IV Vitamin C With Chemotherapy for Cisplatin Ineligible Bladder Cancer Patients: A Forgotten Group
Phase: PHASE1
Conditions: Bladder Cancer
Sponsor: University of Kansas Medical Center

Investigator Initiated Trial 
IV vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients: A forgotten group 
SPONSOR - INVESTIGATOR 
John Taylor III, MD, MS 
Professor & Director Translational Research, Dept. of Urology 
Co-Leader, Experimental Therapeutics, KUCC 
University of Kansas Medical Center 
3901 Rainbow Blvd 
5044 Sudler Hall 
Kansas City, KS 66160 
913-588-2589
Protocol Number: 
NCT Number: 
Study Drug(s): 
Initial Version: 
Amendments 
Email: jtaylor27@kumc.edu 
IIT-2019-IVC-CarboGem 
NCT04046094 
Intravenous ascorbic acid/vitamin C (Investigational) 
Carboplatin (Standard of Care) – commercially available 
Gemcitabine (Standard of Care) – commercially available 
Version 1.0 - 05-29-2019 
Version 2.0 - 02-19-2020 
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John Taylor, III, MD, MS – Principal Investigator 
Rahul Parikh, MD, PhD – Co-Investigator 
Jeanne Drisko, MD – Co-Investigator 
Ben Woolbright, PhD – Co-Investigator 
Qi Chen, PhD – Co-Investigator 
Jeffrey Thompson, PhD – Co-Investigator / Biostatistician 
Katie Glavin – Coordinator 
Ashley Shores – Project Director 
LIST OF COLLABORATORS 

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The trial will be conducted in accordance with International Council on Harmonisation Good Clinical Practice 
(ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the [specify NIH Institute or 
Center (IC) [ Terms and Conditions of Award. The Principal Investigator will assure that no deviation from, or 
changes to the protocol will take place without prior agreement from the funding agency and documented 
approval from the Institutional Review Board (IRB), and the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, if applicable, except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the IRB for review and approval. Approval of both the protocol and the consent form(s) must be obtained 
before any participant is consented. Any amendment to the protocol will require review and approval by the 
IRB before the changes are implemented to the study. All changes to the consent form(s) will be IRB 
approved; a determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
Protocol Number IIT-2019-IVC-CarboGem 
Protocol Title IV vitamin C with chemotherapy for cisplatin ineligible bladder cancer 
patients: A forgotten group 
Protocol Version and Date Version 1.0 - 05-29-2019 
Sponsor/Investigator Name John Taylor, III, MD, MS 
Site Number 001 
Site Name University of Kansas Cancer Center 
 
 
 
 
 
Sponsor/Investigator Signature 
Date 
STATEMENT OF COMPLIANCE / PROTOCOL AGREEMENT 

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LIST OF COLLABORATORS ........................................................................................................................ 2 
STATEMENT OF COMPLIANCE / PROTOCOL AGREEMENT ................................................................... 3 
1 
TABLE OF CONTENTS ..................................................................................................................... 4 
2 
SCHEMATIC OF STUDY DESIGN .................................................................................................... 7 
3 
PROTOCOL SUMMARY .................................................................................................................... 8 
4 
INTRODUCTION: BACKGROUND INFORMATION AND RATIONALE .......................................... 11 
Background Information ........................................................................................................................... 11 
Study Agent(s) / Treatment(s) .................................................................................................................. 11 
4.1 
Other Agent(s) / Treatment(s) ................................................................................................ 15 
4.2 
Rationale ................................................................................................................................ 15 
4.3 
Study Risk / Benefit Ratio ....................................................................................................... 16 
4.3.1 
Study Known Potential Risks ................................................................................ 16 
4.3.2 
Study Known Potential Benefits ........................................................................... 16 
5 
STUDY DESIGN AND METHODS ................................................................................................... 16 
6 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................... 17 
6.1 
OBJECTIVE(S) ....................................................................................................................... 17 
Primary Objective 
17 
Secondary Objective(s) 
17 
Exploratory Objective(s) 
17 
6.2 
ENDPOINTS AND MEASURE(S) .......................................................................................... 18 
6.2.1 
Primary Endpoint .................................................................................................. 18 
6.2.2 
Secondary Endpoint(s) ......................................................................................... 18 
6.2.3 
Exploratory Endpoint(s) ........................................................................................ 18 
7 
STUDY ENROLLMENT / REGISTRATION AND WITHDRAWAL ................................................... 19 
7.1 
Participant Inclusion Criteria ................................................................................................... 19 
7.2 
Participant Exclusion Criteria .................................................................................................. 20 
8 
PARTICIPANT REGISTRATION PROCEDURES ........................................................................... 22 
8.1 
Participant Withdrawal Or Termination ................................................................................... 22 
Reasons For Withdrawal Or Termination ............................................................................................. 22 
Participant Replacement 
23 
9 
MEASUREMENT OF EFFECT ........................................................................................................ 23 
9.1 
Solid Tumor ............................................................................................................................ 23 
Antitumor Effect 
23 
10 
STUDY AGENT(S) / THERAPY / DEVICE ...................................................................................... 24 
10.1 
ASCORBIC ACID / VITAMIN C .............................................................................................. 24 
10.2 
CARBOPLATIN DRUG INFORMATION ................................................................................ 30 
10.3 
GEMCITABINE DRUG INFORMATION ................................................................................. 30 
11 
TREATMENT PLAN ......................................................................................................................... 30 
11.1.1 
Duration Of Therapy ............................................................................................. 30 
Study Agent Accountability Procedures / Participant Compliance ....................................................... 30 
11.1.2 
Nursing Staff Duty Implications............................................................................. 31 
Participant Access To Study Agent At Study Closure .......................................................................... 31 
11.1.3 
Dose Adjustments/Modifications/Delays ............................................................... 31 
SURGICAL TREATMENT PLAN ............................................................................................................. 32 
1 
TABLE OF CONTENTS 

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12 
GUIDELINES FOR MANAGEMENT OF POTENTIAL ADVERSE EVENTS ................................... 32 
INTRAVENOUS ASCORBIC ACID / VITAMIN C .................................................................................... 32 
CARBOPLATIN ........................................................................................................................................ 33 
GEMCITABINE ........................................................................................................................................ 34 
13 
CHILD-BEARING POTENTIAL / PREGNANCY .............................................................................. 34 
14 
STUDY PROCEDURES AND SCHEDULE ..................................................................................... 35 
14.1 
DESCRIPTION OF PROCEDURES / ASSESSMENTS ......................................................... 35 
14.1.1 
Screening/Enrollment/Baseline ............................................................................. 35 
14.1.2 
Procedures During Treatment .............................................................................. 37 
14.1.3 
End Of Treatment / Early Study Termination / Participant Study Withdrawal Visit42 
14.1.4 
Post-EOT/Surgery Follow-Up Visit(s) ................................................................... 42 
14.1.5 
Pregnancy Follow-Up ........................................................................................... 42 
14.1.6 
Long Term Follow-Up ........................................................................................... 42 
SCHEDULE OF EVENTS TABLE ............................................................................................................ 43 
CORRELATIVE / EXPLORATORY STUDIES ............................................................................................. 48 
Abstract 
48 
Objectives and Endpoints (For Correlative / Exploratory Studies Only) .................................................. 48 
Sample Collection Instructions (For Correlative / Exploratory Studies Only) ........................................... 48 
15 
STATISTICAL CONSIDERATIONS ................................................................................................. 48 
15.1 
Sample Size Justification ........................................................................................................ 48 
15.2 
Description Of Statistical Methods .......................................................................................... 49 
15.2.1 
General Approach ................................................................................................ 49 
Analysis Of Primary Objective .............................................................................................................. 49 
Analysis Of Secondary Objective(s) ..................................................................................................... 49 
Analysis Of Exploratory Objective(s) .................................................................................................... 50 
15.3 
Study Stopping Rules ............................................................................................................. 50 
16 
ASSESSMENT OF SAFETY ............................................................................................................ 50 
16.1 
Specification Of Safety Parameters ........................................................................................ 50 
16.1.1 
Definition Of Adverse Events (AE)........................................................................ 51 
16.1.2 
Relationship To Study Agent ................................................................................ 52 
16.2 
Reporting Procedures ............................................................................................................. 53 
Adverse Event Reporting 
53 
16.2.1 
Recording Adverse Events And Documentation In CRIS ..................................... 53 
16.2.2 
Serious Adverse Event Reporting ........................................................................ 54 
16.2.3 
Summary Of Expedited Serious Adverse Event Reporting .................................. 54 
Submitting IND Safety Reports To FDA ............................................................................................... 55 
16.2.4 
Reporting Of Pregnancy ....................................................................................... 55 
17 
DATA AND SAFETY AUDITING AND MONITORING ..................................................................... 55 
DSMC Oversight And Monitoring Plan ..................................................................................................... 55 
Data Management .................................................................................................................................... 56 
Safety Review And Oversight Requirements ........................................................................................... 56 
Serious Adverse Event 
56 
Review Of Serious Adverse Event Rates ............................................................................................. 56 
Study Safety And Progress 56 
18 
REGULATORY CONSIDERATIONS ............................................................................................... 57 
18.1 
Protocol Review And Amendments ........................................................................................ 57 

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19 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS .................................................................... 57 
19.1 
Ethical Standard ..................................................................................................................... 57 
19.2 
Informed Consent Process ..................................................................................................... 57 
20 
DATA HANDLING AND RECORD KEEPING .................................................................................. 58 
20.1 
Data Collection And Management Responsibilities ................................................................ 58 
20.2 
Study Records Retention ........................................................................................................ 58 
20.3 
Protocol Deviations ................................................................................................................. 58 
21 
APPENDICES .................................................................................................................................. 59 
Appendix A: Performance Status ............................................................................................................ 59 
Appendix B: Quality Of Life Questionnaire(s) ......................................................................................... 60 
Appendix C: Bladder Cancer Longitudinal Biorepository Protocol – IRB Approved HSC # STUDY00141546 
61 
22 
LITERATURE REFERENCES ......................................................................................................... 72 

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Cisplatin Ineligible Muscle Invasive Bladder 
Cancer 
Cisplatin Declined Muscle Invasive Bladder 
Cancer 
Cystectomy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
SCHEMATIC OF STUDY DESIGN 
Carboplatin/Gemcitabine NAC 
+ 
Intravenous Vitamin C 
Days 1-28 
13 + 8 participants enrolled 

