Conditions: Colorectal Cancer Pancreatic Cancer Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
This is a multicenter, single arm, 3-cohort, open-label trial of high dose Vitamin C intravenous infusion in subjects with solid tumor malignancies who are eligible for resection (cohort A) or with extended RAS (e.g.KRAS or NRAS) or BRAF mutation metastatic cancer who have received prior systemic treatment (cohort B). Cohort C will involve patients with colorectal cancer having an extended RAS or BRAF mutation who are amenable for localregional therapy of hepatic metastases with Yttrium-90 radioembolization.

Detailed description:
This clinical trial is for men and women with resectable or metastatic solid tumor malignancies. The objective of the study is to investigate whether high dose vitamin C infusion leads to pathological tumor response in resectable colorectal, pancreatic, and lung cancer (cohort A) or objective tumor response in KRAS or BRAF mutant solid tumors (cohort B). For Cohort C, the primary objective is to determine that maximal tolerated dose of the combination of high dose vitamin C with Y90 radioembolization for patients solid tumor malignancies and liver metastases amenable to local-regional therapy

Patients in cohort A receive a high dose vitamin C infusion for 4 days per week for 2-4 consecutive weeks prior to surgery. Patients in cohort B receive high dose vitamin C infusion for 4 days per week for up to 6 months or disease progression. Cohort C will receive high dose vitamin C for 1-3 weeks. During week 1 vitamin C infusion and Y90 radioembolization of hepatic metastases will occur same day.

A tumor sample will be resected after completion of study drug (high dose vitamin C infusion) treatment to examine the effects of study drug (Cohort A only). In addition, organoids will be grown in vitro and continue to be treated with vitamin C added in culture medium to examine tumor response. The resected tumor in this study will

Key eligibility:

* Men and women age 18 and older
* Patients with histologically proven early stage or locally advanced colorectal adenocarcinoma, lung cancer or pancreatic cancer, who are eligible for resection, and have not received chemotherapy or radiotherapy (cohort A) Patients with inoperable, metastatic, KRAS or BRAF mutant colorectal adenocarcinoma, lung cancer and pancreatic cancer, who have received at least 1 line of treatment for metastatic disease (cohort B)
* Patients with metastatic cancer with an extended RAS (e.g. KRAS or NRAS) or BRAF mutation with liver metastases amenable to Y90 radioembolization (cohort C).

Arms:
arm 1: Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks. arm 2: Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for up to 6 months. arm 3: Vitamin C will be administered at a dose of 0.5 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C. arm 4: Vitamin C will be administered at a dose of 0.75 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C. arm 5: Vitamin C will be administered at a dose of 0.75 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C. A single dose of Vitamin C at 0.5g/kg will also be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. arm 6: Vitamin C will be administered at a dose of 1 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C. A single dose of Vitamin C at 0.5g/kg will also be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. arm 7: A single dose of Vitamin C at 0.75g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy. arm 8: A single dose of Vitamin C at 0.75g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1.25 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy. arm 9: A single dose of Vitamin C at 1g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1.25 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy. arm 10: A single dose of Vitamin C at 1.25g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1.25 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy.

Interventions: intervention 1: Vitamin C
Intervention descriptions: intervention 1: Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks (cohort A) or up to 6 months (cohort B). Cohort C will receive high dose vitamin C for 1-3 weeks. During week 1 vitamin C infusion and Y90 radioembolization of hepatic metastases will occur same day.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Cover Page 
“High Dose Vitamin C Intravenous Infusion in PaƟents 
With Resectable or MetastaƟc Solid Tumor 
Malignancies” 
NCT0 3146962 


 
 
  
  
  
  
  
  
  
TITLE: A phase II study of high dose vitamin C intravenous infusion in patients with resectable 
or metastatic solid tumor malignancies.   
  
IRB Protocol #: 1610017688  
IND/IDE # (if applicable): 132719  
Version 8 Date:  08 March 2022  
  
Principal Investigator:   
  
Manish A. Shah, MD  
 
  
1305 York Avenue, 12Pth
P Floor  
 
  
New York, NY 10021  
 
  
Phone 646-962-6200  
 
  
Fax 646-962-1607  
   
  
  
  
  
  
  
  
  
 


Protocol # 1610017688 
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PARTICIPATING SITES  
  
  
 
Uqba Khan, M.D.  
Assistant Professor of Medicine at Weill Cornell Medical School  
Division of Hematology- Oncology  
New York-Presbyterian Brooklyn Methodist Hospital  
263 7th Ave Suite 4H  
Brooklyn, NY 11215  
Email: uqk9001@med.cornell.edu  
  
 
Confidentiality Statement  
  
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM.  
 


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List of Abbreviations  
 
AE  
Adverse Event  
CFR  
Code of Federal Regulations  
CRF  
Case Report Form  
CTSC  
Clinical Translational Science Center   
DSMB  
Data Safety Monitoring Board  
DSMP  
Data Safety Monitoring Plan  
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
HIPAA  
Health Insurance Portability and Accountability Act of 1996  
HRBFA  
Human Research Billing Analysis Form  
HUD  
Humanitarian Use Device   
ICF  
Informed Consent Form  
IDE  
Investigational Device Exemption   
IND  
Investigational New Drug  
IRB  
Institutional Review Board  
PHI  
Protected Health Information  
PI  
Principal Investigator  
REDCap  
Research Electronic Data Capture  
SAE  
Serious Adverse Event  
SUSAR  
Suspected Unexpected Serious Adverse Reaction   
UAP  
Unanticipated Problem  
WCM  
Weill Cornell Medicine  


Protocol # 1610017688 
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Protocol Summary  
 
Full Title:  
A phase II study of high dose Vitamin C intravenous infusion in 
patients with resectable or metastatic solid tumor malignancies  
Short Title:    
  
  
High dose Vitamin C infusion for solid tumor malignancies  
Clinical Phase:  
  
  
Phase II  
Principal Investigator:   
Manish A. Shah, MD  
Sample Size:  
 
Cohort A = 20 evaluable (max 22);  
 
 
Cohort B = 25 evaluable (max 28)  
 
 
Cohort C = 20 patients (max 28)  
Accrual Ceiling:  
 
This study will enroll at most 78 subjects.    
Study Population:  
 
Adult patients with a solid tumor malignancy who are eligible for 
resection (cohort A), or with extended RAS (e.g. KRAS or NRAS 
mutation) or BRAF mutation with metastatic cancer that have had 
at least 1 line of therapy (cohort B). We will target colorectal 
cancer which is known to have 40-50% rate of extended RAS (e.g. 
KRAS or NRAS) or BRAF mutations, as well as patients with 
other solid tumors that are enriched for extended RAS (e.g. KRAS 
or NRAS) or BRAF mutations including pancreatic cancer and 
lung cancer.   
 
 
Cohort C will include patients with metastatic colorectal cancer 
with a known mutation in extended RAS (e.g KRAS or NRAS) or 
BRAF mutation with liver metastases amenable to 
radioembolization (RAE) therapy.  This will be a dose escalation 
cohort with patients receiving ascorbate at 0.5 g/kg, 0.75 g/kg, 1.0 
g/kg, and 1.25 g/kg dosing.  Treatment will commence the week of 
RAE, with the test dose administered prior to RAE, and the 
treatment dose of VIT C to be administered on the day of RAE.  
VIT C will continue for 1-2 weeks following RAE (for a total of  
up to 3 weeks of therapy).  At the maximal tolerated dose, an 
additional 4 patients will be treated in a dose expansion phase.  
Patients who clinically require a 2Pnd
P Y90 treatment may be eligible 
for the study (Cohort C) again and treated at one dose level below 
the currently enrolling dose level if they have not experienced prior 
DLT with previous protocol therapy. 
Accrual Period:  
 
72 months  


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Study Design:  
 
This is a multicenter, single arm, 3-cohort, open-label trial of high 
dose Vitamin C intravenous infusion in subjects with solid tumor 
malignancies who are eligible for resection (cohort A) or with 
extended RAS (e.g.KRAS or NRAS) or BRAF mutation metastatic 
cancer who have received prior systemic treatment (cohort B). 
Cohort C will involve patients with colorectal cancer having an 
extended RAS or BRAF mutation who are amenable for 
localregional therapy of hepatic metastases with Yttrium-90 
radioembolization.   
Study Duration:  
 Patients in cohort A receive a high dose vitamin C infusion for 4 
days per week for 2-4 consecutive weeks prior to surgery. Patients 
in cohort B receive high dose vitamin C infusion for 4 days per 
week for up to 6 months or disease progression. Cohort C will 
receive high dose vitamin C for 1-3 weeks. During week 1 vitamin 
C infusion and Y90 radioembolization of hepatic metastases will 
occur same day.  Follow up is required for up to 8 weeks after 
enrollment of the study for cohort A and C, and up to 12 months 
after enrollment for cohort B. It is estimated that the study will end 
on 06/30/2023.   
Study Agent:                         Vitamin C (ascorbic acid)  
Intervention Description:  
Vitamin C infusion will be administered intravenously at 1.25 g/kg  
for 4 days per week for 2-4 consecutive weeks (cohort A) or up to  
6 months (cohort B).  Cohort C is a dose escalation cohort 
combining Vitamin C infusion with radioembolization for patients 
with liver metastases. This will be a dose escalation cohort with 
colorectal cancer patients receiving ascorbate at 0.5 g/kg, 0.75 
g/kg, 1.0 g/kg, and 1.25 g/kg dosing.    
Primary Objective:   
Preliminary antitumor activity measured by pathologic response 
based on tumor regression grading in cohort A patients. 3-month 
disease control rate (DCR) will be evaluated using RECIST v 
1.1 in cohort B patients.  
For Cohort C, the primary objective is to determine that maximal 
tolerated dose of the combination of high dose vitamin C with Y90 
radioembolization for patients solid tumor malignancies and liver 
metastases amenable to local-regional therapy.   
Secondary Objectives:  
A. Objective response rate (ORR) and progression-free survival 
(PFS) in cohort B and cohort C.   
B. Assessment of pharmacokinetics of high dose vitamin C  
C. Safety of high dose vitamin C administration using CTCAE 
4.03.  


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Exploratory Objectives:  
a. 
In vitro activity of vitamin C in tumor organoids from 
patients treated with high dose vitamin C  
b. 
Pharmacodynamic and exploratory biomarker samples will 
be collected at the time points specified in the protocol.   
Endpoints:  
  
The primary endpoint for Cohort A will be pathologic response as 
assessed by tumor regression grading. Efficacy will be evaluated 
from CT scans (or similar) using RECIST 1.1 criteria to classify 
objective response for cohort B and cohort C. Other endpoints will 
include progression-free survival (cohort B and C), vitamin C 
concentrations, and other biomarkers of interest.  
 
