold can exacerbate these symptoms. Do not use ice chips or other 
forms or oral cryotherapy to decrease stomatitis in conjunction with oxaliplatin 
• Anxiolytics may be used at the physician’s discretion. 
 
 
5.10 Preparation and Administration of Study Drug/Therapy 
Ascorbic Acid Preparation: 
Materials: Ascorbic acid injection (USP, 500 mg/mL) supplied by the Jefferson 
Pharmacy, sterile water for injection (USP, 1,000-mL IV bag), magnesium chloride 
injection (200 mg/mL, 20%), calcium gluconate injection (USP, 100 mg/mL, 10%), 
SmartSite Gravity Set®, and Microbore Extension Set (0.2µm Supor® filter), are used in 
the preparation of the Ascorbic Acid IV Infusion sets. 
 
Preparation: 
1. Spray the inside of the biosafety cabinet, handler's gloves and the sterile water 
filled 1-liter IV bag with 70% isopropyl alcohol as needed. Excess alcohol may be 
26 
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pat dry with a clean paper towel. 
2. Insert a sterile 16-gauge needle into the sterile water IV bag and squeeze the 
bag to drain 250 ml of liquid from the bag into a graduated cylinder. Remove the 
needle from the bag. Discard the drained liquid. This leaves 750mL of sterile 
water contained in the bag. 
3. Attach a different sterile 16-gauge needle to another sterile 60-mL syringe 
4. Draw up a 50mL injection of Ascorbic Acid (AA) into the syringe and inject into 
the bag. 
a. For the 75-g dosage: repeat two times, using a new sterile syringe and 
needle each time (150 mL AA total). 
b. For the 1 00-g dosage: repeat three times, using a new sterile syringe and 
needle each time (200 mL AA total). 
5. Attach either a sterile 18- or 20-gauge needle to a sterile 5-mL syringe. 
6. Draw up 5 mL of Magnesium Chloride (MgCl) into the syringe and inject into the 
bag (5mL total for both concentrations) 
7. Attach a separate sterile 18- or 20-gauge needle to a sterile 1 0-mL syringe. 
a. For the75-g dosage: stop here (10 mL CaGluc total) 
b. For the 100-g dosage: repeat one more time, using a new sterile syringe 
(20 mL CaGluc total) 
8. Mix the solution well by inversion. 
9. Place the bag in a hanging position. Aseptically connect the sterile IV tubing and 
.2µm filter to the bag and allow to drip/infuse into the patients line. 
 
Total volume: 
75g Bag 
100g Bag 
750mL water 
750mL water 
150mL AA 
200mL AA 
5mL MgCL 
5mL MgCl 
10mL CaGluc 
20 mL CaGluc 
915mL total 
volume 
975mL total 
volume 
 
 
5.11 Receiving, Storage, Dispensing and Return 
Receipt of Drug Supplies: 
Ascorbic Acid Injection USP is ordered though the Thomas Jefferson University 
Pharmacy. 
 
Storage: 
The product is stored in a carton protected from light between 2-8°C. It must not be 
frozen. It must be infused within 4 hours of preparing diluted solutions for injection. 
 
Dispensing of Study Drug: 
Regular study drug reconciliation will be performed to document drugs were given as 
per protocol. Since all the drugs involved are intravenous, there will not be a drug log for 
patients to fill out. 
 
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Return or Destruction of Study Drug: 
Drug will not be returned or destroyed. 
 
6.0 
STUDY PROCEDURES 
6.1 
Study Visit Schedule 
See Appendix A. 
 
Screening visit (-28 to day 0): 
Patient will meet with one of the investigators and coordinator to review informed 
consent. Once patient signs consent form, coordinator will review the eligibility criteria, 
review medical history, document concomitant medications and ECOG PS. Physical 
exam including vital signs (height, temperature, pulse, heart rate, and blood pressure) 
and weight will be recorded. Baseline labs, pregnancy test (urine or blood), G6PD 
level, EKG, urinalysis and imaging scans will be performed. Scans should be done 
within 28 days of study entry. 
 