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Title 
IV vitamin C with chemotherapy for cisplatin ineligible bladder cancer 
patients: A forgotten group 
Protocol Number 
IIT-2019-IVC-CarboGem 
Phase 
Clinical study Phase 1b/2 
Design 
Single-arm, Simon 2-stage design, “window of opportunity” trial 
enrolling patients with cisplatin-ineligible MIBC and patients with MIBC 
who decline cisplatin-based NAC 
Study Duration 
2 years 
Study Center(s) 
Single-center 
Objectives 
Primary: To assess pathologic downstaging rate in MIBC cisplatin- 
ineligible patients when IVC is added to a gemcitabine/carboplatin NAC 
regimen. 
Secondary: Quality of life, DFS and DSS. 
Exploratory: Biomarkers for Cell death, IVC related biomarkers and 
cellular outcome biomarkers will be evaluated in tumor samples at 
initial resection and radical cystectomy. 
Adding IVC to a gemcitabine/carboplatin NAC regimen will significantly 
improve pathological downstaging in cisplatin-ineligible/declined MIBC 
patients undergoing cystectomy. We will also study molecular 
mediators for cellular outcome and ascorbate specific mechanism, and 
quality of life (QOL) to gather preliminary information for a larger multi- 
center, randomized, two-arm trial. 
3 
PROTOCOL SUMMARY 

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Number of Participants 
13 – 21. 
Projected Accrual Rate: 1 or more per month. 
The Department of Urology performs more than 100 cystectomies per 
year of which approximately 30% will be cisplatin ineligible or will 
decline cisplatin-based NAC. We fully expect to recruit at least 1 
participant per month to reach our first stage enrollment goal. 
Simon's two-stage minimax34 will be used. Pathologic downstaging to 
non-invasive disease <pT2 is reported as approximately 15% with 
cystectomy alone. Therefore, the null hypothesis; that the true 
response rate of downstaging is 0.15, will be tested against a one-sided 
alternative. Typically, with effective NAC we might expect 30% of 
subjects to respond with downstaging to non-invasive disease. 
Therefore, we will use 0.30 as our desirable rate of response. 
In the first stage of the trial, 13 subjects will be accrued. If there are 1 or 
fewer responses in these 13 subjects, the study will be stopped. 
Otherwise, 8 additional subjects will be accrued for a total of 21. 
Diagnosis and Main 
Inclusion Criteria 
Patients with newly diagnosed cisplatin-ineligible MIBC or ones who 
decline cisplatin-based NAC 
Study Product(s), Dose, 
Route, Regimen 
Intravenous ascorbic acid/ vitamin C. 
A dose escalation regimen will be initiated at a single dose of 25 g, 
administered intravenously 2 to 3 times per week X 4 weeks. 
Duration of 
Administration 
4 weeks 
Reference Therapy 
None 
Interim Monitoring 
We will evaluate efficacy and toxicity after accrual of 13 subjects and 
completion of the stage 1 portion of the 2-stage design. 
We anticipate this will be approximately 6 – 12 months after study 
beginning. 
The study accrual and safety will be evaluated at monthly GU-DWG 
meetings. 
The DSMC of the KUCC is responsible for monitoring participant safety 
for this trial. 

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Statistical Methodology 
For Primary Objective 
Outcome metrics will include pathologic downstaging rates at 
cystectomy, QOL measurements, DFS and DSS. Simon's two-stage 
minimax34 will be used. Pathologic downstaging to non-invasive disease 
<pT2 is reported as approximately 15% with cystectomy alone. 
Therefore, the null hypothesis that the true response rate of 
downstaging is 0.15 will be tested against a one-sided alternative. 
Typically, with effective NAC we might expect 30% of subjects to 
respond with downstaging to non-invasive disease. Therefore, we will 
use 0.30 as our desirable rate of response. In the first stage of the trial, 
13 subjects will be accrued. If there are 1 or fewer responses in these 13 
subjects, the study will be stopped. Otherwise, 8 additional subjects will 
be accrued for a total of 21. The null hypothesis will be rejected if 5 or 
more responses are observed in 21 subjects, which we will take as 
evidence that this treatment should be studied further. This design 
yields a type I error rate of .21 and power of 79% when the true 
response rate is 0.30. 
Correlative Studies / 
Sample Banking For 
Future Research 
Samples to include tumor tissue, blood and urine will be collected at the 
time of entry into and during the study as well as at the time of surgery 
under the IRB approved KUMC Bladder Cancer Longitudinal 
Biorepository for Development of Novel Therapeutics/Biomarkers (PI: 
John Taylor III, MD, MS, IRB#: STUDY00141546, Appendix C). 
Stopping Rules 
If > 20% subjects have Grade 3 or 4 toxicity probably related or directly 
related to IV Vitamin C, we will hold the study for analysis of toxicity. 
Based on a Simon 2-Stage Design, toxicity and efficacy will be evaluated 
after the first 13 subjects are enrolled on this study, prior to enrolling 
additional subjects. 

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Background Information 
Study Agent(s) / Treatment(s) 
 
 
 
 
 
Bladder cancer (BCa) is the fifth most common solid tumor in the United States and has high rates of 
mortality in patients with muscle invasive disease (MIBC). Standard of care (SOC) treatment for MIBC is 
cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy, as NAC has been shown to 
both downstage tumors and improve recurrence free survival (RFS) and disease specific survival (DSS). 
Unfortunately, a large portion of MIBC patients are cisplatin ineligible and other treatment options are 
limited. Additionally, a small group of patients will decline SOC NAC due to concerns for adverse affects due 
to cisplatin (hearing loss, peripheral neuropathy, cardiotoxicity, renal toxicity). While an alternate regimen of 
gemcitabine and carboplatin has been used, it is only minimally effective and there remains no accepted SOC. 
New efficacious therapeutics are sorely needed for these patients. 
 
Previous data from our group indicates intravenous Vitamin C (IVC) is an effective chemotherapeutic agent 
and yields superior pharmacokinetics with >100-fold increases in plasma concentrations . Studies in multiple 
cancer models have demonstrated that IVC is safe, synergistically improves carboplatin1 and gemcitabine 2, 3 
based chemotherapy, has mechanistic plausibility, and affects several cancer tissue markers. BCa is sensitive 
to high dose VC in vitro and in vivo. Based on results of prospective and retrospective studies, IVC may 
potentiate chemotherapeutic effects, improve quality of life, and reduce adverse events in patients receiving 
chemotherapy. 
 
1. Recent studies reveal the pharmacokinetics of intravenous ascorbate/vitamin C (IVC) to be different 
than that of oral vitamin C. Oral ascorbate had been shown non-effective in treating cancer patients. 
It is now recognized that with oral ascorbate, plasma concentrations are tightly controlled by 
mechanisms of intestinal absorption and renal excretion 16, 17 to a plateau of 70~80 µM. When 
ascorbate is administered IV, the “tight control” mechanisms are bypassed, and millimolar (mM) 
concentrations are achieved and maintained for hours until renal excretion reestablishes equilibrium. 
Peak ascorbate concentrations, as high as 25–30 mM, are safely achieved.10, 14, 18 In patients with 
normal glucose-6-phosphate dehydrogenase (G6PD) activity and normal renal function, adverse 
events and toxicities are minimal even with IV doses as high as 1.5 g/kg, which is equivalent to 105 
grams for a 70 kg person.15, 18 These results motivated us to re-examine the role of ascorbate in 
cancer treatment. 
 
 
2. Mechanistic and translational studies support the use of IVC in cancer treatment. At pharmacologic 
concentrations easily achievable with IV administration, ascorbate preferentially induced cytotoxicity 
to cancer cells versus normal cells.8-13, 19-22 Our data in 48 cancer cell lines and 5 normal cells indicate 
that BCa is one of the most sensitive cancers to ascorbate treatment (Fig. 1).10 Ascorbate (2-20 mM) 
at only 1-2 hours exposure, decreases survival in tested BCa cell lines, but does not induce death in 
human peripheral white blood cells, fibroblasts, and epithelial cells.10 The ascorbate-induced cancer 
cell death is mediated by H2O2 as addition of catalase to the cell culture media completely protected 
cancer cells from ascorbate-induced cell death.8-10 
4 
INTRODUCTION: BACKGROUND INFORMATION AND RATIONALE 

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The chemistry is well-known for the formation of H2O2 from ascorbate in the presence of transition metals 
such as iron (Fe2+).23 To investigate whether the formation of H2O2 by ascorbate is physiologically relevant, we 
conducted in vivo studies in rodents. Rats and tumor bearing mice were given high doses of ascorbate (0.25-4 
g/kg body weight) either by intravenous injection (IV), intraperitoneal injection (IP), or oral gavage. Data 
confirmed our hypothesis and showed that only IV or IP administration achieved ascorbate concentrations in 
millimolar ranges in vivo (Fig. 2). 

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H2O2 triggers generation of downstream reactive oxygen species (ROS) and induces cell death. Because blood 
has a rich reducing system to prevent H2O2 accumulation, these ROS induced by ascorbate are not detected 
in blood stream (Fig. 2).8, 9 Therefore, IVC acts as a pro-drug to deliver oxidative stress to tissues, without ROS 
formation in the blood. This central mechanism of ascorbate-induced cytotoxicity, generated by our group, 
now have been confirmed by laboratories around the world.11-13, 19-22, 24-26 
 
 
 
 
Ascorbate generates H2O2 at both tumor sites and in normal tissues, but apparently exerts cytotoxicity 
specifically towards tumor cells and spares the normal cells. The selectivity is suggested by recent studies 
using multiple tumor models to be related to tumor cells’ abnormal energy metabolism and iron 
metabolism.1, 9, 12, 13 First, H2O2 generated by ascorbate damages DNA1, and therefore activates polyADP- 
ribose polymerase (PARP) for repair. Activated PARP catabolizes NAD+, thereby depleting substrate for NADH 
formation and consequent ATP synthesis.1, 9 ROS produced by H2O2 can disrupt intracellular iron metabolism, 
and thereby selectively sensitize cancer cells to ascorbate through pro-oxidant chemistry involving redox- 
active labile iron and enhanced H2O2 formation.13 As a result, cancer cells susceptible to ascorbate have 
elevated levels of redox-active labile iron and increased levels of transferrin receptor (Trf) compared to 
normal cells.13 Ascorbate also selectively kills SVCT2 (sodium-dependent vitamin C transporter 2) high- 
expressing cancer stem cells in hepatocellular carcinoma in theory due to increased uptake of ascorbate by 
SVCT2.27 Our survey of the TCGA database indicates upregulation of both Trf and SVCT in BCa tissues versus 
normal tissues. We will further investigate these mechanisms of cellular susceptibility. 
 