 
 


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Table of Contents  
1. 
STUDY OBJECTIVES ......................................................................................................... 6  
1.1 
Primary Objectives ......................................................................................................... 6  
1.2 
Secondary Objectives ..................................................................................................... 6  
1.3 
Exploratory Objectives ................................................................................................... 6  
2. 
BACKGROUND ................................................................................................................... 6  
2.1 
Diseases .......................................................................................................................... 6  
2.2 
Investigational Agent …………..................................................................................... 8  
2.3 
Rationale........................................................................................................................ 12  
2.4 
Risk/Benefit Assessment .............................................................................................. 15  
2.5 
Correlative Studies Background.................................................................................... 16  
3. 
SUBJECT SELECTION .................................................................................................... 16  
3.1 
Study Population ......................................................................................................... 16  
3.2 
Inclusion Criteria ......................................................................................................... 17  
3.3 
Exclusion Criteria ........................................................................................................ 18  
4. 
REGISTRATION PROCEDURES .................................................................................... 19  
4.1 
Patient Registration ...................................................................................................... 19 
4.2 
Patient Registration – Part 2  ...................................... ................................................. 20 
5. 
STUDY PROCEDURES .................................................................................................... 20  
5.1 
Schedule of Evaluations ............................................................................................... 21  
5.1.1 
Screening Visit .................................................................................................. 26  
5.1.2 
Treatment Phase ................................................................................................ 26 
5.1.3 
End of Study ...................................................................................................... 27 
5.2 
Treatment Administration ............................................................................................ 28  
5.3 
General Concomitant Medication and Supportive Care Guidelines ............................ 28  
5.4 
Duration of Therapy and Criteria for Removal from Study ......................................... 28  
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................. 29  
7. 
ADVERSE EVENT REPORTING REQUIREMENTS ..................................................... 29  
7.1 
Adverse Event Definition ............................................................................................. 30  
7.1.1 
Investigational Agent or Device Risks .............................................................. 30  
7.1.2 
Adverse Event Characteristics and Related Attributions .................................. 30  
7.1.3 
Recording of Adverse Events ............................................................................ 30  
7.1.4 
Reporting of AE to WCMC IRB ....................................................................... 31  
7.2 
Definition of SAE.......................................................................................................... 31  
7.2.1 
  Reporting of SAE to IRB and DSMB ............................................................... 31  


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7.3 
AE/SAE Follow Up ...................................................................................................... 32  
8. 
PHARMACEUTICAL INFORMATION ........................................................................... 32  
8.1 
Investigational Agent .................................................................................................... 32  
8.2 
Availability ................................................................................................................... 33  
 8.3  Agent Accountability ...................................................................................................... 33  
9. 
LABORATORY CORRELATIVE STUDIES .................................................................... 33  
9.1 
Serum Vitamin C Pharmacokinetics ............................................................................. 33  
9.2 
Clonal Hematopoeisis ................................................................................................... 34 
9.3 
Gene Expression Profiling  ........................................................................................... 35 
 
10. MEASUREMENT OF EFFECT.......................................................................................... 35  
10.1 Response Criteria .......................................................................................................... 35  
10.2 Duration of Response (modify as necessary)................................................................. 36  
10.1.1 
Progression-Free Survival (if applicable) .......................................................... 36  
11. DATA REPORTING / REGULATORY CONSIDERATIONS ......................................... 37  
11.1 Data Collection ............................................................................................................. 37  
11.1.1 
REDCap ............................................................................................................. 37  
11.2 Regulatory Considerations ............................................................................................ 37  
12. STATISTICAL CONSIDERATIONS................................................................................. 37  
12.1 Study Design/Endpoints................................................................................................. 37  
12.2 Sample Size/Accrual Rate.............................................................................................. 39  
12.3    Analysis of Secondary Endpoints ................................................................................. 40  
12.4    Reporting and Exclusions ............................................................................................. 40  
12.1.1 
Evaluation of toxicity   ....................................................................................... 40  
12.1.2 
Evaluation of response   ..................................................................................... 40  
13. 
DATA AND SAFETY MONITORING PLAN (DSMP) ................................................ 41  
  
13.1 DSMB Reporting …………………………………………………………………..41  
APPENDIX A …………………………………………………………………………………...42  
APPENDIX B …………………………………………………………………………………...43  
APPENDIX C …………………………………………………………………………………...44  
REFERENCES ............................................................................................................................ 45   
  
  
 
 


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1.  
Study Objectives  
  
  
The objective of the study is to investigate whether high dose vitamin C infusion leads to 
pathological tumor response in resectable colorectal, pancreatic, and lung cancer (cohort A) or 
objective tumor response in extended RAS (e.g. KRAS or NRAS mutantion) or BRAF mutant 
solid tumors (cohort B).   
  
1.1 Primary Objectives   
  
A. 
To assess preliminary antitumor activity (pathological tumor response) of high 
dose vitamin C infusion, measured by pathologic assessment of tumor cell death and 
fibrotic response in resectable colorectal, pancreatic, and lung cancer in Cohort A.  
B. 
To assess disease control rate (DCR) at 3 months as measured from CT scans 
using RECIST v 1.1 in metastatic colon, pancreatic, and lung cancer (Cohort B). 
Disease control is defined as complete tumor response, partial tumor response or 
stable disease at 3 months.  
C. 
To determine the maximal tolerated dose of high dose vitamin C in combination 
with Y90 radioembolization in patients with RAS or BRAF mutant metastatic cancer.   
  
 
1.2 Secondary Objectives  
  
  
A. To evaluate the objective response rate (ORR) and progression-free survival (PFS) 
in cohort B and cohort C.   
B. To evaluate pharmacokinetics of high dose Vitamin C.   
C. To evaluate safety of high dose vitamin C administration using CTCAE 4.03.  
  
1.3 Exploratory Objectives  
  
  
  
  
  
A. 
To examine the in vitro activity of vitamin C in tumor organoids from cohort A 
patients. Correlation of GLUT1 protein expression and baseline FDG uptake with 
pathologic (cohort A) or objective response (cohort B);  
B. 
Pharmacodynamic and exploratory biomarker samples will be collected at the 
time points specified in the protocol.   
  
2.  
Background  
  
2.1 Diseases   
  
Colon cancer  
In 2015, a total of 132,700 new cases of colorectal cancer are expected to be diagnosed in 
the United States accounting for about 8% of all new cancer diagnoses. In this same year 


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49,700 patients will die of metastatic colorectal cancers (mCRC), which will contribute to 
8.4% of all cancer related mortality [1].  Activating KRAS and BRAF mutations are found 
in approximately 40% and 10% of human colorectal cancers (CRCs), respectively [2].  
BRAF is directly downstream of KRAS, and both activate the mitogen-activated protein 
kinase (MAPK) pathway [3]. Clinical studies indicate that activating mutations in KRAS 
and BRAF predict resistance to and lack of survival benefit from epidermal growth factor 
receptor (EGFR)–targeting agents [4-7]. Bevacizumab, a recombinant humanized IgG-1 
antibody against soluble VEGF-A, moderately improved overall survival (OS) when 
added to chemotherapy regimen FOLFOX4 (12.9 mo compared with 10.8 mo for the 
group treated with FOLFOX4 alone (hazard ratio for death 0.75) [8]. BRAF mutation is an 
independent prognostic factor for decreased survival [7, 9]. However, the BRAF inhibitor 
vemurafenib failed to confer response in previously treated CRCs carrying BRAF 
mutation, likely due to reactivation of EGFR pathway [10-12]. Furthermore, the 
combination of a BRAF inhibitor dabrafenib and MEK inhibitor trametinib led to 2% 
complete response and 12% partial response in a study of 43 BRAF V600-mutant patients 
[13]. Thus, novel therapies for KRAS or BRAF mutant CRCs are urgently needed.   
  
Most relapse of colon cancer occurs in the first 2 years after curative resection [14]. 
KRAS exon 2 mutations are independent predictors of shorter time to recurrence (TTR) in 
patients with resected stage III distal colon cancers receiving adjuvant therapy [15].   
  
Pancreatic cancer  
Pancreatic adenocarcinoma remains one of the most devastating solid tumor malignancies 
with a median survival measured in months and 5-year survival rate of less than 6%. It is 
the fourth leading cause of cancer-related death in Europe and the United States. Most 
pancreatic cancers are diagnosed at late stage, and only 15–20% of patients are eligible for 
upfront radical surgery. Despite adjuvant treatment with chemotherapy or chemoradiation, 
recurrent rate is still high. For example, the CONKO-001 randomized trial reported rates 
of 5-year disease-free survival were 16.6% vs. 14.3%, and median disease-free survival of 
13.4 months vs. 6.7 months in the gemcitabine treatment group compared with the 
observation group [16]. In metastatic pancreatic cancer, few regimens significantly 
improved overall survival compared to traditional single agent gemcitabine.  The median 
overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 
months in the gemcitabine group [17]. The recently FDA-approved nabpaclitaxel 
improved median survival from 6.7 to 8.5 months when added to gemcitabine in newly 
diagnosed metastatic patients [18]. Genomic analyses of pancreatic cancer revealed a 
complex mutational landscape with four common oncogenic events in wellknown cancer 
genes (KRAS, TP53, SMAD4 and CDKN2A), with KRAS mutations found in 92% of 456 
cases studied [19].       
  
Lung cancer  
Approximately 30% of lung adenocarcinoma harbor KRAS mutations, however it is rare 
in sqauamous lung cancer [20-22]. KRAS and EGFR mutations are mutually exclusive, 
and KRAS mutations has been proposed as a negative predictor of efficacy from EGFR 


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inhibitor erlotinib [23]. A maintenance basket trial demonstrated patients with EGFR 
mutation who were treated with erlotinib had longer median survival than patients with 
KRAS mutation who were treated with MEK inhibitor selumetinib (3.5 vs 2.3 years), 
following initial platinum doublet chemotherapy [24]. Thus, there is an unmet need to 
develop KRAS mutation-specific therapy.   
   
2.2 Investigational Agent    
  
Ascorbate (vitamin C) is formed in the course of the uronic pathway starting from 
UDP-glucuronate in animals, and its synthesis can be considered as an integral part of 
carbohydrate metabolism [25]. Humans lack the enzyme gulonolactone oxidase 
(GLO) which catalyses the last enzymic step in ascorbate synthesis, thus are unable to 
produce endogenous ascorbate [26]. Ascorbate plays a crucial role in various 
hydroxylation reactions [27]. At low ascorbate concentrations, ascorbate is prone to 
be a pro-oxidant, and at high concentrations, it will tend to be an antioxidant [28]. 
Since the 1950s, ascorbate has been proposed to have anticancer effects, although 
evidence for improved response rates or survival outcomes has been lacking [29]. It is 
postulated that generation of intracellular hydrogen peroxide H2O2 is responsible for 
preferential toxicity to tumor cells [30, 31] (Fig. 1).    
  
The failure of earlier studies to observe anti-tumor activity might be due to 
insufficient dosing to maintain tumor cytotoxic plasma concentrations of ascorbic 
acid [32]. Extracellular concentrations as low 100-200 μM are toxic to some cell 
lines, but many types of malignant cells are killed only at concentrations approaching 
the mM range (Fig. 2). Plasma vitamin C concentrations that are cytotoxic to cancer 
cells in vitro can be achieved clinically by intravenous (but not oral) administration of 
ascorbate. [33].   
  


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Fig. 1:  Dose response of human colon fibroblast CCD-18 and human colon carcinoma cell line [32].  
  
  
Fig. 2: Cytotoxic effects of pharmacological vitamin C concentrations in normal and tumor cells 
[33].  
  
In a recent Phase I trial by Stephenson et al. in 2013, ascorbic acid was administered at 1 g/min 
for 4 consecutive days/week for 4 consecutive weeks [34]. They found maximum serum 
concentration (Cmax) correlates with area under the curve (AUC) well, and a dose of 50 g/m2 
was able to achieve Cmax of 33 mM. Both 70 g/m2 and 90 g/m2 dose achieved Cmax of 49 


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mM, thus a dose higher than 70 g/m2 does not seem to increase Cmax further (Fig. 3). In 
addition, in each of the 3 highest dose groups (70  90  110 g/m2), plasma vitamin C levels 
were maintained between 10 and 20 mM for 5 to 6 hours. The infusion was generally well 
tolerated. Treatment-related nausea and headache (grade 1-2) were common in all cohorts. Dose 
limiting toxicity was hypernatremia and hypokalemia observed at 90 g/m2 and above. Other 
reported adverse events were hypertension, insomnia, abnormal urine color, loss of appetite, 
fatigue, chills, and hyperglycemia. Among 16 patients who completed study, there was no 
objective tumor response. Three patients had stable disease, while 13 had progressive disease. Of 
note, in a patient of 70 kg, dose of 70 g/m2 is equivalent to approximately 1.8 g/kg which is less 
than the 4 g/kg twice a day IP dosing used in the animal study described below [35].   
  