Test dose/doses of ascorbic acid (50 grams IV) will be given prior as per routine 
integrative medicine department policy once patients sign informed consent but before 
the first cycle of FIRINOX. Please see table 1 for ascorbic acid infusions.  
 
Baseline: 
Patient will fill out EORTC QLQ C30, CIPN 20, oxaliplatin neuropathy scale, FACIT 
fatigue scale and SGA. These forms can be filled out during the test dose/doses of 
ascorbic acid infusion prior to cycle 1 
 
Study visits: 
Review medications, AE assessment, symptom directed exam, vital signs, ECOG 
PS, chemistry, hematology, EORTC QLQ-C 30 
 
End of Treatment Study Procedures:  
Review medications, AE assessment, complete physical, exam, vital signs, ECOG PS, 
chemistry, hematology, EORTC QLQ-C 30, EORTC CIPN 20, oxaliplatin neuropathy 
scale, FACIT fatigue scale, SGA. 
 
Post-Treatment/Follow-up:  
Patients will be followed once every 14-28 days after last treatment for a post 
treatment/follow up assessment.  
 
Review medications, AE assessment, complete physical, exam, vital signs, ECOG 
PS, chemistry, hematology, EORTC QLQ-C 30, EORTC CIPN 20, oxaliplatin 
neuropathy scale, FACIT fatigue scale, SGA. If patient is not able to come for an 
office appointment, a telephone follow up will be attempted. If patient refuses to follow 
up or is lost to follow up or dies within 30 days, it will be documented in the chart. 
 
6.2 
Subject Compliance Monitoring 
Since all treatment is intravenous, subjects will be closely monitored at the time of their 
visits. Patients will be evaluated by the treating oncologist at each chemotherapy visit to 
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evaluate for adverse events and compliance to the protocol will be assessed regularly 
by the PI. The investigator at Integrative Medicine will be responsible for monitoring 
infusion of ascorbic acid in the Myrna Brind Center at Thomas Jefferson University. A 
chart will be maintained at the center to record the time, dose and unexpected side 
effects which will be reviewed every 3 months by the PI. 
 
6.3 Definition of Dose-Limiting Toxicities 
• Any Grade 5 event attributable to the regimen 
• Any Grade 4 non-hematological toxicity that is attributable to regimen with the 
exception of alopecia, diarrhea, nausea and vomiting 
• Nausea, vomiting or diarrhea ≥Grade 3 that persists for greater than 72 hours 
despite optimal antiemetic and anti-diarrheal therapy and IV hydration 
• Any Grade 3 non-hematological toxicity that is study drug related that results in 
delay of chemotherapy by greater than 2 weeks 
 
Dose De-escalation Schedule 
Dose Level 
Dose of Intravenous ascorbic acid 
Level 1 
100 grams 
Level -1 
75 grams 
Level -2 
50 grams 
 
6.4 Dose Delays and Dose Modifications 
If a patient experiences several adverse events and there are conflicting 
recommendations, the investigator should use the recommended dose adjustment that 
reduces the dose to the lowest level. If chemotherapy is on hold due to side effects 
clearly attributable to it, ascorbic acid can continue on schedule without any dose 
modifications. 
 
Dose modifications for FIRINOX: 
Neutrophil 
number 
5FU 
Irinotecan 
Oxaliplatin 
>/= 1500 
2400 mg/m2 
180 mg/m2 
85 mg/m2 
           1000-1500 
or if patient had 
• 
Febrile 
neutropenia 
• 
Grade 3 /4 
infection 
• 
Grade 4 
neutropenia >7 
days 
2400 mg/m2 
150 mg/m2 
85 mg/m2 
Less than 1000 on 
day of treatment 
Hold 
Hold 
Hold 
 
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Primary prophylactic GCSF strongly recommended as per NCCN/ASCO/institutional 
guidelines. Reevaluate weekly if treatment is held. 
 