A number of animal tumor models have been tested and high dose parental ascorbate either alone or 
combined with standard chemotherapies showed promising tumor inhibitory effects. In a metastatic ovarian 
cancer model, we have shown that 4 g/kg daily IP injection of ascorbate (equivalent to ~1.3 g/kg by IV, 

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clinically relevant, 9, 10) enhanced treatment effects of carboplatin and paclitaxel.1 Ascorbate (Asc) alone 
reduced tumor burden relative to control group. 
 
Adding ascorbate to Cp and Pax reduced tumor weight by 94%, and completely abrogated ascites formation, 
an effect significantly better than Cp+Pax (Fig. 3A, B). In pancreatic cancer models, our data showed that 4 
g/kg IP ascorbate potentiated gemcitabine effects (Fig. 3C).2, 3 
 
 
 
 
None of these combined treatments nor ascorbate alone influenced body weight or induced any pathological 
changes in liver, kidney or spleen. In vitro combination index also showed strong synergy between ascorbate 
combined with either Cp, Pax, or gemcitabine.1, 28 
 
3. Phase I clinical data in multiple types of cancers showed feasibility, tolerability and potential efficacy 
More than a dozen of early phase trials in multiple types of cancers have shown safety, feasibility, and 
potential efficacy of IVC. A dose finding trial 18 in advanced oncological patients showed that IVC at the dose 
of 1.5 g/kg 3X weekly was safe and free of important toxicity. This dose sustains plasma concentrations >10 
mM for >4 hours, which is sufficient to induce death in many cancer cells. Two phase I trials in patients with 
advanced pancreatic cancers 29, 30 showed the same good tolerance, and had unexpected stable disease and 
prolonged survival when combining IVC with gemcitabine or gemcitabine+erlotinib. Pilot trials with non- 
small-cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) showed again that IVC is safe and well 

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Other Agent(s) / Treatment(s) 
Rationale 
 
tolerated when combine with standard chemo or radiation therapies and that IVC is promising in improving 
patient survival.13 Our Phase I/IIa trial in ovarian cancer patient adding IVC to standard paclitaxel/carboplatin 
therapy showed that IVC was very well tolerated.1 It substantially decreased grade 1 and 2 toxicities, and did 
not increase the rate of grade 3 or 4 toxicities in all categories of toxicity evaluated. The median progress free 
survival time (PFS) was prolonged (25.5 months with IVC versus 16.75 months without IVC). Similar results 
were obtained in our other phase I trial in pancreatic cancer patients: IVC was well tolerated, did not 
influence gemcitabine pharmacokinetic parameters, and tended to prolong median survival. Many cases 
including ours have been reported that IVC showed tumor inhibitory effects.28, 31-33 
 
As an acceptable alternate to standard of care cisplatin, participants will receive a single cycle of carboplatin 
(AUC 5 on day 1) and gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle with cystectomy scheduled 
at termination of the intervention. 
 
 
 
Compelling data from studies in vitro, in vivo and in patients show that pharmacologic concentrations of 
ascorbate have potential as a therapeutic agent for cancer by exerting oxidative damage selectively to 
cancer cells.1, 8-13 High dose intravenous administration of ascorbate (IVC) can provide concentrations 
sufficiently high to kill cancer cells.10, 14 IVC does not have cumulative toxicity, has been shown to work 
synergistically with standard chemotherapies including gemcitabine and carboplatin, and reduces 
toxicities that accompany chemotherapy.1 IVC has wide-spread off-label use in cancer patients.15 If 
clinically adopted, IVC could enhance anti-tumor effects, reduce chemotherapy-associated toxicities, and 
improve QOL. 
 
A number of phase II clinical trials are ongoing or in planning to detect benefits of IVC in multiple types of 
cancers, including prostate, lung, kidney, colon, ovarian, liver, and lymphoma. To our knowledge, IVC has not 
been clinically tested in BCa, and of more importance in treatment of cisplatin-ineligible MIBC patients.. 
Given the compelling data in multiple cancer models, and lack of treatment options for cisplatin ineligible 
MIBC, it is worthwhile to test the low-toxic potentially life-saving treatment of IVC combination therapy. 
 
This pilot study aims to fill gaps currently present in treatment of this understudied patient population, and 
will further explore multiple mechanism-related molecules that have the potential to be developed as true 
biomarkers for treatment response after IVC treatment. 
 
This study will use the BCa tumor bank established by Dr. John Taylor (PI). This is an IRB approved, annotated, 
longitudinal tumor bank of patient samples from initial point of entry to the KU system for up to 2 years post- 
treatment. This tumor bank allows us access to patient tissue throughout the study giving us a broad view of 
the patient response to treatment. 
 
Our primary hypothesis is that adding IVC to a gemcitabine/carboplatin NAC regimen will significantly 
improve pathological downstaging in cisplatin-ineligible MIBC patients, as well as those who decline cisplatin 
based NAC, undergoing cystectomy. We will also study molecular mediators for cellular outcome and 
ascorbate specific mechanism, and quality of life (QOL) to gather preliminary information for a larger multi- 
center, randomized, two-arm trial. 

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Study Risk / Benefit Ratio 
Study Known Potential Risks 
Study Known Potential Benefits 
5 
STUDY DESIGN AND METHODS 
 
 
An expanded trial would utilize The Albert Institute for Bladder Cancer Research, a non-profit headed by Dr. 
Taylor, providing cooperative agreement for trials among leading BCa institutions. Given the expertise and 
reputation of our research team, a multicentered trial would be attractive to our partner institutions. With 
the specificity of the patient population and the limited number of trials open nationally in this space, we 
believe the multicentered trial would be competitive, timely, effective, and likely to have substantial impact 
on the field and on clinical management of MIBC. 
 
 
The potential benefit of this study is judged to outweigh risk; therefore, the risk/benefit ratio is in favor of 
benefit. 
 
 
The research in this study poses greater than minimal risk but is likely to yield generalizable knowledge about 
the participant disorder or condition. 
 
 
Potential benefits include the possibility of increased response and increased overall survival for participants 
enrolling / registering on this study. In addition, participation in this trial may benefit future patients by 
advancing generalizable knowledge of treatments for patients with MIBC. 
 
 
This is a single arm, Simon design, “window of opportunity” trial, enrolling patients with cisplatin ineligible 
MIBC, or those who decline cisplatin base NAC. 
 
Assess rates of pathologic downstaging and quality of life in MIBC cisplatin-ineligible/declined patients 
when IVC is added to gemcitabine-carboplatin NAC. 
We have hypothesized adding IVC to carbo/gem NAC will enhance pathological downstaging and improve 
QOL. The patients eligible for this study (cisplatin ineligible or declined with MIBC) typically proceed straight 
to cystectomy within 6 weeks of first appointment. 
 
In this study, participants will receive a single cycle of an accepted SOC alternate, gemcitabine/carboplatin, 
along with IVC and then proceed to cystectomy. 
 
Outcome metrics will include pathologic downstaging rates at cystectomy, QOL measurements, DFS and DSS. 
 
QOL by patient-reported outcomes will be evaluated using the FACT-Bl questionnaire. All four subscales will 
be used to evaluate physical, social, emotional, and functional well-being. A higher score represents better 
QOL. 
 
Participants will complete these at enrollment, just prior to cystectomy, and then post-cystectomy. 

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6 
STUDY OBJECTIVES AND ENDPOINTS 
OBJECTIVE(S) 
Primary Objective 
Secondary Objective(s) 
Exploratory Objective(s) 
 
 
Adverse events will be evaluated by the NCI Common Terminology Criteria for Adverse Events (CTCAE 5.0), 
and scored from 1-5. . 
 
Evaluate mechanism-related molecules that have the potential to reflect/predict responses to IVC 
treatment when added to NAC. 
1) Assess Mediators of Cancer Cells’ Responses to IVC. As described in Preliminary Data, upregulated TfR 
and SVCT2 expression have been proposed to increase cancer cells susceptibility to ascorbate 
treatment, by increasing cellular liable iron pool and ascorbate uptake.13,27 We will collect tumor 
specimens from all participants at initial resection and at cystectomy via the IRB approved BCa tumor 
bank. For measurement of TfR and SVCT1/2 expression levels, qRT-PCR will be used for detecting 
mRNA expression levels in snap frozen tumor tissues. Immunofluorescence or immunohistochemistry 
assay will be utilized using OCT embedded frozen tissues. The expression levels will be given 
numerical H scores (0-300) by pathologist review, defined as sum of staining intensity (0, 1, 2, 3) 
multiplied by percentage of positive stained cells. The results from those who respond to IVC 
treatment will be compared to non-responders. 
 
2) Assess Mediators of Cellular Outcome and/or Validate IVC-specific Anti-tumorigenic Mechanisms. 
Initially we will evaluate cell death and cellular proliferation as defined mechanisms of the anti- 
cancer activity of ascorbate in complex with carboplatin/gemcitabine in our pre-cystectomy samples 
versus the post-treatment RC samples1. We will use TUNEL staining as a measure of cell death and 
Ki67 as a measure of cell proliferation. Our study found ascorbate treatment robustly enhanced α- 
tubulin acetylation selectively in cancer cells versus normal cells2, presumably because of H2O2 
formation. Ascorbate decreases NAD+, and NAD+ is an essential co-factor for the activity of the 
tubulin deacetylase Sirt-2. Inhibition in Sirt-2 activity elevates acetylation in α-tubulin. Increased 
acetylation in α-tubulin disrupts microtubule dynamics by over-stabilizing polymerized tubulin, and 
therefore inhibited mitosis, and mobility of cancer cells.2 We will detect the levels of α-tubulin 
acetylation by immunofluorescence or immunohistochemistry and H scores will be given. This could 
serve as an indicator for an ascorbate-specific mechanism in our trial. 
 
 
To assess pathologic downstaging rate in MIBC cisplatin-ineligible patients when IVC is added to a 
gemcitabine/carboplatin NAC regimen. 
 
1. To assess Quality of life. 
2. To measure Disease Free Survival (DFS). 
3. To measure Disease Specific Survival (DSS). 
 
Biomarkers for Cell death, IVC related biomarkers and cellular outcome biomarkers will be evaluated in 
tumor samples at initial resection and radical cystectomy. 