In the preclinical study reported by Yun et al, 4 g/kg twice a day IP dosing achieved a Cmax of 
32 mM at 10 min in xenograft mice with KRAS mutant colon cancer [35]. Treatment of at least 
2 weeks was required to achieve at least 30% reduction of tumor volume compared to placebo 
group, with maximum reduction (approximately 50%) achieved at 3-4 weeks. Thus, it is 
reasonable to use 50 or 70 g/m2 for 4 consecutive days/week dosing, and a 4 week infusion 
schedule as described by Stephenson et al. to reach therapeutic concentration and maximize 
tumor response.  In support of this, a Cmax of 26 mM was achieved by infusing 3 days a week 
even when the highest dose of 1.5 g/kg (approximately 56 g/m2) per infusion was given, as 
described by Hoffer et al. [36].  
  
  
Fig. 3: Cmax and AUC values versus ascorbic acid dose [34].    
  
A dose-escalating phase I study examined safety of combining Vitamin C with standard, fixed 
dose gemcitabine and erlotinib in previously untreated metastatic pancreatic patients [37]. 
Fourteen subjects received an 8 week cycle of intravenous ascorbic acid (three infusions per 
week, at doses of 50, 75, or 100 g per infusion). The treatment was well tolerated, and of the 23 
total adverse events (8 being serious adverse events), most were likely attributable to progression 
of disease or concomitant treatment with gemcitabine and/or erlotinib. Plasma ascorbic levels 
were between 25.3 and 31.9 mM in patients who received 100 g per Vitamin C infusion. Among 


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9 patients who completed protocol treatment, 7 had stable disease and 2 had progressive disease 
per RECIST 1.0 criteria.   
  
Based on these studies, we plan to treat patients with an initial test dose of 10 g vitamin C 
infusion on week 1 day 1, followed by daily 1.25 g/kg vitamin C infusion for week 1, days 2-4 
and 4 days out of 5 weekdays in subsequent weeks, as long as no toxicities of grade 3 or higher 
occur. We favor this dosing regimen as it will achieve Cmax of approximately 40-50 mM and 
level above therapeutic concentration of above 10 mM for approximately 3-4 hours in a typical 
patient with very low likelihood of causing grade 3 or 4 toxicity based on the Stephenson[34], 
Hoffer [36], and Monti [37] phase I trials where responses were seen. Infusions will be given on 
a 4 times per week schedule for 2-4 weeks in cohort A to allow resection of primary tumor or 
recurrent/metastatic tumor as clinically indicated, and assess pathological response; or until 
toxicity or disease progression. In cohort B weekly infusions will be continued for up to 6 
months to assess objective response and PFS. Infusions will be halted for toxicity of disease 
progression. The study drug vitamin C, will be provided by Bioniche Pharma USA as Ascorbic 
Acid, Injection, USP.  
  
Although most studies of high dose Vitamin C infusion showed favorable safety data, rare severe 
adverse events of hemorrhage, hemolysis have been reported [38], thus this study will exclude 
patients with known G6PD deficiency who are at higher risk of developing severe hemolysis.    


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2.3 Rationale  
  
Recently, Yun et al demonstrated that cultured human CRC cells harboring KRAS or BRAF 
mutations are selectively killed when exposed to high levels of vitamin C [35]. This effect is 
due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the  
GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular 
DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species 
accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Fig. 4). 
Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic 
crisis and cell death not seen in KRAS and BRAF wild-type cells. Furthermore, high-dose 
vitamin C impairs tumor growth in Apc/KrasPG12D
P mutant mice. These findings suggest 
highdose vitamin C infusion may have anti-tumor activity in KRAS or BRAF mutant colon 
cancer patients.   
  
In cohort A (pre-operative therapy), we will enroll patients with a high likelihood of extended 
RAS (e.g. KRAS or NRAS) or BRAF mutations(eg pancreas, colon, and nonsquamous lung 
cancer).  Patients in this cohort will start treatment with vitamin C prior to the mutation status 
being known (given the ~10-14 day turnaround time for extended RAS (e.g. KRAS or 
NRAS) or BRAF mutation testing), and we will estimate the effect of high dose vitamin C in 
all patients. Outcome differences between KRAS and BRAF mutated cancers and wild-types 
will be important secondary analyses.  
  
In cohort B (salvage therapy for metastatic disease), patients will be pre-screened for 
extended RAS (e.g. KRAS or NRAS) or BRAF mutation status, and those patients with 
mutations will be eligible.  
  


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Fig. 4: Vitamin C–induced ROS inhibits GAPDH by cysteine S-glutathionylation and depletion 
of NAD+ [35].  
  
2.3.1 March 2019 Update  
Preliminary data of of RNA Seq analysis and metabolomics suggest that high dose vitamin C is 
demonstrating evidence of increased DNA damage and ROS increases, with compensatory 
activation of DNA repair and ROS regulation cellular pathways.    
Specifically, 10 patients have enrolled on cohort B. Overall the treatment was well tolerated, and 
the first 6 patients were able to enroll and receive treatment without experiencing dose limiting 
toxicity.  This prompted opening cohort A in June 2018.  Thus far, a total of 10 patients have 
enrolled on cohort B and 3 patients in cohort A.    
  


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Metabolomics and RNA Analysis  
At the cellular level, ascorbate has two forms: reduced form of ascorbate and oxidized form of 
dehydroascorbate (DHA). Tumor cells uptake ascorbate by sodium vitamin C cotransporters 
(SVCTs) via ascorbate form or by glucose transporters (GLUTs) via DHA form. Recent studies 
have shown that Kras mutant human colorectal cancers (CRC) cells up-regulate GLUT1 
expression. Mice studies have shown that ascorbate has a selective accumulation effect on CRC 
cells with Kras mutation, which is known to be mostly refractory to approved targeted therapies.  
  
By use of LC-MS, we found that both ascorbate and DHA accumulate in the Kras-mutated colon 
tumors after patients treated with intravenous ascorbate. DHA seems to be a better marker to assess 
the ascorbate treatment under our conditions. The high levels of threonate, tartarate and other 
degradation products of DHA further demonstrated the uptake of ascorbate/DHA by the 
Krasmutated tumors.  
  
Intracellular DHA is reduced back to ascorbate at the expense of reduced glutathione (GSH) and 
NADPH. Increased DHA uptake causes ROS accumulated and oxidative stress due to the depletion 
of cellular GSH. The DNA damage induced by ROS activates Poly (ADP-ribose) polymerase, 
which, in turn, decreases NAD+ levels. The low NAD+ level decreases GAPDH activity. Then 
glycolysis is inhibited in cells that are highly dependent on energy, leading to an energy crisis and 
cell death. With ascorbate treatment, there is no obviously difference of ATP level observed 
although glycolysis decreases. Some potential oxidative stress biomarkers, such as uric acid, 
ADPribose, and 8-oxoGuo/8-oxoGuo, have been found to increase following ascorbate treatment. 
The pentose phosphate pathway (PPP) metabolite accumulation indicates PPP flux increase, which 
leads to NADPH formation. The increased flux is to restore cytosolic NADPH back to mitigate 
oxidative stress. Interestingly, the level of GSH does not decrease, while the level of its oxidized 
form, glutathione disulfide (GSSG) decreases with ascorbate treatment, which indicates that 
NADPH formed impair the potential oxidative stress.   
  
The level of 2-hydroxyglutarte increases to 2.7-fold following ascorbate treatment, which might 
be related to the changes of phospholipid in the tumor.  
  
Ascorbate treatment also induces other changes in the tumor metabolome, such as polyamine, 
proline, sulfur containing amino acid, branched chain amino acids, aromatic amino acids and 
carnitine.  
  
Additionally, we found evidence of activation of pathways involving ROS handling and DNA 
damage repair.  Specifically, in 6 matched pre- and post- tumor biopsies for whom RNA 
sequencing has been completed, 92 / 123 pathways involving ROS handling were significantly 
upregulated by gene set enrichment analysis.  Similarly, 43/49 pathways involved in oxidative 
stress were also significantly upregulated, as well as 84/ 102 pathways involved in DNA repair.    
  
  


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Rationale for Cohort C  
These data cumulatively suggest that high dose ascorbate is entering the cell and leading to 
increased ROS and resultant DNA damage, but that the cancer cells have upregulated 
compensatory mechanisms to handle this additional stress.  This suggests that adding another direct 
cytotoxic insult to high dose ascorbate treated tissues may have significantly greater activity.  In 
Sept 2018, Alexander and colleagues published their initial report of the safety of high dose 
ascorbate in combination with radiation for pancreatic cancer, in combination with 
gemcitabine[39].  In this study, patients with locally advanced or metastatic pancreatic cancer 
received weekly gemcitabine, along with standard radiation to 50.4 Gy in standard fractionation 
or 50 Gy by intensity modulated RT (IMRT), along with high dose ascorbate given in escalating 
doses (50 g  75 g  100 g) daily during radiation.  This study found that 75 g ascorbate given 
intravenously daily during radiotherapy and weekly gemcitabine was safe and tolerable. There was 
preliminary evidence of improved efficacy as well, with median overall survival of 21.7 months, 
which compared favorably to a similar historical control population[39].   
  
Recent PK analysis demonstrates that Vitamin C is no longer measurable in the serum after 24 
hours from injection.  We therefore believe that we can greatly increase the synergy between 
Y90 therapy and high dose vitamin C by concurrent administration. For this reason, the study 
schema for Cohort C has been updated to allow Vitamin C to be administered same-day, prior 
to or within 24 hours of a Y90 treatment by an expansion of the phase I study.   
 
Additionally, it is apparent that Y90 therapy is now commonly performed with super-selective 
Y90 delivery to the specific tumor being treated.  This limits toxicity and allows for an 
ablative dose to be delivered safely to the target lesion.  For this reason, patients may require a 
2Pnd
P Y90 therapy to target remaining hepatic metastases. Subjects who clinically require an 
additional Y90 treatment may be eligible for second treatment with high dose Vitamin C after 
reconsideration of eligibility for Cohort C.  During the dose escalation phase, eligible patients 
will be treated at one dose level below the currently enrolling dose level if they have not 
experienced prior DLT with previous protocol therapy.  
 