Platelets 
5FU 
Irinotecan 
Oxaliplatin 
>/= 100,000 
2400mg/m2 
180 mg/m2 
85 mg/m2 
75,000 to 100,000 
1800mg/m2 
150 mg/m2 
60 mg/m2 
Less than 75,000 
Hold 
Hold 
Hold 
 
Reevaluate weekly. If counts have not recovered after a delay of two weeks, despite 
appropriate supportive measures, it is recommended that treatment be stopped.  
Renal Impairment CrCL Dose (% of original): 
Renal Impairment 
CrCL 
Dose 
5FU 
No change 
No change 
Irinotecan 
No change 
No change 
Oxaliplatin 
<20 
Contraindicated 
 
Hepatic Impairment 
Drug 
Bilirubin 
Dose 
5FU 
</=3 
No change 
>3 
Avoid 
Irinotecan 
1- 1.5 
135mg/m2 
1.5 to 3 
90mg/m2 
>/=3 
Avoid 
Oxaliplatin 
</=3 
No change 
>3 
Avoid 
 
Diarrhea 
CTCAE 4.03 grade 1 or 2 diarrhea occurring between cycles does not  necessitate 
dose modification, unless accompanied by fever or neutropenia. If the diarrhea is 
more than grade 2 on day of treatment, delay treatment by 7 days and reassess. 
Dose adjust 5FU and irinotecan as below 
 
Diarrhea 
5FU 
Irinotecan 
Oxaliplatin 
Grade 1 
2400mg/m2 
150mg/m2 
85mg/m2 
Grade 2 
1800mg/m2 
135mg/m2 
85mg/m2 
Grade 3 or higher 
Hold 
Hold 
Hold 
 
Fluorouracil-Specific Dose Modifications: 
If a Grade 3 or 4stomatitis occurs, reduce the fluorouracil infusion doses to 75% of the 
original dose. For a Grade 3 or 4 Palmer-Plantar Erythrodysesthesia, reduce the 
fluorouracil infusion doses to 75% of the original dose. 
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Oxaliplatin-Specific Dose Modifications: 
If the neurosensory toxicity is CTCAE Grade 1 or 2 and last < 7 days, administer the full 
dose of oxaliplatin. If the toxicity is CTCAE Grade 2 and persists 7 or more days, reduce 
the oxaliplatin dose to 60mg/m2. Oxaliplatin should be discontinued for neurosensory 
toxicities CTCAE Grade 3 or above and 5FU and Irinotecan can continue to be given. 
 
Peripheral 
Neuropathy 
5FU 
Irinotecan 
Oxaliplatin 
Grade 1 
2400mg/m2 
180mg/m2 
85mg/m2 
Grade 2 
2400mg/ m2 
180mg/m2 
60mg/m2 
Grade 3 or higher 
2400mg/m2 
180mg/m2 
Hold 
 
For transient cold-related dysesthesia or paresthesia without pain, there is no need to 
delay or reduce oxaliplatin. For acute laryngopharygeal dysesthesia, increase the 
infusion time to 4 hours. 
 
7.0  STATISTICAL PLAN 
7.1 
Sample Size Determination 
8 patients as described below. 
 
7.2 
Statistical Methods 
The study will follow a Phase I design for toxicities called the time-to-event continual 
reassessment method (TITE-CRM). (Cheung & Chappell, 2000; Normolle & Lawrence, 
2006) We will enroll 8 patients with toxicities monitored for 28 days. We expect to enroll 
one patient a month on average. The first patient will be started at the highest dose. 
Previous studies suggest that the probability of toxicity at the highest dose is less than 
10% and so we assume prior probabilities of toxicity 0.02, 0.04, and 0.08 for the three 
dose levels of 50grams, 75grams, and 100grams, respectively. Assigned dose will be 
administered three times per week of treatment with the target probability of toxicity for 
the optimal dose is 0.10. Results from 1000 simulated data sets when the true toxicities 
match our assumptions indicate selection of the highest dose 93.2% of the time with an 
expected sample sizes of 0.60, 1.08, and 6.24 for the three doses and 0.50 toxicities 
expected at the highest dose. 
 