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Primary Endpoint 
Secondary Endpoint(s) 
Exploratory Endpoint(s) 
 
 
 
 
 
 
What is being measured 
Measurement time frame 
How will change be evaluated or 
measured 
Post treatment pathological 
staging 
4 to 6 weeks after first IVC 
infusion 
Pre and Post treatment specimen 
pathology results evaluated per 
American Joint Committee on Cancer 
(AJCC) staging guidelines 
 
 
 
 
What is being measured 
Measurement time frame 
How will change be evaluated or 
measured 
Overall change in patient- 
reported quality of life outcomes 
6 to 8 weeks 
Fact-Bladder (FACT-BI) Quality of life 
questionnaire 
Disease free survival rate (DFS) 
among participants 
Up to 3 years 
Medical Record 
Overall survival rate among 
participants 
Up to 5 years 
Medical Record 
 
 
 
What is being measured 
Measurement time frame 
How will change be evaluated 
or measured 
Cellular outcome markers 
Initial resection and at 
cystectomy 
TUNEL staining 
Ki67 
IVC uptake - Levels of SLC23A2 (SVCT2, 
vitamin C tissue receptor). 
IVC specific mechanism markers – Acetylated 
tubulin levels and transferrin receptor levels. 
Cell death. 
Cell proliferation. 
ENDPOINTS AND MEASURE(S) 

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Participant Inclusion Criteria 
 
 
 
 
Males and females of all races and ethnicities are eligible to participate in this study and must meet all of the 
inclusion criteria listed below to participate in this study. 
 
MRN 
INITIALS 
Verified 
Criteria 
Ability of participant OR Legally Authorized Representative (LAR) to understand this study, and 
participant or LAR willingness to sign a written informed consent 
Age ≥ 18 years 
Age: 
ECOG Performance Status = 0 -- 2 (Appendix A). 
PS: 
Diagnosis/disease status 
Cisplatin-ineligible or declined muscle invasive bladder cancer. 
Cisplatin ineligibility will be defined based on Galsky criteria: 
• 
CTCAE ver. 5.0 Grade 2 or greater peripheral neuropathy. 
• 
CTCAE ver. 5.0 Grade 2 or greater hearing loss. 
• 
Creatinine clearance estimated or calculated < 60 
ml/min. 
Type: 
DX Date: 
Patients must have adequate organ function at enrollment, defined as follows: 
Result 
Date 
Absolute neutrophil count ≥ 1,500/μL 
μL 
Platelets ≥ 100,000/μL 
μL 
Hemoglobin ≥ 9 g/dL 
dL 
Creatinine clearance (estimated or calculated) ≥ 30 ml/min 
Total bilirubin ≤ 2.0 mg/dl 
AST(SGOT) 
≤ 2.5 X institutional upper limit of normal 
ALT(SGPT) 
≤ 2.5 X institutional upper limit of normal 
Normal Glucose-6-phosphate dehydrogenase (G6PD) status 
Women of child-bearing potential and men with partners of child-bearing potential must agree 
to practice sexual abstinence, or to use the forms of contraception listed below, prior to study 
entry, for the duration of study participation, and for WOMEN: 6 months after EOT, MEN: 
3 months after EOT following completion of therapy. If a woman becomes pregnant or suspect 
she is pregnant while participating in this study, she should inform her treating physician 
immediately. 
7 
STUDY ENROLLMENT / REGISTRATION AND WITHDRAWAL 

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Participant Exclusion Criteria 
 
 
MRN 
INITIALS 
Verified 
Criteria 
A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) who meets the following criteria: (Please check the 
appropriate response and mark the other response as N/A). 
Has not undergone a hysterectomy or bilateral oophorectomy; 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had 
menses at any time in the preceding 12 consecutive months) and is < 45 years of age. 
Men of child-bearing potential must not donate sperm while on this study and for 3 months 
after their last study treatment. 
Acceptable birth control methods include: (Please check the appropriate response and mark the other 
responses as N/A). 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation: 
Oral 
Intravaginal 
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
Oral 
Injectable 
Implantable 
Other Methods: 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner 
Sexual abstinence, if this is the preferred and usual lifestyle of the participant 
 
 
Participants meeting any of the exclusion criteria listed below at screening will be excluded from study 
participation. 
 
Absent 
Criteria 
Patient simultaneously enrolled in any therapeutic clinical trial 
Current or anticipated use of other investigational agents while participating in this study 
Psychiatric illness/social situations that would limit compliance with study requirements 
Pregnant or breast feeding. There is a potential for congenital abnormalities and for this 
regimen to harm breast feeding infants. 
Women of childbearing age expecting to conceive children while receiving study treatment 
and for 3 months after the last dose of study treatment 
Other study specific criteria 

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MRN 
Initials 
Absent 
Criteria 
Histology of pure adenocarcinoma, pure squamous cell carcinoma, or pure small cell 
carcinoma in the TURBT sample 
Prior systemic chemotherapy (prior intravesical therapy is allowed) for bladder cancer and/ or 
prior radiation therapy to the urinary bladder with curative intent for bladder cancer. 
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhea, 
Current consumption of tobacco products, patients may be asked to quit for 2–3 weeks prior 
to enrollment 
If tobacco use is suspected at any point during the trial, continine level will be obtained 
History of G6PD deficiency 
History of oxalate renal calculi 
 
 
Eligibility 
Confirmed by 
Print Name 
Signature 
Date 
Clinical Research 
Coordinator 
Clinical Research 
Coordinator 
Double Check 
Treating Physician 
 
Once eligibility has been confirmed, use the link below to register your participant. 
Please allow up to 24 business hours for the registration process. 
 
https://redcap.kumc.edu/surveys/?s=TTLWNND9TP 

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Participant Withdrawal Or Termination 
Reasons For Withdrawal Or Termination 
 
 
 
 
General Guidelines 
Eligible participants will be registered through the KUCC Clinical Research Office central registration process. 
Registration must occur prior to the initiation of therapy, with treatment assignment provided by KUCC. Any 
participant not registered to the protocol before treatment begins will be considered ineligible and study 
treatment will be denied. 
 
The completed source documentation for eligibility verification and registration must be kept in the 
participant binder for monitoring purposes and documentation. 
 
Issues that would cause treatment delays should be discussed with the Sponsor - Investigator. If a participant 
does not receive protocol therapy following registration, notify the KU Cancer Center Project Director or 
designee and update participant’s status in the CRIS system. 
 
Registration Process 
The Coordinating Center (KUCC) is accessible for registration Monday through Friday from 8:00 AM to 5:00 
PM Central Time. Please allow up to 24 hours for completion of registration. 
 
The registration procedures are as follows: 
1. Obtain written informed consent from the patient prior to the performance of any study related 
procedures or assessments. Tests required at screening and performed as part of customary care 
prior to signing consent, are allowed IF those tests were performed within the timeframe listed in the 
section of this protocol with title STUDY PROCEDURES AND SCHEDULE. 
2. Complete appropriate baseline demographic information in CRIS. Print, complete and obtain 
appropriate signatures for the inclusion/exclusion criteria to document eligibility. Maintain 
completed documents in participant’s research record. Participants must meet all eligibility criteria to 
be eligible for registration. 
3. Use the hyperlink at the bottom of the eligibility criteria, complete information and submit to initiate 
the registration process. 
4. Email confirmation of registration will be sent to the person initiating the registration. Registration 
confirmation should be maintained as part of the participant’s research record. 
 
 
 
Participants can be taken off the study treatment and/or study at any time at their own request, or they may 
be withdrawn at the discretion of the investigator. The reason(s) for discontinuation will be documented and 
may include: 
• 
Participant voluntarily withdraws from treatment (follow-up permitted); 
• 
Participant withdraws consent (termination of treatment and follow-up); 
• 
Participant is unable to comply with protocol requirements; 
• 
Participant demonstrates disease progression (unless continued treatment with study drug is 
deemed appropriate at the discretion of the investigator); 
• 
Participant experiences toxicity that makes continuation in the protocol unsafe; 
8 
PARTICIPANT REGISTRATION PROCEDURES 

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Participant Replacement 
9 
MEASUREMENT OF EFFECT 
Solid Tumor 
Antitumor Effect 
 
• 
Inter-current illness that prevents further administration of treatment 
• 
Treating physician judges continuation on the study would not be in the participant’s best 
interest; 
• 
Participant becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
• 
Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
• 
Lost to follow-up. 
 
 
Since this is small single arm study, participants who do not complete study treatment or undergo definitive 
surgery will be replaced. All participants will be evaluated for toxicity. 
 
 
 
 
Definitions 
Evaluable for toxicity. All participants will be evaluable for toxicity from the time of signing of consent. 
 
Evaluable for objective response. Only those participants who have disease present at baseline, and have 
received one cycle of therapy, and have had their disease re-evaluated at definitive surgery will be 
considered evaluable for response. These participants will have their response classified according to the 
definitions stated below. 
 
Disease Parameters 
 
Methods for Evaluation of Disease: 
We will evaluate the patients for response after definitive surgery (radical cystectomy). Pathologic 
downstaging to non-invasive disease <pT2 via pathological inspection of cystectomy specimen will be 
recorded after enrolling 13 subjects and based on these results, an additional 8 subjects may be enrolled by a 
Simon 2-stage design. 
 
Evaluation of Overall Response: 
The number of subjects who have downstaging of their tumor to non-invasive disease ( <ypT2 disease) will be 
evaluated after surgery. 
 
In addition, we will evaluate the complete response rate defined as patients with no evidence of residual 
disease at radical cystectomy (ypT0). 
 
Disease-Free Survival (DFS) 

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10  STUDY AGENT(S) / THERAPY / DEVICE 
ASCORBIC ACID / VITAMIN C 
 
 
DFS will be defined as time from cystectomy to disease recurrence or death resulting from disease. Patients 
alive without disease progression at the time of analysis were censored at the date of last disease 
assessment. 
 
Overall Survival (OS) 
Overall survival is defined as the duration of time from start of treatment to death. Participants who do not 
experience death during the evaluation period, or are lost to follow-up, will be censored on the date they 
were last known to be alive. 
 
 
 
 
ASCORBIC ACID/VITAMIN C is investigational. 
 
IV DRUG 
PHARMACOLOGY - 
Please refer to current Package Insert. 
 
PHARMACOKINETICS 
 
Please refer to current Package Insert. 
 
ADVERSE EFFECTS 
 
There are no contraindications to the administration of ascorbic acid except for high-dose infusion (over 15 
grams) with enzyme G6PD deficiency, which results in hemolysis when high-dose intravenous ascorbic acid is 
given. As part of the requirement for enrollment, study participants will have their G6PD status screened and 
if below normal activity, they will not be allowed to participate. 
 
Oxalate renal calculi have been theorized to occur in susceptible individuals after infusions of high-dose 
ascorbate. As part of the Inclusion/Exclusion criteria, patients with a history of oxalate renal calculi will not be 
allowed to enroll in the study. This information will be collected at screening. In addition, there will be close 
monitoring of the renal function by urinalysis and blood tests. This occurrence has not been identified in our 
prior clinical trials and clinic experience. 
 
Shifts in serum calcium levels have been theorized to occur from intravenous ascorbic acid and manifests as 
shaking or shivering. This was not found in our pharmacokinetic study (Unpublished data). 
 