2.4 Risk/Benefit Assessment   
  
  
This is a Phase II study to study the effect of vitamin C in patients with solid tumor 
malignancies.  The preclinical data suggest that the activity of vitamin C is specific for 
tumors that harbor the prevalent KRAS or BRAF cancer mutation so we will preferentially 
treat such tumors (e.g. pancreas, colon, and lung cancer).  The pre-operative setting is chosen 
because it offers an opportunity to obtain tissue following a short course of medical therapy 
to specifically identify the effect of that therapy on the tumor.  The risk to subjects is minimal 
as there is often a 3-4 week time period from initial evaluation to resection and thus the trial 
will not extend the time to surgery.  For cohort B, the risks are also minimal.  There are no 
standard therapies for KRAS or BRAF mutant colon, pancreas, or lung cancers.  We will 
monitor for efficacy and toxicity closely.  Patients who are not benefiting from therapy may 
go on to receive other palliative therapy for their disease, as appropriate.  Risks of large doses 


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of vitamin C are rare, and include electrolyte changes (hypokalemia, hypernatremia), 
headaches, nausea, hypertension, insomnia, abnormal urine color, loss of appetite, fatigue, 
chills, and hyperglycemia.  For Cohort C, high dose vitamin C has not previously been 
administered to patients who also receive Yttrium-90 radioembolisation for liver metastases.  
However, high dose vitamin C has been previously safely been given to patients receiving 
external beam radiation to primary pancreatic tumors.  We believe the risks of combining 
vitamin C with radioembolization are minimal, but will carefully examine the safety and 
tolerability of this combination in a standard dose escalation phase I cohort design.  The 
starting dose of Vitamin C will be 0.5 g/kg given 3-4 x/week for 1week prior to and 
following standard dose Y-90 radioembolization.  
  
Malignancies with KRAS or BRAF mutations tend to be more aggressive and offer a worse 
prognosis than wild-type tumors. Therefore, there may a benefit if we can demonstrate 
antitumor activity with vitamin C therapy.    
  
2.5 Correlative Studies Background  
     
1. Yun and colleagues showed that the oxidized form of vitamin C (dehydroascorbic 
acid (DHA)) is shuttled intracellularly via GLUT1 in KRAS or BRAF mutated 
colorectal cancer (CRC) cell lines and mouse models which resulted in growth 
inhibition and cell death [35]. We expect higher baseline tumor GLUT1 protein 
expression predict tumor response to Vitamin C infusion.     
  
2. In a preclinical study, AMP-activated protein kinase (AMPK) was activated within 1 
hour of Vitamin C treatment, suggesting Vitamin C infusion exerts anti-tumor effect 
by inhibiting glycolysis and depleting ATP [35]. We plan to assess tumor energy 
stress by measuring ROS level or phosphor-AMPK IHC in resected tumor samples 
from cohort A patients.  
  
3. We will examine tissue specimens for molecular and metabolic changes associated 
with vitamin C use. This will include RNA sequencing (both bulk and single cell 
RNA sequencing depending on tissue availability), and whole exome sequencing.  
Additionally, we will grow organoids from tissue specimens and treat with vitamin C 
in vitro.    
 
4. Patients with solid tumors demonstrate elevated rates of clonal hematopoiesis (CH) 
thus placing them at elevated risk of subsequent cardiovascular disease and 
hematologic cancer[40, 41]. Thus, development of a management strategy to mitigate 
this risk represents an important unmet need. Environmental stimuli can impact the 
expansion, attrition, and disease impact of CH clones including high glucose, 
metformin, and vitamin C. Our objective is therefore to assess the impact of high dose 
vitamin C on existing CH clones in cancer patients under study. We will isolate 
peripheral blood and buccal swabs from patients. Genomic DNA will be isolated and 


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we will perform DNA and RNA sequencing to detect and characterize clonal 
hematopoiesis.  
 
  
 
3.  
Subject Selection  
  
3.1 Study Population  
  
Adult patients with solid tumor malignancy who are eligible for resection and meet 
the inclusion and exclusion criteria will be considered for participation in cohort A. 
Patients with metastatic tumors who meet the inclusion and exclusion criteria will be 
eligible for participation in cohort B. Patients eligible for cohort C will be patients 
with colorectal cancer with hepatic metastases amenable to Y90 radioembolization.  
  
3.2 Inclusion Criteria  
  
1. Male or female ≥ 18 years of age.  
  
2. Patients with histologically proven early stage or locally advanced colorectal 
adenocarcinoma, lung cancer or pancreatic cancer, who are eligible for resection 
(cohort A).  
  
3. Patients with inoperable, metastatic extended RAS (e.g. KRAS or NRAS) or BRAF 
mutant colorectal adenocarcinoma,lung cancer and pancreatic cancer, or other solid 
tumor, who have received at least 1 line of treatment for metastatic disease (cohort 
B).   
  
  Note: If subject refuses chemotherapy and therefore has no prior chemotherapy, they 
can be eligible for the trial with approval from the primary investigator.   
  
3.1 Patients with metastatic cancer with an extended RAS (e.g. KRAS or NRAS) or 
BRAF mutation with liver metastases amenable to Y90 radioembolization (cohort C).   
  
4. ECOG performance status 0-1.  
  
5. Life expectancy of at least 6 months.  
  
6. All women of child-bearing potential and all sexually active male patients must 
agree to use effective contraception.  
  
7. Patient with adequate organ and marrow function as follows:  


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• 
ANC ≥ 1000 mm3,   
• 
Platelets ≥ 100,000/mm3   
• 
Hemoglobin ≥ 9 g/dL,  
• 
Serum creatinine ≤1.8 mg/dL or creatinine clearance > 50 mL/min (Appendix  
C: Estimating Creatinine Clearance)   o Note: Patients with a serum 
creatinine > 1.8 mg/dl will be excluded. For patients with a serum 
creatinine less than 1.8 mg/dl, an estimated calculated GFR of > 50 
ml/min will be required.   
• 
bilirubin ≤ 1.5 x ULN mg/dL  o note: patients with Gilbert Syndrome must 
have a serum bilirubin      
 < 3.0 x ULN  
• 
Alanine aminotransferase (ALT), aspartate transaminase (AST) ≤ 2.5 times the 
upper limit of normal if no liver involvement or ≤ 5 times the upper limit of 
normal with liver metastases.  
  
8. Patients with serum electrolytes (including calcium, magnesium, phosphorous, 
sodium and potassium) within normal limits (supplementation to maintain normal 
electrolytes is allowed).  
  
9. Patients taking Vitamin C will have stopped taking oral vitamin C more than 1 
week before planned study treatment.   
 
10. 
Patients capable of understanding and complying with the protocol and who 
have signed the informed consent document.  
  
3.3 Exclusion Criteria   
    
  
1. Patients with uncontrolled intercurrent illness including, but not limited to 
uncontrolled infection, symptomatic congestive heart failure (NYHA class III and 
IV), uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements (Appendix B: New York Heart 
Association (NYHA) Classifications).  
  
2. Patients with active heart disease including myocardial infarction within previous 
3 months, symptomatic coronary artery disease, arrhythmias not controlled by 
medication, unstable angina pectoris, or uncontrolled congestive heart failure 
(NYHA class III and IV) (Appendix B: New York Heart Association (NYHA) 
Classifications).  
  
3. Patients who have received systemic chemotherapy or targeted therapy for 
metastatic disease within 2 weeks from start of study drug treatment (cohort B).   
  


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4. Patients who have received an investigational drug within 21 days of the first dose 
of study drug.  
  
5. Patient who have not recovered to grade ≤ 1 from adverse events (AEs) due to 
investigational drugs or other medications, which were administered more than 4 
weeks prior to the first dose of study drug.  
  
6. Patients who are pregnant or lactating.  
  
7. Patients who are known to be positive for the human immunodeficiency virus 
(HIV). The effect of Vitamin C on HIV medications is unknown. Note: HIV 
testing is not required for eligibility, but if performed previously and was positive, 
the patient is ineligible for the study.  
  
8. Patients who have the inability or unwillingness to abide by the study protocol or 
cooperate fully with the investigator or designee.  
  
9. Patient who are receiving drugs which are known to interact with Vitamin C, 
potential risk and eligibility will be evaluated individually by the investigator.   a. 
Most of the known interactions with vitamin C are from oral use and acidification 
of the stomach lining.  There are few known interactions with high dose 
intravenous vitamin C.  We recommend not using deferoxamine as there may be 
an association with ventricular dysfunction (unknown mechanism).   
  
10. Patients who have uncontrolled or severe hyponatremia, hypernatremia, SIADH, 
hypokalemia, hyperkalemia, hypomagnesemia, or hypermagnesemia  
  
11. Patients who have uncontrolled or severe coagulopathies or a history of clinically 
significant bleeding within the past 6 months, such as hemoptysis, epistaxis, 
hematochezia, hematuria, or gastrointestinal bleeding.   
  
12. Patients who require therapeutic doses of warfarin is prohibited.    
  
13. Patients who have uncontrolled seizure disorder, ascites, iron overload, edema, or 
dehydration.   
  
14. Patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, 
hereditary spherocytosis, or other conditions predisposing patient to hemolysis.   
  
15. Patients who have a known history of recurrent oxalate renal calculi or multiple      
 
oxalate.  
  


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4.  
Registration Procedures   
  
4.1 Patient Registration – Part 1  
  
 Patients will be centrally registered with the Office of Billing Compliance. To 
register a patient, submit the following documents via the JIRA Registration Process:   
• 
Legible copy of the HRBAF  
• 
First and last page of signed informed consent form   
  
 Registration must be completed within 24 hours of the signing of informed consent.   
  
4.2 Patient Registration – Part 2   
  
Study participants will be centrally registered with the Weill Cornell Medicine Joint Clinical 
Trials Office (JCTO).  To register a new study subject, email the following documents to 
UJCTOIIT@med.cornell.eduU :  
  
• 
Completed WCM subject registration form  
• 
First and last page of the fully executed informed consent form, plus additional pages 
if checkboxes for correlative studies are required  
• 
Fully executed HIPAA research authorization form  
• 
Eligibility checklist signed and dated by investigator and research nurse  
• 
Documentation of any eligibility waivers granted   
• 
Source documentation to verify eligibility   
  
Note that attachments larger than 4.5 MB are not accepted, so larger attachments should be 
split into more than one email. Central registration information is reviewed and entered into 
the REDCap database.    
  
 
5.  
Study Procedures  
  
This section is a visit-by-visit listing of all the procedures that will take place at each visit. 
If the study will have multiple procedures in one day (e.g. blood draws for a PK study) 
then the timing of each of these should be included.  
  
This is a single arm study, all eligible subjects will be given Vitamin C infusion. In cohort 
A, tumor sample from all patients will be tested for extended RAS (e.g. KRAS or NRAS),  
BRAF mutations, but all eligible patients will start study drug treatment before test result 
is available. For cohort A, tissue specimens will collected from an optional screening 
biopsy (screening biopsy is not mandatory, but highly encouraged) .and from the on study 
surgical resection.  For cohort B patients a separate tissue biopsy will be required at 
screening and between weeks 3 and 6. This is to confirm extended RAS (e.g. KRAS or 


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NRAS) or BRAF mutational status and collection of tissue for correlative studies. For 
Cohort C patients, biopsies will be collected at screening and at approximately 6-8 weeks,  
and will be examined for evidence of increased oxidative stress (eg. RNASeq, 
metabolomics, and Organoid development if not already performed).   
  
March 2021 Update: 
Cohort C patients will receive vitamin C infusion and Yttrium-90 (Y90) during week 1 of 
therapy and again for 1-2 weeks following Y90 therapy, with a single dose of Vitamin C 
administered on the day of Y90 therapy, just prior to Y90 therapy, or within 24 hours of 
Y90 therapy.   
 
Previously treated subjects from Cohort C, may be considered to participate in additional 
treatment if they have not experienced prior DLT with previous protocol therapy. Once 
eligibility is confirmed, subjects will be treated at one dose level below the currently 
enrolling dose level in the dose escalation phase.  
 