Change in quality of life over the six measurement times will be modeled using mixed 
effects linear regression to account for correlation among repeated measurements from 
the same subjects. Average change in QoL from baseline to follow-up will be 
computed. Assuming at least 6 patients receive the highest dose, we expect 80% 
power to detect an effect size of 3.19 (average change in global QoL score of 1.44 
standard deviations) using a two-sided paired t-test with alpha=0.05. 
 
7.3 Subject Population(s) for Analysis 
Patients who received at least 2 cycles of FIRINOX will be included in the final 
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analysis. If a patient comes off study earlier than 2 cycles of FIRINOX for any reason 
other than DLT, those patients will be replaced so that adequate number of QOL 
questionnaires can be collected. All patients who receive at least one dose of 
intravenous ascorbic acid will be followed for safety but will not be included for 
analysis of TITE-CRM if they received less than 2 cycles. 
 
8.0 
SAFETY AND ADVERSE EVENTS 
8.1 
Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study. Intercurrent illnesses or injuries  
should  be  regarded  as  adverse  events. Abnormal results of diagnostic procedures 
are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious. 
 
A serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance. They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above. For 
example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded 
as non-serious adverse events. 
 
8.2 
Adverse Event Reporting 
Adverse Event Reporting Period: 
The study period which adverse events must be reported is normally defined as the 
period from the initiation for any study procedures to the end of the study treatment 
follow-up. For this study, the study treatment follow-up is defined as 30 days following 
32 
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the last administration of study treatment. 
 
Preexisting Condition: 
A preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings: 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as 
an adverse event. 
 
Post-Study Adverse Event: 
All unresolved adverse events should be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained. At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study. The investigator 
should notify the study sponsor of any death or adverse event occurring at any time 
after a subject has discontinued or terminated study participation that may reasonably 
be related to this study. The sponsor should also be notified if the investigator should 
become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study. 
 
Abnormal Laboratory Values: 
A clinical laboratory abnormality should be documented as an adverse event if any one 
of the following conditions is met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g., change 
of dose, discontinuation of the drug, more frequent follow-up assessments, 
further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery: 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documents and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol. Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
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diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of 
the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
 
8.3 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination. Information on all 
adverse events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF). All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should be recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded in the CRF 
 
The clinical course of each event should be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the cause.  
Serious adverse events that are still ongoing at the end of the study period must be 
followed up to determine the final outcome. Any serious adverse event that occurs 
after the study period and is considered to be possibly related to the study treatment or 
study participation should be recorded and reported immediately. 
 
8.4 Stopping Rules 
We will review data after 4 patients are enrolled on the study and receive at least one 
dose of intravenous ascorbic acid. If 2 out of the 4 cannot complete 2 cycles of 
FIRINOX then we will halt the study and discuss a corrective plan in the GI MDG. The 
SKCC DSMB will follow all patients and monitor all AEs as per institutional guidelines. 
 
8.5 Data and Safety Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site. This safety monitoring will included careful assessment and appropriate 
reporting of adverse events as noted above, as well as the compliance and 
implementation of the SKCC data and safety-monitoring plan. Medical monitoring will 
include a regular assessment of the number and type of serious adverse events by 
both the assigned Medical Monitor and the SKCC DSMC. 
 
8.5.1 Medical Monitoring and AE/SAE Reporting 
A Medical Monitor is assigned to this study at the Thomas Jefferson University. This is a 
physician/pharmacist who is not directly involved in the trial, and is not currently 
collaborating with the sponsor/investigator on any other trial. The role of the Medical 
Monitor is to review all reportable AEs/SAEs (in real-time) including grading, toxicity 
assignments, non-reportable AEs (quarterly), protocol violations/deviations, as well as 
all other safety data and activity data observed in the ongoing clinical trial occurring at 
Thomas Jefferson University. The Medical Monitor may recommend reporting of 
adverse events and relevant safety data, and may also recommend suspension or 
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termination of the study to the DSMC and TJU IRB. 
 