Theoretical concerns that have not been reported or not seen by the Principal Investigator or her colleagues 
include pH abnormalities, hypoglycemia, electrolyte disturbances, cardiac arrhythmias, and uric acid 
nephropathy. We will evaluate metabolic profiles and clinical status as part of the routine monitoring of the 
study participants. 

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It is always possible that phlebitis could result from venipuncture or intravenous line placement. It is also 
possible that phlebitis and cellulites could result from infiltration of the study drug fluid outside of the vein. 
This will be routinely monitored by the staff of the consortium sites. This is considered only a slight risk. 
 
Transient mild soreness may occur at the site of intramuscular or subcutaneous injection. 
 
It is possible that a study participant could experience an idiosyncratic reaction to the study drug that could 
result in a hypersensitivity reaction or potentially anaphylaxis. Patients’ vital signs and status are monitored 
as part of routine care. 
 
General Precautions 
Too-rapid intravenous injection is to be avoided. Too-rapid intravenous administration of the solution may 
cause temporary faintness or dizziness. 
 
Laboratory Tests 
Diabetics taking more than 500 mg of ascorbic acid daily, may obtain false reading of the urinary glucose test. 
No exogenous ascorbic acid should be ingested for 48 to 72 hours before amine dependent stool occult blood 
tests are conducted because possible false negative results may occur. 
 
Pregnancy and Lactation: 
 
Usage in Pregnancy 
Pregnancy Category C 
Animal reproduction studies have not been conducted with Ascorbic Acid Injection. It is also not known 
whether Ascorbic Acid Injection can cause fetal harm when administered to a pregnant woman or can affect 
reproduction capacity. Ascorbic Acid Injection should be given to a pregnant woman only if clearly needed. 
 
Nursing Mothers 
Caution should be exercised when Ascorbic Acid Injection is administered to a nursing woman. 
 
Drug Interactions: 
 
Limited evidence suggests that ascorbic acid may influence the intensity and duration of action of 
bishydroxycoumarin. 
 
Permitted and Excluded Concomitant Medications. 
Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed at the 
discretion of the site specific Investigator 

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Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc]) 
Should be used, when necessary, for all 
patients 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
Excluded concomitant medications 
Prohibited Concomitant Medications 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy other 
than those under investigation in this study 
Should not be given concomitantly while the patient 
is on study treatment 
Limited evidence suggests that ascorbic acid 
may influence the intensity and duration of 
action of bishydroxycoumarin. 
Appropriate monitoring for participants who 
continue anticoagulation therapy with 
bishydroxycoumarin. 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study 
Other than paclitaxel/carboplatin chemotherapy 
included in this trial, no other chemotherapy will be 
given concomitantly while the patient is on study 
treatment. (Concurrent use of hormones for non- 
cancer-related conditions [e.g., insulin for diabetes ] 
is acceptable. Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is 
acceptable [e.g., by local surgery or radiotherapy]) 
Diabetics should not undergo glucose 
monitoring by glucometer fingerstick method 
within 4 hours of receiving intravenous 
ascorbic acid. False positive elevations of 
glucose readings result because of testing 
method error. 
All glucose monitoring 4 hours post intravenous 
ascorbic acid must be done by phlebotomy and 
routine laboratory testing. All decisions about 
insulin dosing post IV vitamin C infusion must be 
based on laboratory metabolic testing and not on 
glucometer fingerstick method as hypoglycemia 
may result from false reading. 
 
DOSING & ADMINISTRATION 
 
See Method of Administration below, sections with titles TREATMENT PLAN and DESCRIPTION OF 
PROCEDURES. 
 
HOW SUPPLIED 
 
Ascorbic acid/vitamin C will be supplied as 500 mg/ml in a 50 mL vial (total 25 grams/vial). 
 
The sterile dispensing vials contain per mL: Ascorbic Acid 500 mg, Disodium Edetate 0.25mg in Water for 
Injection q.s. pH (range 5.5-7.0) , adjusted with Sodium Bicarbonate and Sodium Hydroxide. Contains no 
preservatives. 

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STORAGE, PREPARATION & STABILITY 
 
Storage 
 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product 
should be kept in secondary packaging until use to prevent excessive light exposure. 
 
Preparation and Stability 
 
The dose of intravenous vitamin C for administration must be prepared by the Investigator’s or site’s 
designated INVESTIGATIONAL PHARMACY using usual technique. Total time from needle puncture of the 
Ascorbic acid/Vitamin C vial to the start of administration should not exceed: 
• 
2 hours at 2°C to 8°C (36°F to 46°F). 
• 
2 hours at room temperature. 
Infusion solution must be allowed to equilibrate to room temperature prior to commencement of 
administration. 
 
For 25gm dose: remove 50mL from a 500mL bag of Lactated Ringers. Inject 25gm (50mL or 1 bottle) of 
ascorbic acid and 2mL of MgCl into the bag. 
 
For the 50gm dose: Remove 100mL from a 1L bag of Sterile Water for Injection. Inject 50gm (100mL or 2 
bottles) of ascorbic and 2mL of MgCl into the bag. 
 
For the 75gm dose: Remove 150mL from a 1L bag of Sterile Water for Injection. Inject 75gm (150mL or 3 
bottles) of ascorbic acid and 2ml of MgCl into the bag. 
 
For 100gm dose: Remove 200mL from a 1L bag of Sterile Water for Injection. Inject 100gm (200mL or 4 
bottles) of ascorbic acid and 2mL of MgCl into the bag. 
 
For 125gm dose: Remove 250mL from a 1L bag of Sterile Water for Injection. Inject 125gm (250mL or 5 
bottles) of ascorbic acid and 2mL of MgCl into the bag. 

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DOSE ESCALATION/PREPARATION TABLE 
Na Ascorbic Acid 
(calculated using 
500mg/mL ascorbic 
acid) 
Osmolarity calculated in Sterile 
Water 
Osmolarity calculated in Ringer’s 
Lactate 
250 mL 
500 mL 
1000 mL 
250 mL 
500 mL 
1000 mL 
25 grams 
1212 
606 
303 
1433 
857 
568 
50 grams 
2400 
1200 
600 
2565 
1423 
851 
75 grams 
3588 
1794 
897 
3697 
1989 
1134 
100 grams 
4776 
2388 
1194 
4829 
2555 
1427 
125 grams 
XXX 
XXX 
1191 
XXX 
XXX 
XXX 
 
• 
All mixing and dispensing will occur at the site’s Investigational Pharmacy or oncologist’s infusion 
center where logs will be kept of product lot numbers and dispensing volumes, dates and times. 
• 
Product will be ordered from supplier by the University of Kansas study team and shipped to 
dispensing sites via Federal Express in temperature-controlled containers. 
• 
All records and necessary documentation of product delivery and condition will be kept in the study 
log in Investigational Pharmacy or dispensing site. 
• 
After delivery of product to the site, the vials will be kept in a dark secure location and refrigerated at 
2˚ to 8˚ C until use. 
• 
Mixing in the appropriate carrier fluid must not occur more than 2 hours prior to infusion to prevent 
degradation of the ascorbic acid and delivered to the site immediately upon mixing. 
• 
The MgCl prevents vascular spasm and discomfort during infusion. 
• 
Standard IV tubing is used and the infusion is delivered by infusion pump so that the IV vitamin C 
solution is delivered at 0.5 grams/minute. For example, 75 grams of vitamin C solution will be 
delivered over 150 minutes. 
• 
In the event of opened study material not used or expired material, the ascorbic acid will be disposed 
of in Investigational Pharmacy at each site according to procedure. Records of discarded material will 
be kept in the Investigational Pharmacy study log. 
Route of Administration 
 
IV infusion. Do not administer as an IV push or bolus injection. 
 
 
Method of Administration 
 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion set used 
after the contents of the IV bag are fully administered, or complete the infusion according to institutional 
policy to ensure the full dose is administered and document if the line was not flushed. 

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Ascorbic Acid/vitamin C at escalating doses will be administered at room temperature (approximately 25°C) 
by controlled infusion into a peripheral or central vein. 
 
Starting dose of vitamin C will begin at 25 grams and may be escalated to 125 grams based on plasma vitamin 
C level. 
 
One dose of 25 grams will be administered, then the Dose Escalation/Preparation Table outlining dose 
escalations (above) will be used. Following preparation of vitamin C for infusion, the entire contents of the IV 
bag should be administered as an IV infusion at a rate of 0.5 grams/minute (i.e. 50 grams = 100 minutes), 
using a volumetric pump with a 0.2-1.2 micron in-line filter at the protocol specified dose. It is not to be 
administered as an IV push or bolus injection. 
 
Dose escalation will continue until a plasama level of at least 350 mg/dL is reached but will not exceed 125 
grams of vitamin C. 
 
In the event that there are interruptions during infusion, the total allowed time should not exceed 2 hours 
for the 25g and 50 g doses. 
 
Do not co-administer other drugs through the same infusion line. 
 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared from new 
vials. Injectable ascorbate does not contain preservatives, and any unused portion must be discarded. 
 
DRUG ORDERING AND ACCOUNTABILITY 
 
Drug Ordering 
 
Ascorbic Acid/Vitamin C will be ordered through vendor. 
Ordering will be managed by KUMC study team. 
 
Drug Handling and Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents received from vendor. 
 
Drug return and/or disposition instruction 
 
Per institutional standard procedures. 

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GEMCITABINE DRUG INFORMATION 
Duration Of Therapy 
 
 
 
Carboplatin is considered standard of care in this setting. 
Please refer to current Package Insert. 
 
 
Gemcitabine is considered standard of care in this setting. 
Please refer to current Package Insert. 
 
 
Participants will receive a single cycle of an accepted SOC alternate, gemcitabine/carboplatin, along with IVC 
and then proceed to cystectomy. 
 
IVC administration is established by dose escalation regimen1, 2 initiated at a single dose of 25 g and titrated 
up to a target peak plasma concentration of 350 to 400 mg/dL (~20 mM), monitored by HPLC detection.1 
Dose of vitamin C can be increased up to but not more than 125 grams to reach target plasma level. Once the 
therapeutic dose is established, the participants will continue to receive IVC 2 to 3 times per week at the 
Westwood Urologic Oncology treatment clinics during the 28-day window leading into cystectomy. 
 
If target plasma level is not reached with dose escalation, surreptitious tabocco use will be evaluated by 
continine blood level. If positive for tobacco use, participant will be removed from trial and replaced. 
 
Participants will receive a single cycle of carboplatin (AUC 5 on day 1) and gemcitabine 1000 mg/m2 on days 1 
and 8 of a 21-day cycle with cystectomy scheduled at termination of the intervention. Thus, there is no delay 
in surgery based on the proposed NAC regimen. 
 