Y-90 radioembolization is the selective internal radiation therapy of liver tumors utilizing 
SIR-Spheres Y-90 resin microspheres, which were approved by the FDA in 2002. SIR-
Spheres Y-90 resin microspheres are microscopic resin beads that contain the radioactive 
isotope yttrium-90 (Y-90) which emits beta radiation. Due to their small size (average 
size 32.5 microns) and similar specific gravity to blood cells, the microspheres travel 
easily through the hepatic artery. The radioactive microspheres become lodged in the 
tumor microvasculature. Selective Internal Radiation Therapy (SIRT) with SIR-Spheres 
Y-90 resin microspheres is considered a safe and effective method of using radiation to 
treat colorectal liver metastases and are often used in conjunction with chemotherapy. 
SIRSpheres Y-90 resin microspheres are currently being offered at more than 1,230 
medical centers around the world, including more than 300 centers in the U.S. Over 
92,000 doses of SIR-Spheres Y-90 resin microspheres have been supplied worldwide.  
  
Vitamin C protocol will allow for the use of samples collected through the biobank 
protocol #090810582 "Weill Cornell Digestive Disease Registry" PI: Manish Shah and 
the protocol # 1305013903 “Research for Precision Medicine” PI: Cora Sternberg, M.D  
  
5.1 Schedule of Evaluations  
  
After initial screening, patients will receive the agent infusion in four days per week (no  
more than 2 consecutive days of infusion)). Weekly blood testing will be performed once per 
week. Cohort A patients will receive infusions on weeks 1-4 or until surgery (minimum 2 weeks 
of vitamin C (8 infusions) are required to consider the patient evaluable). Cohort B patients will 
receive infusions for up to 6 months or until disease progression. On Day 1 of week 2 (Preferred; 
Day 1 or Day 3 of weeks 2 to 5 is also allowed) patients will remain in the clinic for up to 12 
hours for vitamin C pharmacokinetic study. Patients need to receive at least 1 week (4 full doses, 
the test dose is not accounted) of Vit C to be considered evaluable.    


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For Cohort C, the vitamin C dose will be escalated in successive cohorts.  Specifically, the first 3 
patients were enrolled at a dose of 0.5 g/kg intravenously for 4 days /week for 1-2 weeks prior to 
and following Y90 therapy for a total of 4 weeks of vitamin C.  No dose limiting toxicities were 
identified. The next group of 3 patients received a dose of 0.75 g/kg intravenously for 4 days/ 
week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C.  
Subsequent dose escalations will  involve including a single dose of Vitamin C on the day of Y90, 
administered prior to or within 24 hours of a Y90 treatment, as well as continued dose escalation 
to 1 g/kg and 1.25 g/kg intravenously (Dose levels 3-6).  Patients will not be treated at a dose 
higher than 1.25 g/kg. Dose limiting toxicity will be defined as any grade 3-4 adverse event 
possibly, probably, or definitely attributed to vitamin C therapy in the 21 days of protocol therapy. 
In any group of 3 patients, if one patient experiences dose limiting toxicity, the group will be 
expanded by 3 additional patients (eg. 6 for that group).  If, at any dose level, 2 or more patients 
experience a dose limiting toxicity, the maximal tolerated dose will be reached, and further dose 
escalation will not be pursued.  The dose level may then be expanded up to 10 additional patients 
to confirm the safety and toxicity at that dose level.   Additional dose levels may be included 
depending on toxicity observed. Patients who require additional Y90 treatment, clinically, may be 
considered for second treatment at the currently enrolling dose level if they have not experienced 
prior DLT with previous protocol therapy. Cohort C Dose levels are as follows: 
 
Dose level 
Vit C dose per infusion 
(weekly monotherapy) 
Vit C dose on 
Day of Y90 Rx 
Dose level 1 
0.5 g/kg 
0 
Dose level 2 
0.75 g/kg 
0 
Dose level 3 
0.75 g/kg 
0.5 g/kg 
Dose level 4 
1.0 g/kg 
0.5 g/kg 
Dose level 5 
1.0 g/kg 
0.75 g/kg 
Dose level 6 
1.25 g/kg 
0.75 g/kg 
January 2020 update:  Dose level 1 has enrolled without dose limiting toxicity, and patients are 
currently being treated at dose level 2, also without dose limiting toxicity thus far.  
March 2021 update:  Subjects are currently being treated at dose level 4. 
 
March 2022 update: Beginning with Dose level 5, we stopped administering Vitamin C in Weeks 1 
and 2, prior to Y90 treatment.  Additionally, we have not observed any dose limiting toxicity through 
dose level 6.  As a result, we will continue our dose escalation with dose levels 7 and 8, as per the table 
below.  We will also plan to treat up to 4 additional patients at the maximal tolerated dose, so the total 
accrual for Cohort C will remain 28 evaluable patients.  
 
Dose level 
Vit C wk 2-3 
Day of Y90 Rx 
Dose level 5 
1.0 g/kg 
0.75 g/kg 
Dose level 6 
1.25 g/kg 
0.75 g/kg 
Dose level 7 
1.25 g/kg 
1.0 g/kg 
Dose level 8 
1.25 g/kg 
1.25 g/kg 
 
 
 


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Table 1. Schedule of Evaluations (Cohort A)   
  
Screening  
Wk1Pa
P  
Wk2Pa
P  
Wk3Pa
P  
Wk4Pa
P  
Wk5  
End of  StudyPh
P  
  
Day -28 to -1  
  
  
  
  
SurgeryPi
P  
Wk 4-16  
  
UAgent AdministrationU   
  
  
  
X  
  
X  
  
X  
  
X  
  
  
  
  
Informed consent 
X 
 
 
 
 
 
  
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Concurrent medication 
X 
X 
X 
X 
X 
 
X 
Eligibility Criteria 
X 
 
 
 
 
 
 
Physical exam with ECOG 
X 
X 
X 
X 
X 
 
X 
Vital signs Pb 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
CBC w/diff 
X 
X 
XPg 
X 
X 
 
X 
Serum chemistry Pc 
X 
X 
XPg 
X 
X 
 
X 
PT/PTT 
X 
 
 
  
  
  
  
EKG 
X 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
 
X 
Fresh Tissue Collection  
X d  
  
  
X d-  
  
PET-CT (with contrast) 
X 
  
  
  
  
  
   
Urinalysis 
X 
  
  
  
  
  
  
G6PD enzyme 
X 
   
   
  
  
  
   
 
Serum Pregnancy Test 
  
X  
   
   
   
   
   
   
Vitamin C pharmacokinetics Pf 
 
 
X 
  
   
  
 
Tumor markers: CEA, CA19-9 
X 
 
 
 
X 
 
X 
a: Agent administered on four days/week, other testing done on day 1   
b: 5-minute sitting blood pressure, pulse, respiratory rate, oral temperature, weight c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, LDH, calcium, magnesium, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
d. Baseline fresh biopsy is highly encouraged, but not mandatory. If not performed, archived tissue is requested. Pathologic review of surgical 
resection. Surgical Resection can occur at any time point between Week 3 and 5.  
e: Women of childbearing potential f: PKs will be collected at Day 1 of Week 2 (Preferred; Day 1 or Day 3 of weeks 2 to 3 is also allowed) the 
following time points: prior to infusion, 1hr post start of infusion, end of infusion, 2hrs, 3hrs, 4hrs, 6hrs, 24hrs post end of infusion  
g. CBC and chemistries can be collected within 3 days of treatment.; 1 day preferred  
h. End of Study assessments are to be completed between week 4 and 16 after surgical resection  
i. Vit C treatment is given for 2-4 weeks. Surgery is to occur as per clinical schedule. 
  
 
 
 
 
 
 


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Table 2. Schedule of Evaluations (Cohort B)   
  
  
  
Screening  
Wk1Pa
P  
Wk2a  Wk3Pa
P  Wk4Pa
P  
Wk5Pa
P  Wk6Pa
P  Wk7-11Pa
P  Wk12Pa
P  Wk13-24Pa
P  
End of Study   
  
Day -28 to -1 
  
  
  
  
  
  
  
  
  
4-8 weeks post  
Vit C 
completion Pk
P  
UAgent AdministrationU  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
Informed consent  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concurrent medication  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Eligibility Criteria  
X  
  
  
  
  
  
  
  
  
  
  
Physical exam with ECOG  
  
X  
  
X  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
Vital signsPb
P  
  
X  
  
X  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
Height  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC w/diff Pe
P  
  
X  
  
X  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
Serum chemistry Pc, e
P  
  
X  
  
X  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
PT/PTT  
X  
  
  
  
  
  
  
  
  
  
  
EKG   
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse event evaluation  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
PET-CT (with contrast)  
XPi
P  
  
  
  
  
  
X  
  
X  
Xh  
  
G6PD enzyme  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis  
X  
  
  
  
  
  
  
  
  
  
  
Serum Pregnancy Test Pd   
XPd
P  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitamin C pharmacokinetics Pf  
  
  
  
  
Xg  
  
  
  
  
  
  
  
  
  
  
  
Tumor markers: CEA, CA19-
9  
  
X  
  
  
  
  
  
  
X  
  
  
X  
  
  
X  
Biopsy Collection  
X  
  
  
  
Xj   
  
  
  
  


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a: Agent administered on three-four days/week, blood work (CBC/ Chemistry) performed once per week  
b: Sitting blood pressure, pulse, respiratory rate, oral temperature, weight  
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, calcium, magnesium, phosphorus, 
potassium, total protein, SGOT[AST], SGPT[ALT], sodium.  
d: Applicable for women of childbearing potential  
e: CBC and chemistries can be collected within 3 days of treatment; 1 day 
preferred.   
f: PKs will be collected at the following time points on Day 1 week 2 prior to infusion, 1hr post start of infusion, end of infusion, 2hrs, 3hrs, 4hrs, 6hrs, 
24hrs post end of infusion.    
g: If PK sample collection is not possible on Week 2, Day 1 , the blood sample should then be collected on day 1 or Day 3 between subsequent weeks 2 to 
5  
h: PET-CT will occur at week 6, 12 and 
24.  
i. Screening PET-CT must be done within 30 days prior to enrollment  
j. On treatment, biopsy can take place between week 3 and week 6.  
k. End of study assessments can be done via telephone call (only adverse event & concurrent medication evaluation will be necessary with a telephone 
assessment.)   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3. Schedule of Evaluations (Cohort C)   
 
 
Screening 
Wk1 
Wk2 
Wk3 
Wk4 
End of Study 
Week 8-16Pi 
 
Day -28 to -1 Day 1 
Y90 Rx 
Day 2 (+2 day 
window) 
 
 
 
Agent AdministrationPa 
 
 
 
X 
 
XPb
P (single 
dose) 
  
X 
X  
  
 
 
 
Informed consent 
  
X  
 
  
  
  
  
  
  
  
  
 
 
Demographics 
  
X  
 
  
  
  
  
  
  
  
  
 
 
Medical history 
  
X  
 
  
  
  
  
  
  
  
  
 
X  
 
Concurrent medication 
  
X  
 
  
X  
  
X  
  
  
  
X  
 
 
Eligibility Criteria 
  
X  
 
  
  
  
  
  
  
  
  
 
 
Physical exam with 
ECOG 
  
X  
 
  
X  
  
X  
  
  
  
X  
 
X  
Vital signsPc 
 
X  
X  
X  
  
  
 
X  
X  
Height 
X 
 
 
  
  
  
 
 
CBC w/diffPe 
  
X  
 
  
X  
  
X  
  
  
  
X  
X 
Serum chemistryPd,e 
X 
 
X 
X 
 
X 
X 
PT/PTT 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 Adverse event evaluation  
  
 
 X  
 X  
   
 X  
X 
Biopsy Collection 
X 
 
 
 