Every SKCC investigator initiated protocol includes requirements for reporting of 
adverse events based on CTC 4.0. All events are reported to the IRB and Medical 
Monitor using a password protected web-site. In addition all unexpected and serious 
adverse events (SAEs) are reported to the TJU IRB and to the Food and Drug 
Administration (FDA) if applicable. The investigator is required to submit all unexpected 
and serious adverse events to the TJU IRB and the Medical Monitor within the 
timeframes outlined in the below table. All AE/SAEs will be reported to the DSMC at the 
quarterly DSMC review meetings; however, if the Medical Monitor determines corrective 
action is necessary, an “ad hoc” DSMC meeting will be called. Fatal adverse events 
related to treatment which are unexpected must be reported within 24 hours to the TJU 
IRB and the DSMC. Fatalities not related to the study drug/device must be reported 
within 5 days. A summary of the reporting requirements for SKCC investigator initiated 
Phase I and Phase II studies are presented below. 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 4 
and 5 
Unexpected 
and 
Expected 
Unexpected Expected 
Unexpected 
with 
Hospitalization 
Unexpected 
without 
Hospitalization 
Expected with 
Hospitalization 
Expected 
without 
Hospitalization 
Unexpected 
and Expected 
Unrelated 
 
Unlikely 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 - 
48 Hours 
(Death: 24 Hour
 
Phase 2 - 
5 Working Days
Possible 
 
Probable 
  
Definite 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 working 
days 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
48 Hours 
 
(Death: 24 
Hours) 
Phase 1 - 
48 Hours 
Phase 2 - 
5 Working 
Days 
48 Hours 
(Death: 24 
Hours) 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 
and Phase 2 -
48 Hours 
(Death: 24 
Hours) 
 
** NOTE: This table is based on the NCI AE/SAE reporting Guidelines and the TJU IRB Policy and 
Procedures. Please follow the individual protocol AE/SAE reporting guidelines if more stringent reporting 
procedures are specified. 
 
If an IND study, the participating site will also be responsible for completing FDA 
MedWatch 3500A Form and send to TJU Study Coordinator and IND holder/designated 
personnel for submission to the FDA. 
 
Safety Reporting Requirements for IND Holders: 
In accordance with 21 CFR 212.32, sponsor-investigator of studies conducted under an 
IND must comply with following safety reporting requirements: 
 
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Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life- threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 
related to the use of intravenous ascorbic acid. An unexpected adverse event is one 
that is not already described. 
 
Such reports are to be telephoned or faxed to the FDA within 7 calendar days and to 
the IRB within 24 hours of first learning of the event. Each telephone call or fax 
transmission (see fax number below) should be directed to the FDA new drug review 
division in the Center for Drug Evaluation and Research or in the product review 
division for the Center for Biologics Evaluation and Research, whichever is 
responsible for the review of the IND. 
 
15 Calendar-Day Written Report: 
The Sponsor-Investigator is also required to notify the FDA and all participating 
investigators, in a written IND Safety Report, of any serious, unexpected AE that is 
considered possibly related to the use of ascorbic acid. An unexpected adverse event 
is one that is not already described in the Investigator Brochure. 
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed with the IND 
concerning similar events should be analyzed. The new report should contain 
comments on the significance of the new event in light of the previous, similar reports. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a MedWatch 3500A Form but alternative 
formats are acceptable (e.g. summary letter). 
 
FDA fax number for IND Safety Reports:1 (800) FDA – 0178 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must 
also be faxed to: 
 
Thomas Jefferson University IRB 
 
IND Annual Reports: 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall 
within 60 days of the anniversary date that the IND went into effect submit a brief 
report of the progress of the investigation. Please refer to Code of Federal Regulations, 
21 CFR § 312.32 for a list of the elements required for the annual report. All IND 
annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
TJU IRB. Copies of such reports should be mailed to: 
 