QOL by patient-reported outcomes will be evaluated using the FACT-Bl questionnaire. All four subscales will 
be used to evaluate physical, social, emotional, and functional well-being. A higher score represents better 
QOL. Participants will complete these at enrollment, just prior to cystectomy, and then post-cystectomy. 
 
Outcome metrics will include pathologic downstaging rates at cystectomy, QOL measurements, DFS and DSS. 
 
 
Participants will be enrolled and treated for one 28 day cycle (21 days for Gem/Carbo, 28 days for IVC.). 
Treatment will occur during the 4 to 6 weeks after diagnosis and before standard of care surgery. 
 
 
Study drug accountability per Institutional standard operating procedures. 
CARBOPLATIN DRUG INFORMATION 
11  TREATMENT PLAN 
Study Agent Accountability Procedures / Participant Compliance 

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Participant Access To Study Agent At Study Closure 
Dose Adjustments/Modifications/Delays 
 
 
 
 
 
NOTE for nursing staff: 
Intravenous vitamin C administration may be infused through surgically implanted indwelling venous 
catheters that are commonly placed during oncology care. If an indwelling catheter is not available, 
peripheral venous access may be used. Access and deaccess must be undertaken via standard of care policies 
of the sub-site institutions. 
 
Infusion administered with infusion pumps to assure 0.5 gram/ minute infusion rate (i.e. 75 grams = 150 
minutes). 
 
Diabetics should not undergo glucose monitoring by glucometer fingerstick method within 4 hours of 
receiving intravenous ascorbic acid. False positive elevations of glucose readings result because of testing 
method error. All glucose monitoring 4 hours post intravenous ascorbic acid must be done by phlebotomy 
and routine laboratory testing. 
 
All decisions about insulin dosing post IV vitamin C infusion must be based on laboratory metabolic testing 
and not on glucometer fingerstick method as hypoglycemia may result from false reading with subsequent 
insulin administration. 
 
 
Participant can have access to IV vitamin C at study closure. Note: Participants may incur out-of-pocket costs 
(IV vitamin C off-study may not be covered by participant insurance). 
 
Potential referral for infusion site trained in IV C administration can be found at 
 
http://www.acam.org/ or http://www.faim.org/international-college-of-integrative-medicine 
 
 
Any participant who receives treatment on this protocol will be evaluable for toxicity. Each participant will be 
assessed for the development of toxicity according to the Schedule of Events table. CTCAE term (AE 
description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting and toxicity assessment. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Information and links regarding CTCAE version 5.0 can be found at the CTEP website: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
1. Adverse events, whether volunteered by the study participant, discovered by the investigators during 
questioning, or detected by physical examination, laboratory tests, or other means will be collected and 
Nursing Staff Duty Implications 

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SURGICAL TREATMENT PLAN 
12  GUIDELINES FOR MANAGEMENT OF POTENTIAL ADVERSE EVENTS 
INTRAVENOUS ASCORBIC ACID / VITAMIN C 
 
 
recorded. An adverse event is any undesirable sign, symptom, or medical condition occurring after starting 
the study drugs even if the event is not considered to be related to study drugs. Pre-existing medical 
conditions will be considered adverse events if they worsen during study protocol. Events will be recorded 
from the time the consent is signed until 4 weeks after the study protocol is discontinued. 
2. Patients experiencing Grade 4 neutropenia, Grade 3 thrombocytopenia, or Grade 2 peripheral neuropathy 
that do not recover will have treatment protocol discontinued. 
3. Colony-stimulating factors will be prescribed at the discretion of the treating oncologist. 
4. Although intravenous ascorbic acid in the doses administered in this study has been shown not to be toxic, 
to ensure that these therapies are non-toxic, liver enzymes and creatinine will be monitored during the 
treatment phase. 
5. Idiosyncratic intolerance of intravenous ascorbic acid such as acute hypersensitivity will be recorded. 
6. Significant adverse events related to the study drug will necessitate removal from the protocol. The study 
participants will be monitored until the AE resolves. 
 
 
Patients will undergo a radical cystectomy with lymph node dissection as is standard of care for MIBC. This is 
not part of this study or the study experimental procedures. 
 
 
Participants will be monitored for AEs from the time of signing informed consent through their last follow-up 
visit (90 days after the date of the last dose of study drug treatment.) Participants will be instructed to notify 
their physician immediately at the onset of any AE. Seriousness, severity grade, and relationship to study 
treatment of AEs will be determined by the investigator. AE severity will be graded by the investigator in 
accordance with CTCAE v.5.0. 
 
 
Guidelines for management of potential adverse events for intravenous Vitamin C are not needed. 
 
Previous studies and clinical experience have shown no toxicities to the dose of IV Vit C to be used in this 
study. 
 
Adverse events will be collected in the usual manner using CTCAE v 5.0. Dose modifications will not be made 
after the dose for IV C has been established. There have been no dose limiting toxicities identified from our 
previous clinical trials, the clinical trial experience of others, or our extensive clinical experience administering 
IV C. Previous studies and clinical experience have shown no toxicities referable to the doses of IV C to be 
used in this study. 

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Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also 
the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during carboplatin 
injection treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in 
patients receiving single agent carboplatin. In general, single intermittent courses of carboplatin should not 
be repeated until leukocyte, neutrophil, and platelet counts have recovered. 
 
Since anemia is cumulative, transfusions may be needed during treatment with carboplatin, particularly in 
patients receiving prolonged therapy. 
 
Bone marrow suppression is increased in patients who have received prior therapy, especially regimens 
including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial 
carboplatin injection dosages in these patients should be appropriately reduced and blood counts should be 
carefully monitored between courses. The use of carboplatin in combination with other bone marrow 
suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize 
additive effects. 
 
Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted 
in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both 
drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was 
administered at higher than recommended doses in combination with other ototoxic agents. 
 
Carboplatin can induce emesis, which can be more severe in patients previously receiving emetogenic 
therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. 
Although no conclusive efficacy data exist with the following schedules of carboplatin, lengthening the 
duration of single intravenous administration to 24 hours or dividing the total dose over five consecutive 
daily pulse doses has resulted in reduced emesis. 
 
Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and 
in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in 
about 70% of the patients receiving carboplatin as secondary treatment. 
 
Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin with 
doses higher than those recommended in the package insert. Vision appears to recover totally or to a 
significant extent within weeks of stopping these high doses. 
 
As in the case of other platinum-coordination compounds, allergic reactions to carboplatin have been 
reported. These may occur within minutes of administration and should be managed with appropriate 
supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously 
exposed to platinum therapy 
CARBOPLATIN 

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13  CHILD-BEARING POTENTIAL / PREGNANCY 
 
 
 
 
Prophylaxis against sepsis: At the occurrence of fever >38.5°C (regardless of neutrophil count), the subjects 
should contact their physician and begin treatment with oral antibiotics per institutional guidelines (e.g., 
ciprofloxacin 500 mg PO twice per day or levofloxacin 500 mg PO once a day). It is advised that all subjects 
should be given a prescription for the appropriate antibiotics so they can immediately begin treatment with 
the first appearance of the fever. 
 
Colony stimulation factors: These should be given according to institutional guidelines. 
 
Interstitial pneumonitis: This can be seen with either Abraxane or GEM or the combination. Study 
medications should be immediately discontinued. If an infection etiology is ruled out, corticosteroids should 
be initiated. 
 
Posterior reversible encephalopathy syndrome (PRES): GEM should be permanently discontinued and 
supportive measures implemented, including blood pressure control and anti-seizure therapy, if PRES 
develops during therapy. 
 
Capillary leak syndrome: GEM should be discontinued and supportive measures implemented if capillary leak 
syndrome develops during therapy. 
 
 
Women, Men, and Pregnancy 
 
Because the effect of the study drug(s) is considered possibly teratogenic and has potential risks to the fetus, 
pregnant females will not be included in the study. However, no female of childbearing potential will be 
excluded from the study. Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with study drug(s), breastfeeding should be discontinued if the 
mother is treated with study drug(s). An effective form of contraception of the woman’s choice will be 
required at all times during study. Female participants should not get pregnant or breastfeed while in this 
study and for 6 months after the last dose of study medication. Male participants should not father a baby or 
donate sperm while in this study and for 3 months after the last dose of the study medication. A pregnancy 
test will be performed on enrollment/registration women of childbearing potential and men must agree to 
use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry 
and for the duration of study participation. If a woman becomes pregnant or suspects she is pregnant while 
participating in this study or if her male partner is a participant in this study, the treating physician should be 
informed immediately. 
 
The effects of the study drug(s), on the developing human fetus are unknown. 
 
A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) who meets the following criteria: 
Has not undergone a hysterectomy or bilateral oophorectomy; 
or 
GEMCITABINE 

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14  STUDY PROCEDURES AND SCHEDULE 
DESCRIPTION OF PROCEDURES / ASSESSMENTS 
 
 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time 
in the preceding 12 consecutive months) 
 
NOTE: Acceptable forms of birth control are listed below and must be documented in the participant’s chart: 
 
• 
Sexual Abstinence OR 
o One Barrier method (cervical cap with spermicide plus male condom; diaphragm with 
spermicide plus male condom) 
PLUS 
o Hormonal method (oral contraceptives, implants, or injections) or an intrauterine device 
(e.g., Copper-T). 
 
Women of child-bearing potential and men with partners of child-bearing potential must agree to practice 
sexual abstinence, or to use two forms of adequate contraception (hormonal AND barrier method of birth 
control) prior to study entry, for the duration of study participation, and for 6 months (for women) and 3 
months (for men) following completion of therapy. 
 
• 
If a woman becomes pregnant or suspects she is pregnant (missed or late menstrual period) while 
participating in this study, she should inform her treating physician immediately. 
 
• 
If the partner of a man becomes pregnant or suspects she is pregnant (missed or late menstrual 
period) while he is participating in this study, he should inform his treating physician immediately. 
 
• 
Men of child-bearing potential must not father a child or donate sperm while on this study and for 3 
months after their last study treatment. 
 
• 
Pregnancy must be reported along the same timelines as a serious adverse event. 
 
 
 
 
Please refer to the Schedule of Events Table(s) for summarized timelines of procedures. 
 
 
If the tests required at screening were performed as part of standard of care prior to signing consent for this 
study, the results from those tests are allowed in this study if the tests were completed within the timeframe 
listed below. 
 
All screening procedures must be performed within 28 Days prior to registration unless otherwise stated. 
Screening/Enrollment/Baseline 

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SCREENING VISIT 
 
• 
Informed Consent 
 
• 
Medical history 
o Complete medical (including child-bearing status), surgical and oncology history are obtained 
at screening. Any changes from time of signing consent (e.g. worsening severity or abnormal 
findings) are considered to be adverse events (AEs). 
 