 
X 
 
Correlative BloodsPj 
X 
 
 
 
 
X 
 
Radioembolization (Y90)Pb 
 
 
XPb
P(single 
dose) 
 
 
 
 
PET-CT (with contrast) 
XPh 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
G6PD enzyme 
X 
 
 
 
 
 
 
 Serum Pregnancy TestP g 
 X  
 
  
   
   
   
 
Vitamin C pharmacokinetics Pf 
 
 
Tumor markers: CEA, CA19-9  
  
X  
 
  
  
  
  
  
 X 
  
 
X 


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a: Agent administered on three-four days/week, blood work (CBC/ Chemistry) performed once per week 
b: Single dose Y90 administered same day or within 24 hours of Vitamin C treatment on day 2 (+2 day window). 
c: Sitting blood pressure, pulse, respiratory rate, oral temperature, weight 
d: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, calcium, 
magnesium, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
e: CBC and chemistries can be collected within 3 days of treatment; 1 day preferred. 
f: PK is performed for cohorts A and B only.  
g: Applicable for women of childbearing potential. 
h: Screening PET-CT must be done within 30 days prior to enrollment. 
i: End of study assessments can be done via telephone call (only adverse event & concurrent medication evaluation will be 
necessary with a telephone assessment.) 
j: Correlative bloods are for clonal hematopoiesis analysis 
 
 
 
 
5.1.1 Screening Visit  
(Within 4 weeks (28 days) of start of treatment, unless otherwise noted)  
• 
Informed consent (within 30 days)  
• 
Demographics  
• 
Medical history  
• 
Concomitant Medications  
• 
Physical exam  
• 
Height  
• 
Vital signs (5-minute sitting blood pressure, pulse, respiratory rate, 
temperature, weight)  
• 
ECOG performance status (Appendix A: ECOG Performance Status  
Criteria)  
• 
Serum Pregnancy Test  
• 
Complete Blood Count (CBC) with differential  
• 
PT/PTT  
• 
Urinalysis  
• 
Serum chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH,  
calcium, magnesium, phosphorus, potassium, total protein, 
SGOT[AST], SGPT[ALT], sodium)  
• 
G6PD enzyme  
• 
Tumor markers: (specific to the cancer type such as CEA, CA19-9)  
• 
EKG   
• 
PET-CT (within 30 days)  
• 
Tissue Collection (screening biopsy is not required if tumor lesion is 
too small or per PI discretion. Non WCMC site should have a 
documented discussion with the principle investigator)  
• 
Correlative Bloods (Cohort C Only)  
 


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5.1.2  Treatment Phase  
  
  
  
  
  
Infusions will be given on 4 out of 5 days each week on week 1-4 in cohort A 
and weeks 1-24 in cohort B – or until disease progression. In Cohort C, 
infusions will be given on weeks 1-3  (up to 3 weeks total). Following an 
initial Vitamin C test dose on day 1 week 1,  a single dose of Y90 will be 
administered on the same day or within 24 hours of the Vitamin C infusion. 
Radioembolization (Y90) should occur on day 2 (+2 day window) during 
week 1. No more than 2 consecutive days of infusions should be 
administered per week.  VIT C will continue for 1-2 weeks following RAE 
(for a total of  up to 3 weeks of therapy).   
  
  
  
  
  
 
5.1.2.1  
One day of each week when infusion given:  
• 
Physical exam  
• 
Vital signs (blood pressure, pulse, respiratory rate, oral temperature, 
weight) the vital signs are recorded pre-dose each infusion day.  
• 
ECOG performance status (Appendix A: ECOG Performance Status  
Criteria)  
• 
PKs will be collected at the following time points on Day 1 of Week 2 
(Preferred; Day 1or Day 3 of weeks 2 to 5 is also allowed)): prior to 
infusion, 1hr post start of infusion, end of infusion, 2hrs, 3hrs, 4hrs, 
6hrs, 24hrs post end of infusion (+/- 15 minutes).  
• 
Complete blood count (CBC) with differential collected within 3 days 
of treatment; 1 day preferred  
• 
Serum chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
calcium, magnesium, phosphorus, potassium, total protein, 
SGOT[AST], SGPT[ALT], sodium) collected within 3 days of 
treatment; 1 day preferred  
• 
Tumor markers: CEA, CA19-9 (only at week 4 for Cohort A & C, at week 6 
for Cohort B)  
• 
Adverse event evaluation  
             5.1.2.2. Other On Study Evaluations 
• 
PET CT (with contrast) are to be performed on weeks 6, 12 and 24 for 
Cohort B. They will be performed at screening for Cohort A. And at 
screening and between week 6-8 for Cohort C.  
• 
Post treatment research biopsy to be performed between week 6-8 
(cohort C) 
• 
 Surgical Resection (cohort A) 
• 
On-study Biopsy between week 3-6 (Cohort B)  
• 
Correlative Bloods between week 6-8 (Cohort C Only)  
 
 


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5.1.3  End of Study  
For cohort A, end of study assessments can be done after surgical resection between weeks 
4 and 16. For cohort B, end of study assessment will occur 4-8 weeks from end of 
treatment (+/- 4 weeks). For Cohort C, end of study assessment will occur between weeks 8-
16.  Note: end of study assessments for all cohorts can be done as a telephone assessment, 
in which only adverse & concurrent medication is reviewed with the patient. 
• 
Vital signs (blood pressure, pulse, respiratory rate, oral temperature, 
weight)   
• 
Physical Exam  
• 
ECOG performance status   
• 
Complete blood count (CBC) with differential  
• 
Serum chemistry (albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH,  
calcium, magnesium, phosphorus, potassium, total protein, 
SGOT[AST], SGPT[ALT], sodium)  
• 
Adverse event evaluation  
• 
Tumor markers- CEA, CA19-9  
 
5.2 Treatment Administration  
  
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications for vitamin 
C are described in Section 6.    
  
Patients will be treated with a test dose of 10 g vitamin C infusion on day 1 of week 1. 
If there is no grade 3 toxicity, patients will be given a proposed dose of on day 2 and 
subsequent infusions. Vitamin C will be administered over 2 hours for 4 days/week 
for 4 consecutive weeks in cohort A.  In Cohort B, vitamin C will be administered 
over 2 hours for 4 days/week for up to 6 months, until progression or unacceptable 
adverse events.  In cohort C, Vitamin C will be administered over 2 hours for 4 
days/week. During week 1, Vitamin C will be administered on day 2 (+2 day 
window) prior to or within 24 hours of a Y90 treatment. Infusions will take place over 
a total of up to 3 weeks. Patients may receive Vitamin C for 3 days/week for logistical 
issues or patient preference after discussion with the PI or co-PI. Treatment cannot be 
given on 3 consecutive days.  
  
For patients receiving doses of 100g or more of Vitamin C, infusion times may exceed 
2 hours due to limitations of IV pump rates    
  
5.3 General Concomitant Medication and Supportive Care Guidelines  
  


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Supportive measures including analgesics, blood transfusions, and antimicrobials are 
permitted throughout the trial. Concurrent chemotherapy or other anti-neoplastic 
agents are not allowed.  
  
5.4 Duration of Therapy and Criteria for Removal from Study  
  
In the absence of treatment delays due to adverse event(s), treatment may continue for 
2-4 weeks in cohort A and up to 6 months in cohort B and up to 4 weeks for Cohort 
C, or until one of the following criteria applies:  
  
o Treatment related toxicity which results in a delay of planned curative   
 surgery,  
  
o Disease progression,  
  
o Intercurrent illness that prevents further administration of treatment,  
  
o Unacceptable adverse event(s),  
  
o Patient decides to withdraw from the study, or  
  
o General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator.  
  
  
  
 
6.  
Dosing Delays/Dose Modifications  
  
Table 4A . For Cohort A and B 
  
AGENT(S)  
DOSE  
ROUTE  
VISIT  
Vitamin C  
10 g  
Intravenous  
Week 1, Day1– Test Dose  
Vitamin C  
1.25 g/kg  
Intravenous   
Wk 1 D2 – Wk1 D4  
Wk X D1 – WkX D4 (subsequent weeks)  
Vitamin C  
1.25 g/kg  
Intravenous  
3- 4 days/week until EOS   
  
Patient who do not tolerate the test dose, should not continue with the study.  There is no 
dosing cap for vitamin C therapy.   
  
Patients may receive treatment if they have not experienced any grade 3-4 event attributable 
to IV vitamin C.    


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If a grade 3-4 attributable event occurs, it must improve to grade 2 or better prior to resuming 
therapy.  Vitamin C would then be administered at a reduced dose of 1.0 g/kg IV for up to 4 
days per week.   
  
A delay in treatment of up to 2 weeks is permitted. If a treatment visit week does not occur, 
the following week should be the next treatment week  
 
Table 4B. For Cohort C 
The study design for cohort C is a traditional 3+3 dose escalation design. Sequential 
dose levels will accrue as per the following dosing schema.  
Dose level 
Vit C dose per infusion 
(weekly monotherapy) 
Vit C dose on 
Day of Y90 Rx 
Dose level 1 
0.5 g/kg 
0 
Dose level 2 
0.75 g/kg 
0 
Dose level 3 
0.75 g/kg 
0.5 g/kg 
Dose level 4 
1.0 g/kg 
0.5 g/kg 
Dose level 5 
1.0 g/kg 
0.75 g/kg 
Dose level 6 
1.25 g/kg 
0.75 g/kg 
 
 
 
 
The DLT observation period will start with the first vitamin C infusion prior to 
radioembolization and end after the last vitamin C infusion post-embolization. A DLT is 
defined as a grade 3+ (latest CTCAE version) adverse event that is at least possibly related to 
the vitamin C infusion. 
  
 
7.  
Adverse Event Reporting Requirements   
  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  Safety 
will be monitored by evaluation of adverse events reported by patients or observed by 
investigators or research staff, as well as by other investigations such as clinical laboratory 
tests, x-rays, electrocardiographs, etc.  
  
7.1 Adverse Event Definition  
  
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality. An adverse event can arise with any use of the drug (e.g., off-label use, use 


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in combination with another drug) and with any route of administration, formulation, 
or dose, including an overdose.   
   
 
  
  
7.1.1  Investigational Agent or Device Risks   
The following adverse events were reported in previous clinical studies of 
Vitamin C infusion:   
  
Proteinuria, hypertension, tumor fever, leg edema, hypoalbuminemia,  
hypokalemia, hypernatremia, hypercalcemia, increased creatinine, 
hyperglycemia, peripheral neuropathy, headache, hemolysis, hemorrhage, 
elevated aminotransferase, and kidney stones.   
  
 
  
7.1.2  Adverse Event Characteristics and Related Attributions  
  
NCI Common Terminology Criteria for Adverse Events (CTCAE) will be 
utilized for tracking adverse events during the conduct of this study.      
CTCAE term (AE description) and grade:  The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site (Uhttp://ctep.cancer.govU).  
  
 
  Attribution of the AE:  
- Definite – The AE is clearly related to the study treatment.  
- Probable – The AE is likely related to the study treatment.  
- Possible – The AE may be related to the study treatment.  
- Unlikely – The AE is doubtfully related to the study treatment.  
- Unrelated – The AE is clearly NOT related to the study treatment.  
  
  
  
 
  
7.1.3    Recording of Adverse Events  
  
All adverse events will be recorded on a patient specific AE log after 
Week 1, Day 1. The AE log will be maintained by the research staff and 
kept in the patient’s research chart.      
  