8.5.2 Data and Safety Monitoring Committee 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring 
Board (DSMB) for the SKCC. The DSMC is a multidisciplinary committee charged with 
overseeing the monitoring of safety of participants in clinical trials, and the conduct, 
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progress, validity, and integrity of the data for all clinical trials at the Thomas Jefferson 
University SKCC. The committee meets quarterly to review the progress and safety of 
all active research protocols that are not monitored by another safety and data 
monitoring committee or board. 
• The DSMC meets quarterly. Additional DSMC meetings are scheduled based on 
the nature and number of trials being monitored over a specified time period. The 
DSMC meets (by conference call) within 24 hours following the notification of an 
unexpected adverse event felt to be related to the study drug. 
• Prior to each DSMC meeting, each board member, is provided a printout of all 
reported AEs and SAEs occurring during the reporting period for this clinical trial. 
The principal investigator provides a detailed and comprehensive narrative 
assessment of current adverse events to date, indicating their possible 
significance and whether these toxicities have affected the conduct of the trial. 
DSMC members are provided with the principal investigator’s assessment, a 
written report summarizing adverse events, safety data, and activity data 
observed during the specified time period described in each protocol, as well as 
recommendations from the Medical Monitor. A review of outcome results 
(response, toxicity and adverse events) and factors external to the study (such as 
scientific or therapeutic developments) is discussed, and the Committee votes on 
the status of each study. 
• A summary of the board’s action is sent to each investigator, the CCRRC and 
TJU IRBs. The DSMC actions may include recommendations/requirements that 
will lead to improved patient safety and/or efficacy, significant benefits or risks 
that have developed, or other changes determined to be necessary. The DSMC 
may also take note of slow accrual or lack of scientific progress, and refer such 
issues to the Protocol Review Committee (PRC). The DSMC provides the 
investigator with the rationale for any decision made. 
 
9.0 
DATA HANDLING AND RECORD KEEPING 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following: 
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
 
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9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents. Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the 
study. All data requested on the CRF must be recorded. All missing data must be 
explained. If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”. If the item is not applicable to the individual 
case, write “N/A”. All entries should be printed legibly in black ink. If any entry error 
has been made, to correct such an error, draw a single straight line through the 
incorrect entry and enter the correct data above it. All such changes must be 
initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of 
illegible or uncertain entries, print the clarification above the item, then initial and date 
it. 
 
9.4 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 
years after the formal discontinuation of clinical trial. These documents should be 
retained for a longer period if required. 
 
10.0 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities. The Investigator 
will also ensure that the medical monitor or other compliance or quality assurance 
reviewer is given access to all the above noted study-related documents and study 
related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to 
conduct the monitoring visit. 
 
SKCC Investigator Initiated Phase I Studies 
Phase I studies require continuous monitoring by the PI of the study with quarterly 
safety and monitoring reports submitted to the CTO and the DSMC. Each protocol is 
assigned to a medical monitor (a physician or other member of the DSMC who 
has expertise in the therapeutic area of the protocol and is not directly involved in this 
trial). The medical monitor reviews all adverse events (in addition to unexpected 
adverse events), safety data and activity data observed in the ongoing clinical trial at 
each new dose level, prior to dose escalation. 
 
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity data, and any 
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corrective action that occurred on a quarterly basis. The medical monitor also provides 
a summary of their review. The summary of all discussions of adverse events are 
submitted to the DSMC, and these reports are reviewed during the DSMC meetings that 
take place quarterly. Patients are only identified by initials, and no other personal health 
information (PHI) is included in the reports. 
 
The medical monitor may recommend reporting adverse events and relevant safety 
data not previously reported, and may recommend suspension or termination of the trial 
based on their review of AE/SAE data observed throughout the life of a clinical trial. In 
such circumstances, and “ad hoc” DSMC meeting will be called to discuss corrective 
action with the PI. If for any reason the PI of the trial disagrees with the conclusions of 
the Medical Monitor or DSMC, the issue will be referred to the Associate Director of 
Clinical Investigations, who will be responsible for dispute resolution. 
 
The summary of all discussions of adverse events are included in the SKCC 
investigator’s reports to the TJU IRBs as part of its annual progress report. The DSMC 
and the TJU IRBs may, based on the monitor’s recommendation suspend or terminate 
the trial. The quarterly safety and monitoring reports include a statement as to whether 
this data has invoked any stopping criteria in the clinical protocol. 
 