• 
Demographics 
o Demographic profile will include date of birth, gender, race, and zip code. 
 
• 
Review participant eligibility criteria 
o Review of eligibility criteria to ensure participant qualification for study entry. 
 
• 
Review previous and concomitant medications 
o All prior medication taken by the participant within 4 weeks before starting the study is to be 
recorded. Concomitant medications taken by the participant during the study are to be 
recorded up until 30-days after last study dose. If a reportable adverse event (see section 
with title Adverse Events) occurs within 30 days after last study dose, recording of 
concomitant medications should continue until resolution of the adverse event. 
 
• 
Physical exam 
o Exam will include vital signs, height and weight – height to be measured at 
screening/baseline only 
o Note: Vital signs include temperature, pulse, SpO2, blood pressure 
 
• 
Performance status - ECOG 
o Performance status evaluated prior to study entry and at specified study visits. 
 
• 
Adverse event assessment - CTCAE v5.0 
o Baseline assessment via medical history, for determining later adverse events. 
 
• 
Urinalysis 
 
Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for 
red blood cells if clinically indicated. 

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Procedures During Treatment 
 
• 
Hematology 
o Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC), and 
differential. 
 
 
• 
Serum chemistries 
o Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), 
glucose, and total bilirubin. 
 
• 
Additional chemistries: 
o Glucose-6-Phosphate Dehydrogenase (G6PD) at baseline only 
 
• 
ECG 
o Standard 12-lead electro-cardiogram will be performed at screening only (ECG to be repeated 
at later study visits per PI discretion/if clinically indicated 
 
• 
Urine Pregnancy test (for females of child bearing potential) only done at screening 
 
• 
Tumor Biopsies, Blood and Urine Sample Collection [REQUIRED for participants] 
Tumor tissue, blood and urine will be collected under the current, IRB approved, bladder cancer tumor bank 
(Appendix C). Tissue evaluated under this study will be pre-treatment transurethral resection (TURBT) and 
post-treatment cystectomy specimens obtained from the bladder cancer biorepository (PI: John Taylor, III, 
MD, MS). 
 
Archival tissue will be accepted for pre-treatment specimens if TURBT was performed outside of KUMC. 
 
 
 
All participants will receive a single cycle of standard of care chemotherapy with Carboplatin AUC5 on day 1 
and Gemcitabine 1000 mg/m2 on days 1 and 8 of a 21 day cycle. 
ONE TREATMENT CYCLE for IVC = 28 DAYS TO INCLUDE INITIAL 1 WEEK FOR IV C DOSE ESCALATION + 21 
DAYS FOR CHEMOTHERAPY TREATMENT 
 
Week 1 Day 1 IV Vitamin C dosing 
NOTE: - Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do not need to be 
repeated 
• 
Physical exam, including weight, vital signs (temperature, pulse, SpO2, blood pressure) 
• 
Review previous and concomitant medications 
• 
Baseline FACT-Bl QOL instrument 
• 
CBC (WINDOW: + / - 7 DAYS) - Tests as listed in the table in SCREENING VISIT, above. 
• 
Serum chemistries (WINDOW: + / - 7 DAYS) - Tests as listed in the table in SCREENING VISIT, 
above. 
• 
ECOG 

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• 
Urinalysis - Tests as listed in the table in SCREENING VISIT, above 
• 
Adverse Events Review 
• 
IV VITAMIN C INFUSION (WINDOW: + / - 3 DAYS) 
• 
IV Carboplatin Infusion 
• 
IV Gemcitabine Infusion 
 
Monitoring of intravenous vitamin C dose administration - On the first infusion day, participants will be 
monitored and vital signs collected/recorded prior to and after infusion described below. 
• 
BP and pulse will be collected from participants before and after each infusion at the 
following times (based on a 60-minute infusion): 
• 
Prior to the beginning of the infusion (measured once from approximately 30 minutes before 
up to 0 minutes [i.e., the beginning of the infusion]) 
• 
At the end of the infusion( ±5 minutes) 
• 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated. A 1-hour 
observation period is recommended after the first infusion of vitamin C. 
• 
IV C up to 3 days/week while participanting in dose escalation phase of the trial. 
 
Infusion schedule for escalating doses of vitamin C/ascorbic acid 
• 
Percutaneous intravenous catheters will be placed in all study participants for venous access 
approximately 30 minutes prior to infusion. If indwelling ports are available, they will be 
accessed according to standard protocol. 
• 
Infusion materials will be prepared by Investigational Pharmacy and delivered to the clinic 
responsible for infusion by standard procedure. 
• 
All infusions will be administered by infusion pump at a rate of 0.5 grams/minute (i.e. 50 
grams = 100 minutes). 
 
Week 1 Ascorbic Acid Dose Escalation 
1st Infusion schedule for escalating doses of vitamin C/ascorbic acid 
• 
First Infusion of ascorbate: The starting infusion is one dose of 25 grams of Ascorbic acid in 
ringer’s lactate administered at 0.5 grams per minute (see instructions for mixing 
requirements). The first infusion will be administered preferably on Monday. No plasma 
sampling on day 1 for ascorbate levels after 25-gram dose. 
• 
CARBOPLATIN / GEMCITABINE IV INFUSION schedule, this will be standard of care dosing 
with adjustments made per discretion of treating oncologist to be administered in Westwood 
treatment area/ clinic as outlined above. 
NOTE: During the IV VIT C dose escalation phase, Cycle 1 chemotherapy may be started and can be given 
after an IV C dose or on alternate day. There is no inhibition of chemotherapy when IV C is given prior to the 
chemotherapy and can be used as the fluid loading dose if desired. In fact, there is an additive effect when IV 
C and carboplatin and gemcitabine are combined. 
Week 1 Day 3 
• 
Review previous and concomitant medications 
• 
Adverse events review 

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• 
IV VITAMIN C INFUSION (WINDOW: + / - 3 DAYS) 
• 
Monitoring of subsequent infusions - BP, pulse and other vital signs should be measured, 
collected/recorded prior to the start of the infusion. Patients should be carefully monitored 
and BP and other vital signs should be measured post infusion as clinically indicated 
• 
IV up to 3 days/week for the first weekdose escalation phase trial. 
2nd Infusion schedule for escalating doses of vitamin C/ascorbic acid 
• 
Percutaneous intravenous catheters will be placed in all study participants for venous access 
approximately 30 minutes prior to infusion. If indwelling ports are available, they will be 
accessed according to standard protocol. 
• 
Infusion materials will be prepared by Investigational Pharmacy or prepared in oncologist’s 
infusion center at the participating sites and delivered to the clinic responsible for infusion by 
standard procedure. 
• 
All infusions will be administered by infusion pump at a rate of 0.5 grams/minute (i.e. 50 
grams = 100 minutes). 
Week 1 Day 3 Ascorbic Acid Dose Escalation 
• 
Second infusion of ascorbate: The second infusion will not be given less than 24 hours apart 
and preferably on Wednesday. The second dose of ascorbic acid is scheduled to be 50 grams 
administered at 0.5 gram per minute in the Westwood treatment area of investigators. 
Plasma sampling for ascorbate level is mandatory at this dose level. Please note further 
dose escalation may not be necessary if 2nd dose given reaches targeted plasma level of 
350-450 mg/dL. 
• 
Sampling of plasma for ascorbic acid levels – Blood (10 mL in dark green top tube with 
sodium heparin) drawn immediately upon the completion of IVC infusion in the dose 
escalation phase, and immediately put on ice and transferred to the research laboratory and 
centrifuged at 4ºC at 1500 × g for 10 min. Plasma is taken and stored at -80ºC until analysis 
by HPLC for detection of ascorbate. 
• 
Plasma remains frozen at -80˚C and placed on dry ice 
• 
Attention: Qi Chen, PhD 
• 
The sample processing and HPLC analysis are performed according to a method established 
by Levine et al. Plasma is diluted 5~1000 times in 90% methanol with 1 mM EDTA, vortex, 
and then centrifuged at 4ºC at 20,000 × g for 15 min. Supernatant is analyzed by Waters 
e2695 HPLC (Waters, Milford, MA) with electrochemical detection (ESA, Chelmsford, MA). 
The column used is an ODS-DABS Ul Trasphere, 5µ, 4.6 mm × 25 mm (Beckman Coulter, 
Fullerton, CA). Mobile phase is run at a flow rate of 1 mL/min, containing 30% methanol, 0.05 
M sodium phosphate monobasic, 0.05 M sodium acetate, 189 µM dodecyltrimethyl- 
ammonium chloride, and 36.6 µM tetraoctylammonium bromide. The Empower II software 
(Waters, MA) is used for instrument control and data analysis. 
Week 1 Day 5 
• 
Review previous and concomitant medications 
• 
Adverse events review 
• 
IV VITAMIN C INFUSION (WINDOW: + / - 3 DAYS 

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• 
Monitoring of dose escalation infusions - BP, pulse and other vital signs should be measured, 
collected/recorded prior to the start of the infusion. Patients should be carefully monitored 
and BP and other vital signs should be measured post infusion as clinically indicated 
• 
IV C up to 3 days/week for the first week only while participant is on dose escalation phase 
trial. 
3rd Infusion schedule for escalating doses of vitamin C/ascorbic acid 
• 
Percutaneous intravenous catheters will be placed in all study participants for venous access 
approximately 30 minutes prior to infusion. If indwelling ports are available, they will be 
accessed according to standard protocol. 
• 
Infusion materials will be prepared by Investigational Pharmacy or prepared in oncologist’s 
infusion center at the participating sites and delivered to the clinic responsible for infusion by 
standard procedure. 
• 
All infusions will be administered by infusion pump at a rate of 0.5 grams/minute (i.e. 50 
grams = 100 minutes). 
Week 1 Day 5 Ascorbic Acid Dose Escalation 
• 
Please note this dose may not be necessary if 2nd dose given reaches targeted plasma level 
of 350-450 mg/dL. Third infusion of ascorbate: The final dose of the week will be 75 grams of 
ascorbic acid given at 0.5 gm/minute. Plasma sampling for ascorbate level is mandatory at 
this dose level. 
 