 
  
7.1.4   Reporting of AE to WCMC IRB  
  
All AEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immed 
iate_Reporting_Policy.pdf.   
  


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7.2 Definition of SAE  
An adverse event or suspected adverse reaction is considered “serious” if, in 
the view of the investigator it results in any of the following outcomes:  
• Death (NOTE: death due to disease progression will be recorded on the CRF 
and does not need to be reported as an SAE.  
• A life-threatening adverse drug experience—any adverse experience that 
placed the patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred. It does not include an adverse 
experience that, had it occurred in a more severe form, might have caused 
death.  
• Requires at least a 24-hour inpatient hospitalization or prolongation of existing 
hospitalization.  
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.  
• A congenital anomaly/birth defect.  
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
  
 
  
7.2.1  Reporting of SAE to IRB and DSMB  
All SAEs occurring on this study will be reported to the IRB and DSMB 
according to the IRB policy, which can be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immed 
iate_Reporting_Policy.pdf.   
  
   
For investigator-initiated studies where the WCM investigator holds the IND, the 
following reporting guidelines apply:   
  
a. 
A Mandatory MedWatch Form 3500A must be completed and sent to the 
FDA. Specific instructions on how to complete the MedWatch Form 3500A can 
be found on the FDA website.   
b. 
If the protocol requires SAEs to be reported to an outside agency (i.e., to the 
supplier of the study drug), specific instructions will be stated in the protocol.   


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c. 
If the study utilizes the WCM Data and Safety Monitoring Board (DSMB), a 
narrative of the event will be submitted to the Regulatory Coordinator on a 
modified SAE cover sheet. The completed form serves as acknowledgement of the 
SAE’s occurrence and will be used to complete the DSMB periodic report. A copy 
should be filed in the regulatory binder.   
  
d. 
For multicenter studies, the multicenter core within the Quality Assurance 
Unit (QAU) will distribute the IND Safety Report to participating sites. The  
MedWatch and SAE cover sheet must be emailed to JCTOIIT@med.cornell.edu 
within 7 days of the investigator notification.   
  
  
7.3 AE/SAE Follow Up  
  
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
AE/SAEs attributed to Vitamin C should be followed until resolution. This requirement 
indicates that follow-up may be required for some events after the patient discontinues 
participation from the study.   
  
 
8.   
Pharmaceutical Information  
  
A list of the adverse events and potential risks associated with vitamin C can be found in 
Section 7.1.    
  
8.1 Investigational Agent    
  
Vitamin C is supplied as Ascorbic Acid for Injection USP, dissolved in water, 500 
mg/mL, packaged in a 50 mL sterile dispensing vial, each mL contains Ascorbic Acid 
500 mg, Edetate Disodium 0.025%, Sodium Hydroxide 0.011%, Water for injection q.s. 
pH 5.5-7.0 adjusted with Sodium Bicarbonate. The vials should be stored in carton until 
time of use. Store between 2°-8° C (36°-46° F).  
  
8.2 Availability  
  
Vitamin C is available through commercial supply.  
  
  
8.3 Agent Accountability  
  
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all agents 


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received on a site Drug Accountability Record Form. Participating sites should follow 
their institutional standard for drug accountability.   
  
9.0 Laboratory Correlative Studies  
 
Using data from this trial, the relationship between molecular markers associated with 
Vitamin C transport and glycolysis, and the clinical outcomes with Vitamin C infusion will be 
explored. Tissue collections will be performed for for GLUT1, metabolomics, RNA 
sequencing, organoids and future correlative studies.  Vitamin C pharmacokinetics will also 
be assessed.  
 
9.1 Serum Vitamin C pharmacokinetics  
 
Vitamin C pharmacokinetics will be measured on the week 2 day 1 of infusion, when 
proposed dose will be administered. If for any reason, PK sample collection is not possible on 
week 2 day 1, the blood sample should then be collected on day 1 or Day 3 between 
subsequent weeks 2 to 5. For Cohort C, the blood collection for PK analyses may occur 
during week 2, 4 or 5, on day 1 or 3 of that week.   
 
9.1.1 Method of Assessment  
  
Liquid-chromatography/mass spectrometry (LC/MS) will be performed to measure 
Vitamin C levels. Plasma samples will be incubated with 2.5 mM MBB in CH3OH:H2O 
(80:20) at room temperature for 30 min, then diluted with same or 10-fold volume of 
CH3CN:H2O (70:30) containing 0.025% formic acid. The diluted samples will be briefly 
vortexed and centrifuged for 20 min at 20,000g to pellet precipitated proteins. The 
supernatants will be transferred to autosampler vials with 3 μL solution injection for 
analysis by LC/MS. For absolute concentration of vitamin C measurements, MBB treated 
plasma will be diluted with 6-fold volume of 70% CH3CN containing 0.025% formic acid 
and 1 μL solution was injected for LC/MS.  
  
Q-TOF LC/MS analysis will be performed as referenced [42]. Ascorbic acid will be 
detected in both negative mode ([M-H]- at m/z 175.0248) and positive mode ([M+H]- at 
m/z 177.0394) with retention times of 1.92 min and 0.99 min for ANP and RP columns, 
respectively. A vitamin C calibration curve will be established for free plasma in the 0-
600 uM concentration range. Accuracy and precision will be evaluated by analyzing 
spiked vitamin C standards in plasma.   
  
9.1.2 Collection of Specimen(s)  
 
For Vitamin C pharmacokinetics, peripheral blood will be collected at the following time 
points: (+/- 15 minute window)  


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0 (prior to infusion start)  
1 hour (during infusion)  
2 hour (end of infusion)  
4 hour (2 hours after end of infusion)  
5 hour (3 hours after end of infusion)  
6 hour (4 hours after end of infusion)  
8 hour (6 hours after end of infusion)  
24 hour (22 hours after end of infusion and prior to the start of the next 
dose)   
 
9.1.3 Handling of Specimens  
Refer to Vitamin C Lab Manual regarding handling of specimens.   
  
9.2 Clonal Hematopoeisis  
 
9.2.1 Assessment  
20 cc of peripheral blood (purple cap tube) and 1 buccal swab. Buffy coat will be 
isolated. 10 cc will be used to generate DNA and RNA. 10 cc will be saved for single 
cell sequencing and/or flow cytometry.   
9.2.2 Method of Assessment  
We will isolate peripheral blood and buccal swabs from patients. Genomic DNA will 
be isolated and we will perform DNA and RNA sequencing to detect and 
characterize clonal hematopoiesis  
9.2.3 Timing of Assessment  
Baseline and week 6-8 (two time points only) 
 
  9.3 Gene expression profiling by RNA sequencing 
 
9.3.1 Assessment  
  
To explore potential correlation of gene expression pattern with anti-tumor activity of 
vitamin C, we plan to perform RNA sequencing using surgical sample in cohort A 
patients who will receive vitamin C infusion pre-operatively.  
  
9.3.2 Method of Assessment  
  
RNA extraction: RNA will be extracted from frozen tissue or FFPE using the RNeasy 
Mini Kit and purified with the RNeasy Min Elute Cleanup Kit (Qiagen, Venlo, The 
Netherlands) according to the manufacturer’s instructions. RNA quality was assessed 
with a 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA). High quality RNA 


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will show a 28S rRNA band at 4.5 kb that should be twice the intensity of the 18S 
rRNA band at 1.9 kb.   
  
RNA sequencing: mRNA will be purified from total RNA and fragmented following 
protocols from Illumina Inc. (San Diego, CA).  cDNA library will be constructed by 
cDNA synthesis, end repair, addition of ‘A’ Bases to the 3' end, adapter ligation, and 
PCR amplification. The library will be denatured and hybridized onto a flow cell 
using cBot to generate clonal clusters of the DNA fragments. Paired end sequencing-
by-synthesis will be performed on the HiSeq4000 platform. After the HiSeq 
generates the sequencing images, the data is analyzed in three steps: image analysis, 
base calling, and sequence analysis.   
  
9.3.3 Timing of Assessment  
  
RNA extraction and subsequent sequencing will be performed at the baseline tumor 
biopsy and after surgical resection of tumors in cohort A, or at baseline and the week 
6-8 tumor biopsy for Cohort C.  
  
 
10.  
Measurement of Effect  
  
10.1 Response Criteria  
  
10.1.1 Pathologic response  
Pathologic response will be used in cohort A of this study. Surgical specimens will be 
evaluated for grading of tumor regression according to Mandard [40].  
  
TRG 1: (complete regression): absence of residual cancer and fibrosis extending through the 
different layers of the colon wall in the cases of colon cancer, or pancreatic or lung tissue in 
the cases of pancreatic and lung cancer, respectively;   
TRG 2: presence of rare residual cancer cells scattered through the fibrosis;   
TRG 3: increase in the number of residual cancer cells, but fibrosis still predominated;   
TRG 4: residual cancer outgrowing fibrosis;    
TRG 5: absence of regressive changes.  
 
10.1.2 Objective response  
  
PET-CT will be performed at 6 weeks and 3 months from start of study treatment in cohort 
B patients or at early discontinuation of study. RECIST v 1.1 criteria to assess response for 
target lesions will be used to determine response.   
  
Disease Control Rate (DCR) and Clinical Benefit Rate (CBR) are defined as the percentage 
of patients with advanced or metastatic cancer who have achieved complete response (CR), 
partial response (PR) and stable disease (SD) to the study agents.  


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Objective Response (ORR) is defined as the proportion of patients with a documented 
complete response or partial response (CR + PR) based on RECIST 1.1.   
  
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.  
  
Disease control (DC): this is defined as a CR, PR or SD.  
  
10.2 Duration of Response   
  
 
  
10.2.1 Progress-free survival (PFS)  
  
PFS is defined as the time from study enrollment until the first objective observation of 
disease progression or death from any cause.   
            
 
10.3  Other Response Parameters  
 
  
  
  
N/A  
  
 
11.  
Data Reporting / Regulatory Considerations  
  
11.1 Data Collection  
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled patients.   
11.1.1 REDCap  
  
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool 
for the creation of customized, secure data management systems that include 
Webbased data-entry forms, reporting tools, and a full array of security features 
including user and group based privileges, authentication using institution LDAP 
system, with a full audit trail of data manipulation and export procedures.  REDCap is 
maintained on CTSC-owned servers that are backed up nightly and support encrypted 


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(SSL-based) connections.  Nationally, the software is developed, enhanced and 
supported through a multi-institutional consortium led by the Vanderbilt University 
CTSA.  
  
11.2 Regulatory Considerations  
  
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating 
sites. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission.  
  
 
12.  
Statistical Considerations  
  
12.1 Study Design/Endpoints  
  
The study design for cohort A (patients who will be treated prior to tumor resection) is 
a two-stage trial with no stopping for the interim analysis. It will consist of a 
maximum of 20 total evaluable patients. The minimum pathologic tumor response 
rate that would warrant further study is 25%. The maximum pathologic tumor 
response rate (pRR) that would be uninteresting is 5%. The disease control rate is the 
rate not having progressive disease as defined by RECIST 1.1. criteria.  The 
pathologic response rate is determined by a tumor regression grade (TRG).  Both the 
RECIST radiology assessment (Eisenhauer et al. Eur J Cancer 2009;45: 228-247) and 
the TRG score (Thies et al. Front Oncol 2013;3:262) are standard criteria applied for 
oncologic studies. If after the first 13 patients, there has been 1 pRR the trial will 
continue to accrue an additional 7 patients. If after 20 patients are accrued, 3 or more 
patients have a pRR, the regimen will be recommended for further testing. If the 
regimen is inactive, there is a 51% chance that the trial will be stopped early.  
  