The investigator is required to submit all unexpected on-site adverse events and serious 
adverse events (SAEs) to the TJU IRB and the DSMB within 48 hours. Fatal adverse 
events which are unexpected must be reported within 24 hours to the TJU IRB and the 
DSMB. Fatalities not related to the study drug/device must be reported within 5 days. 
 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
10.1.1 Independent External and Internal Audits 
All studies initiated by SKCC investigators are audited by an independent auditor once 
they have achieved 10% of target accrual. However, a study can be audited at any 
time based on recommendations by the IRB, DSMC, PRC and/or the Director of 
Clinical Investigations, SKCC. Studies are re-audited once they have achieved 50% of 
target accrual. Special audits may be recommended by the IRB, DSMC or PRC based 
on prior findings, allegations of scientific misconduct and where significant irregularities 
are found through quality control procedures. Any irregularities identified as part of this 
process would result in a full audit of that study. 
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In addition to the audits at 10 and 50%, the CTO randomly audits at least 10 percent of 
all patients entered into therapeutic SKCC trials and other trials as necessary, on at 
least a bi-annual basis, to verify that there is a signed and dated patient consent form, 
the patient has met the eligibility criteria, and that SAEs are documented and reported to 
the TJU IRB. 
 
All audit reports are submitted to the DSMC for review and action (when appropriate). A 
copy of this report and recommended DSMC action is sent to the PRC and TJU IRB. 
The committee regards the scientific review process as dynamic and constructive rather 
than punitive. The review process is designed to assist Principal Investigators in 
ensuring the safety of study subjects and the adequacy and accuracy of any data 
generated. The TJU IRB may, based on the DSMC and auditor’s recommendation, 
suspend or terminate the trial. 
 
11.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct. The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator before 
commencement of this study. 
 
All subjects for this study will be provided a consent form that is compliant with local 
and federal regulations, describing this study and providing sufficient information for 
subjects to make an informed decision about their participation in this study. See 
Attachment for a copy of the Subject Informed Consent Form. This consent form will 
be submitted with the protocol for review and approval by the IRB for the study. The 
formal consent of a subject, using the IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure. This consent form must be 
signed by the subject or legally acceptable surrogate, and the investigator-designated 
research professional obtaining the consent. 
 
12.0 STUDY FINANCES 
12.1 Funding Source 
Financing of this study will be via the Myrna Brind Foundation Special Purpose Fund 
and the Department of Medical Oncology. 
 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by the institution, etc.) 
must have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 
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approved by the study sponsor prior to participation in this study. All Jefferson 
University Investigators will follow the TJU Conflicts of Interest Policy for Employees 
(107.03). 
 
12.3 Subject Stipends or Payments 
Patients will not be paid any stipends to participate in this clinical trial. 
 
13.0  PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this 
protocol will be published or passed on to any third party without the consent of the 
principal investigator and the University. Every effort will be made to publish the results 
of this clinical trial in peer reviewed scientific journals by the principal investigators or 
co-investigators. 
 
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10.1016/j.jamcollsurg.2011.12.017 
 
Yip, D., Karapetis, C., Strickland, A., Steer, C. B., & Goldstein, D. (2006). 
Chemotherapy and radiotherapy for inoperable advanced pancreatic cancer. Cochrane 
Database Syst Rev(3), CD002093. doi: 10.1002/14651858.CD002093.pub2 
 
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15.0 APPENDICES 
Appendix 1: Study Procedures/Study Visit Schedule 
 
Procedures 
Screening (Day –28o 0) 
Baseline  (Day -28 to 
0) 
Study Visit 1* (Day 0 
±3) CYCLE 1 
Study Visit 2* (Day 15 ± 
3)  CYCLE 2 
Study Visit 3*(Day 29± 
3)  CYCLE 3 
Study Visit 4* (Day 43± 
3)  CYCLE 4 
Study Completion/EOT 
Follow up/ Post 
treatment 
Signed Consent Form 
X 
Assessment of Eligibility 
Criteria 
X 
Review of Medical History, 
demographics 
X 
Review of Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Study Intervention 
X 
X 
X 
X 
Physical Examination 
Complete 
X 
X 
X 
Symptom- 
Directed 
X 
X 
X 
X 
Vital Signs 
(Temperature, 
Pulse, HR, BP 
and weight) 
Xe 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse 
Events 
X 
X 
X 
X 
X 
X 
 
 
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Procedures 
Screening (Day –28 to 0) 
Baseline  (Day -28 to 0) 
Study Visit 1* (Day 0 ±3) 
Cycle 1 
Study Visit 2* (Day14 ± 3) 
Cycle 2 
Study Visit 3*(Day 28 ± 3) 
Cycle 3 
Study Visit 4* (Day 4 ± 3) 
Cycle 4 
Study Completion/EOT 
Follow up post 
treatment 
Clinical Laboratory 
Pregnancy 
test^, PT, PTT 
X 
Chemistrya 
X 
X 
X 
X 
X 
X 
X 
Hematologyb 
X 
X 
X 
X 
X 
X 
X 
Urinalysis, 
G6PD level, 
EKG 
X 
GI tumor 
marker 
X 
X 
X 
Imaging C 
X# 
 
 
 
 
X 
 
 
Other Procedures d 
EORTC 
QLQC 30 
X 
X 
X 
X 
X 
X 
X 
EORTC CIPN 
20 
X 
X 
X 
X 
X 
Oxaliplatin 
neuropathy 
scale 
X 
X 
X 
X 
X 
FACIT fatigue 
scale 
X 
X 
X 
X 
SGA 
X 
X 
X 
X 
Treatment 
FIRINOX 
X 
X 
X 
X 
Ascorbic Acid 
Test Dosef 
X 
 
 
 
 
 
 
Ascorbic acid will be given as per the table below. No other study related 
procedures will be performed on the day of ascorbic acid infusion 
 
Example schema: 
Monday 
D1 - FIRINOX 
D8 - Ascorbic acid 
Tuesday 
D2 - 5FU 
D9  
Wednesday 
D3 - 5FU disconnect + 
Ascorbic acid 
D10 - Ascorbic acid 
Thursday 
D4  
D11  
Friday 
D5 Ascorbic acid 
D12 - Ascorbic acid 
Saturday 
D6 
D13 
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Sunday 
D7 
D14 
Abbreviations: HR=Heart rate, BP=Blood Pressure, ECOG=Eastern Cooperative 
Oncology Group, PT=Prothrombin Time, PTT=Partial thromboplatin time, 
G6PD=Glucose 6 Phosphatase deficiency, EKG= Electrocardiogram, GI= 
Gastrointestinal, EORTC= European Organization for Research and Treatment of 
Cancer, QLQ= Quality of Life Questionnaire, CIPN= Chemotherapy Induced Peripheral 
Neuropathy, FACIT= Functional Assessment of Chronic Illness Therapy), SGA= 
Subjective Global Assessment, FIRINOX = 5FU+IRInotecan+Oxaliplatin 
 
$ Any evaluation can be omitted if done within 72 hours 
 
* Study visit 1-4 repeated every 4 cycles 
 
** Not mandatory 
 
# Baseline scans within 28 days of screening. 
 
^ Only for premenopausal females. Serum or urine is acceptable 
 
a CMP, LDH 
 
b CBC with differential 
 
c CT of chest, abdomen and pelvis recommended every 8 weeks (± 1 week). MRI of abdomen can be 
performed if clinically appropriate instead of CT scan 
 
d QOL questionnaires can be performed during ascorbic acid infusions. 
 
e Height will be calculated at baseline for BSA measurement. 
 
f. test dose of ascorbic acid is 50 grams IV  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2: ECOG Performance Status 
 
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Appendix 3 EORTC QLQ-C30 
 
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Appendix 4: EORTC CIPN 20 
 
 
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Appendix 5: Oxaliplatin associated neuropathy questionnaire 
 
 
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Appendix 6: FACIT fatigue scale 
 
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Appendix 7: PG-SGA questionnaire 
 
 
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Appendix 8: AE log 
 
 
 
 
 
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