The study design for cohort B (patients with metastatic tumors with extended RAS 
(e.g. KRAS or NRAS) or BRAF mutations) is a two-stage trial with no stopping for 
the interim analysis. A maximum of 25 evaluable patients will be accrued. The 
primary endpoint is the 3-month disease control rate (DCR). The minimum 3-month 
DCR that would warrant further study is 30%. The maximum 3-month DCR that 
would be uninteresting is 10%. If after the first 16 patients, 2 or more have disease 
control at 3-months, the trial will continue to accrue an additional 14 patients. If 5 or 
more patients out of 25 patients have disease control at 3 months, the regimen would 
be considered of interest for further testing. If the true 3-month DCR is 10% or less, 
the trial has a 51% chance of stopping early.  
  
The study design for cohort C is a traditional 3+3 dose escalation design. Sequential 
dose levels will accrue as per the following dosing schema.  
 


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Dose level 
Vit C dose per infusion 
(weekly monotherapy) 
Vit C dose on 
Day of Y90 Rx 
Dose level 1 
0.5 g/kg 
0 
Dose level 2 
0.75 g/kg 
0 
Dose level 3 
0.75 g/kg 
0.5 g/kg 
Dose level 4 
1.0 g/kg 
0.5 g/kg 
Dose level 5 
1.0 g/kg 
0.75 g/kg 
Dose level 6 
1.25 g/kg 
0.75 g/kg 
 
 
 
The DLT observation period will start with the first vitamin C infusion prior to 
radioembolization and end after the last vitamin C infusion post-embolization. A DLT 
is defined as a grade 3+ (latest CTCAE version) adverse event that is at least possibly 
related to the vitamin C infusion. Three patients will be enrolled at dose level 0.5 
g/kg. if there are no DLTs observed for this cohort, the next cohort of three wil be 
treated with 0.75 g/kg. If there is 1 DLT at the 0.5g/kg level out of three patients, 
three more patients will be enrolled at this dose. If no additional DLTs are observed (1 
of 6 patients with a DLT), the next three patients will be enrolled at the 0.75 g/kg 
level. If 2 or more out of 3 or 2 or more out of 6 experience a DLT at the 0.5 g/kg 
level, the trial will stop and it will be concluded the treatment has unacceptable 
toxicity. Dose escalations will continue if 0 of 3 or 1 of 6 patients experience a DLT. 
The recommended dose will be the dose immediately less that the dose that had 2 or 
more out of 3 or 6 patients with a DLT. An expansion cohort of at most 10 additional 
patients is planned at the recommended dose level (the dose immediate below the 
MTD, which is the dose level where 2 or more out of 3 or 6 patients experience a  
DLT).  If the MTD is not reached, the 1.25 g/kg will be the recommended dose level.  
  
   
12.2 Sample Size/Accrual Rate  
  
The primary objective for cohort A is to evaluate the pathological response rate  
(pRR). Based on historical data for patients with extended RAS (e.g. KRAS or  
NRAS) or BRAF mutations and preclinical activity of Vitamin C in extended RAS 
(e.g. KRAS or NRAS) or BRAF  mutant vs wild type colon cancer, the proposed null 
hypothesis (H0) is that the pRR for cohort A patients is ≤ 5%.  The alternative 
hypothesis (Ha) is that the pRR is ≥ 25% after treatment with Vitamin C 
supplementation in cohort A patients. This assumes a pRR of >40% extended RAS 
(e.g. KRAS or NRAS) or BRAF mutated cancers and 5% in wild type, and a 50% rate 
of extended RAS (e.g. KRAS or NRAS) or BRAF cohort. A sample size of 20 
evaluable patients in Cohort A will have one-sided significance of 0.1 and 90% power 
with the indicated null and alternative hypotheses and the proposed interim analysis. 


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Patients in Cohort A will be considered evaluable if they received at least 8 vitamin C 
infusions prior to surgery, and TRG grading is available from surgery. Patients not 
fulfilling these requirements will be considered not evaluable and will be replaced. To 
account for patients who are not evaluable, the target accrual will be 22 patients.  
  
The primary objective for cohort B is to determine the 3-month disease control rate 
(DCR). It is assumed that the 3-month DCR for this patient cohort without any further 
treatment is 10% (proposed null hypothesis, H0) and that the 3-month DCR for 
patients with extended RAS (e.g. KRAS or NRAS) or BRAF mutant tumors will be 
30% or more when treated with high-dose vitamin C supplementation (alternative 
hypothesis Ha). A sample size of evaluable 25 patients will have a one-sided 
significance of 0.1 and power of 90%. Patients in Cohort B will be considered 
evaluable if they have 3-month scans available or have documented progression 
before 3-months, and they have received at least 4 vitamin C infusions. Patients not 
fulfilling these requirements will be considered not evaluable and will be replaced. To 
account for patients who are not evaluable, the target accrual will be 28 patients.  
  
We project an accrual rate of 4.2 patients/months across the two cohorts over one 
year.   
  
The minimum sample size for cohort C is 3 patients and will occur if 2 or more DLTs 
occur in the first 3 patients enrolled at dose level 0.5 g/kg. The maximum sample size 
is 34 patients and will occur if each dose level requires 6 patients be enrolled and 
there are 10 patients enrolled at the recommended dose (which would be 1.25 g/kg).  
  
12.3 Analysis of Secondary Endpoints  
  
In cohort A, Cmax and AUC of Vitamin C plasma levels and phosph-AMPK IHC will 
be analyzed for correlation with tumor response using a two-sample t-test (comparing 
values for patients with tumors that had a pRR and those who did not). Molecular 
signature of vitamin C efficacy will be determined using RNA sequencing and 
compared between extended RAS (e.g. KRAS or NRAS) or BRAF mutant vs wild 
type tumors. Organoids will be prepared from resected tumor samples and treated 
with vitamin C. Change of organoid growth from baseline will be compared in 
extended RAS (e.g. KRAS or NRAS) or BRAF mutant vs. wild type tumors by 
performing a two-sample t-test of the area under the growth curves. A comparisons of 
pRR between patients with extended RAS (e.g. KRAS or NRAS) or BRAF mutated 
tumors (cohort A) will be done using a Fisher’s exact test. Finally there will be 
comparisons of the endpoints done for tumors with SUV < 10 versus tumors with 
SUV ≥ 10 and with GLUT1 IHC0/1 versus 2+/3+. The PFS of patients in cohirt B 
will be summarized with a Kaplan-Meier curve. For discrete endpoints (i.e. tumor 
response) the comparison will be done with Fisher’s exact test and for time to event 


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endpoints (e.g. PFS) the comparison will be done with Kaplan-Meier curves and a log 
rank test.  
  
The adverse events will be tabulated as the frequency and relative frequency by each 
dose level. Tumor responses will be evaluated using RECIST criteria. A patient will 
have a tumor response if they have a complete or partial response. The tumor 
response rate will be estimated for across all enrolled patients as well as by dose level. 
Tumor response will be reported a binomial point estimate and 95% confidence 
interval. In addition, we will access and report the disease control rate as defined for 
cohort B.   
   
12.4 Reporting and Exclusions  
  
12.4.1 Evaluation of adverse events   
All patients will be evaluable for  adverse events  from the time of their first 
treatment with vitamin C.  
  
12.4.2 Evaluation of response    
All patients included in the study will be assessed for response to treatment if they 
have received at least 8 (Cohort A) 4 (Cohort B), or any (Cohort C)vitamin C 
infusions.    
  
 
 
 
13.   
Data and Safety Monitoring Plan (DSMP)  
  
This study will be monitored by the Weill Cornell Medicine DSMB. All adverse events 
will be summarized and reported to the DSMB. The study team will review AEs on a 
monthly basis via a report generated by the study statistician. Treatment will be modified 
for individual patients according to the dose-modifications described in section 6. Patients 
will discontinue protocol treatment for reasons described in Section 5, including 
treatmentrelated toxicities which result in a delay of planned curative surgery.   
  
The study will begin with recruitment of six patients in cohort B. If after at least 4 weeks 
of treatment no more than 1 patient experienced a treatment-related toxicity requiring 
treatment interruption, recruitment may continue into cohort B and commence into cohort 
A.  
   
Cohort A will recruit 5 patients initially. Once 5 patients have been accrued, the study will 
be temporarily suspended for cohort A patients if 20% or more of patients experience a 
grade 3+ AE that requires a delay of surgery for 1 week or longer. Upon review of the 
events and discussion with the IRB and DSMB, a decision will be made whether to reopen 


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the study as is, modify the study and reopen, or permanently close the study to cohort A 
patients.   
  
The study will be temporarily suspended for cohort B patients if 2 of the first 6 patients or 
if 25% or more of patients thereafter experience a grade 3+ AE . Upon review of the events 
and discussion with the IRB and DSMB, a decision will be made whether to reopen the 
study as is, modify the study and reopen, or permanently close the study to cohort A 
patients.   
  
There are not planned interim analyses for this trial. The primary endpoint data for each 
cohort will be summarized and presented to the DSMB for review.  
  
For cohort C, the study team will determine whether doses can be escalated. All escalation 
decisions and observed AEs will be reported to the DSMB as part of the routine DSMB 
report.  
  
  
 
13.1  DSMB Reporting  
  
It is proposed that this study be reviewed by the DSMB every six months.  
  
  
 
 


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Appendix A  
  
ECOG Performance Status Criteria  
  
Grade  
Descriptions   
  
0  
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.  
  
1  
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, 
light housework, office work).  
  
2  
In bed < 50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.  
  
3  
In bed > 50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.  
  
4  
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.  
  
5  Dead  
  
  
  
   
  
 


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Appendix B  
  
New York Heart Association (NYHA)  
  
Classifications Class   
Functional Capacity   
Objective Assessment   
I  
Patients with cardiac disease but without 
resulting limitations of physical activity. 
Ordinary physical activity does not 
cause undue fatigue, palpitation, 
dyspnea, or anginal pain.   
No objective evidence 
of cardiovascular 
disease.   
II  
Patients with cardiac disease resulting 
in slight limitation of physical activity. 
They are comfortable at rest. Ordinary 
physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.   
Objective evidence of  
minimal 
cardiovascular 
disease.   
III  
Patients with cardiac disease resulting 
in marked limitation of physical 
activity. They are comfortable at rest. 
Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or 
anginal pain.   
Objective evidence of 
moderately 
severe 
cardiovascular 
disease.   
IV  
Patients with cardiac disease resulting 
in inability to carry on any physical 
activity without discomfort. Symptoms 
of heart failure or the anginal 
syndrome may be present even at rest. 
If any physical activity is undertaken, 
discomfort is increased.   
Objective evidence of 
severe cardiovascular 
disease.   
Source: The Criteria Committee of New York Heart Association.  
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and 
Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256.   
  
  
  
  
  
 
 
 
Appendix C  


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Cockcroft-Gault Formula for Calculation of Creatinine Clearance  
  
  
  
 
P  
PMales:  
 
P  
P                                       (140 −age 〈years〉 × body weight 〈kg〉)  
 
P  
PCreatinine Clearance=    
 
 
P  
P                                             (72) × (serum creatinine 〈mg/dL〉)  
  
  
 
P  
PFemales:  
 
P  
P                                      (140 −age 〈years〉 × body weight 〈kg〉)  
 
P  
PCreatinine Clearance=                                         ×0.85  
 
P  
P                                            (72) × (serum creatinine 〈mg/dL〉)  
 
  
 
  
  
  
  
   
  
 
 


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