Ascorbic acid plasma sample preparation: 
• 
Sampling of plasma for ascorbic acid levels – Blood (10 mL in dark green top tube with 
sodium heparin) drawn immediately upon the completion of IVC infusion in the dose 
escalation phase, and immediately put on ice and transferred to the research laboratory and 
centrifuged at 4ºC at 1500 × g for 10 min. Plasma is taken and stored at -80ºC until analysis 
by HPLC for detection of ascorbate. 
• 
Plasma remains frozen at -80˚C and placed on dry ice 
• 
Attention: Qi Chen, PhD 
• 
The sample processing and HPLC analysis are performed according to a method established 
by Levine et al (61,62). Plasma is diluted 5~1000 times in 90% methanol with 1 mM EDTA, 
vortex, and then centrifuged at 4ºC at 20,000 × g for 15 min. Supernatant is analyzed by 
Waters e2695 HPLC (Waters, Milford, MA) with electrochemical detection (ESA, Chelmsford, 
MA). The column used is an ODS-DABS Ul Trasphere, 5µ, 4.6 mm × 25 mm (Beckman Coulter, 
Fullerton, CA). Mobile phase is run at a flow rate of 1 mL/min, containing 30% methanol, 0.05 
M sodium phosphate monobasic, 0.05 M sodium acetate, 189 µM dodecyltrimethyl- 
ammonium chloride, and 36.6 µM tetraoctylammonium bromide. The Empower II software 
(Waters, MA) is used for instrument control and data analysis. 
Week 2 Day 8 
• 
Review previous and concomitant medications 
• 
Adverse events review 
• 
IV VITAMIN C INFUSION (WINDOW: + / - 3 DAYS) 
o Monitoring of subsequent infusions - BP, pulse and other vital signs should be 
measured, collected/recorded prior to the start of the infusion. Patients should be 

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carefully monitored and BP and other vital signs should be measured post infusion as 
clinically indicated 
• 
IV C continues 2 days/week while participant is on trial. 
• 
If necessary, dose escalation may continue until plasma vitamin C level reaches targeted level 
of 350 – 450 mg/dL up to 125 grams of IV vitamin C. 
• 
If dose escalation fails to reach targeted plasma vitamin C level, it will be necessary to 
consider surreptitious tobacco use and a cotinine level will need to be drawn to confirm or 
refute. If participant is found to have findings consistent with tobacco use, the participant 
will be removed from trial. 
• 
IV Gemcitabine Infusion 
Week 2 Day 10 
• 
Review previous and concomitant medications 
• 
Adverse events review 
• 
IV VITAMIN C INFUSION (WINDOW: + / - 3 DAYS) 
o Monitoring of subsequent infusions - BP, pulse and other vital signs should be 
measured, collected/recorded prior to the start of the infusion. Patients should be 
carefully monitored and BP and other vital signs should be measured post infusion as 
clinically indicated 
• 
IV C continues 2 days/week while participant is on trial. 
Week 2 Day 12 
• 
Review previous and concomitant medications 
• 
Adverse events review 
Week 3 Days 15-19 
• 
Review previous and concomitant medications 
• 
Adverse events review 
• 
IV VITAMIN C INFUSION (WINDOW: + / - 3 DAYS) 
o Monitoring of subsequent infusions - BP, pulse and other vital signs should be 
measured, collected/recorded prior to the start of the infusion. Patients should be 
carefully monitored and BP and other vital signs should be measured post infusion as 
clinically indicated 
• 
IV C continues 2 days/week while participant is on trial. 
Week 4 Pre-Operative Period 
• 
Physical exam, including weight, vital signs (temperature, pulse, SpO2, blood pressure) 
• 
Review previous and concomitant medications 
• 
CBC (WINDOW: + / - 7 DAYS) 
 
Tests as listed in the table in SCREENING VISIT, above. 
• 
Serum chemistries (WINDOW: + / - 7 DAYS) 
o Tests as listed in the table in SCREENING VISIT, above. 
• 
ECOG 
• 
Adverse Events Review 
• 
Administer FACT-Bl QOL instrument 
Week 4 Days 22-26 
• 
Review previous and concomitant medications 

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14.1.3 End Of Treatment / Early Study Termination / Participant Study Withdrawal Visit 
Post-EOT/Surgery Follow-Up Visit(s) 
14.1.5 Pregnancy Follow-Up 
14.1.6 Long Term Follow-Up 
 
• 
Adverse events review 
• 
IV VITAMIN C INFUSION (WINDOW: + / - 3 DAYS) 
• 
Monitoring of subsequent infusions - BP, pulse and other vital signs should be measured, 
collected/recorded prior to the start of the infusion. Patients should be carefully monitored 
and BP and other vital signs should be measured post infusion as clinically indicated 
• 
IV C continues 2 days/week while participant is on trial. 
 
Termination of Treatment Phase to be scheduled for surgery 
 
 
• 
Review previous and concomitant medications 
• 
Hematology (WINDOW: + / - 7 DAYS) - Tests as listed in SCREENING VISIT, above. 
• 
Serum chemistries: (WINDOW: + / - 7 DAYS) - .Tests as listed in SCREENING VISIT, above. 
• 
Adverse Events review 
• 
Blood and Urine Sample Collection [REQUIRED for participants]under current IRB approved bladder 
cancer tumor bank (Appendix C) 
• 
Final Biopsy (WINDOW: + / - 7 DAYS) [REQUIRED for participants]. Post-treatment tumor tissue 
collection to be done during SOC surgery under current IRB approved bladder cancer tumor bank 
(Appendix C) 
 
 
EOT visit will occur during SOC post-surgical office follow-up at 42 days (approximately 6 weeks) post- 
operatively 
• 
Physical exam, vital signs 
• 
Review previous and concomitant medications 
• 
Adverse events review 
• 
FACT-Bl questionnaire 
 
 
3 months after EOT for women 
6 months after EOT for men 
 
• 
Phone call to check pregnancy status 
 
 
1, 3 and 5 years after EOT 
 
• 
Visit or phone call to check Disease Free Survival (DFS). 
• 
Visit or phone call to check Disease Specific Survival (DSS). 

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Cycles = 28 days 
(21 days for Chemotherapy 
[Gemcitabine and 
Carboplatin] 
28 days for IVC) 
Week 1 
Week 2 
Week 3 
Week 4 
EOT / 
Day of 
Surgery 
Post- 
Surgery / 
EOT 
Follow- 
Up 
Pregnancy 
Follow 
Up 
Long Term 
Follow Up 
Protocol 
Activity 
Eligibility 
Screening 
and 
Baseline 
-28 to 1 
Days 1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
42 days 
(approxi 
mately 6 
weeks) 
after 
surgery/ 
EOT) per 
SOC 
Women: 6 
months 
after EOT 
Men: 3 
months 
after EOT 
(+/- 7 
days) 
1, 3 and 5 
years after 
EOT 
Informed 
Consent 
X 
Medical History 
X 
Demographics 
X 
Review 
Eligibility 
Criteria 
X 
Review 
Concomitant 
Medications 
X 
With infusions 
X 
X 
Physical Exam 
(Height at 
screening only) 
X 
With infusions 
X 
Weight 
X 
X 
SCHEDULE OF EVENTS TABLE 

IIT-2019-IVC-GarboGem 
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Cycles = 28 days 
(21 days for Chemotherapy 
[Gemcitabine and 
Carboplatin] 
28 days for IVC) 
Week 1 
Week 2 
Week 3 
Week 4 
EOT / 
Day of 
Surgery 
Post- 
Surgery / 
EOT 
Follow- 
Up 
Pregnancy 
Follow 
Up 
Long Term 
Follow Up 
Protocol 
Activity 
Eligibility 
Screening 
and 
Baseline 
-28 to 1 
Days 1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
42 days 
(approxi 
mately 6 
weeks) 
after 
surgery/ 
EOT) per 
SOC 
Women: 6 
months 
after EOT 
Men: 3 
months 
after EOT 
(+/- 7 
days) 
1, 3 and 5 
years after 
EOT 
ECOG 
Performance 
Status 
X 
X 
Adverse Event 
Assessment 
X 
With infusions 
X 
X 
FACT-BL 
X 
Day 1 
X 
X 
CBC with Diff 
X 
X 
Day 1 
X 
X 
CMP 
X 
X 
Day 1 
X 
X 
Plasma 
sampling for 
During 2nd 
and 3rd 
IVC 

IIT-2019-IVC-GarboGem 
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2020-02-20 Version 2.0 
 
 
 
Cycles = 28 days 
(21 days for Chemotherapy 
[Gemcitabine and 
Carboplatin] 
28 days for IVC) 
Week 1 
Week 2 
Week 3 
Week 4 
EOT / 
Day of 
Surgery 
Post- 
Surgery / 
EOT 
Follow- 
Up 
Pregnancy 
Follow 
Up 
Long Term 
Follow Up 
Protocol 
Activity 
Eligibility 
Screening 
and 
Baseline 
-28 to 1 
Days 1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
42 days 
(approxi 
mately 6 
weeks) 
after 
surgery/ 
EOT) per 
SOC 
Women: 6 
months 
after EOT 
Men: 3 
months 
after EOT 
(+/- 7 
days) 
1, 3 and 5 
years after 
EOT 
ascorbate level 
assessment 
infusion – 
note 3rd 
may not 
be 
necessary 
G6PD 
X 
Urinalysis 
X 
X 
Day 1 
Serum 
Pregnancy1 
X 
12 Lead ECG 
X 
IV Ascorbic 
Acid Infusion 
Week 1: 
dose 
escalation 
up to 3 
doses, 
Days 1, 3, 
5 
Weeks 2-4 - maximum of 2 to 
3 doses / week if dose 
escalation is indicated; if no 
further dose escalation 
needed then 2 doses / week 

IIT-2019-IVC-GarboGem 
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Page 46 of 75 
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Cycles = 28 days 
(21 days for Chemotherapy 
[Gemcitabine and 
Carboplatin] 
28 days for IVC) 
Week 1 
Week 2 
Week 3 
Week 4 
EOT / 
Day of 
Surgery 
Post- 
Surgery / 
EOT 
Follow- 
Up 
Pregnancy 
Follow 
Up 
Long Term 
Follow Up 
Protocol 
Activity 
Eligibility 
Screening 
and 
Baseline 
-28 to 1 
Days 1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
42 days 
(approxi 
mately 6 
weeks) 
after 
surgery/ 
EOT) per 
SOC 
Women: 6 
months 
after EOT 
Men: 3 
months 
after EOT 
(+/- 7 
days) 
1, 3 and 5 
years after 
EOT 
Carboplatin 
Infusion 
X 
Day 1 
Gemcitabine 
Infusion 
X 
Day 1 
X 
Day 8 
Urine Sample 
Collection 
REQUIRED for 
participants 
X 
X 
Blood Sample 
Collection 
REQUIRED for 
participants 
X 
X 
Tumor tissue 
Collection 
REQUIRED for 
participants 
X 
X 

IIT-2019-IVC-GarboGem 
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Cycles = 28 days 
(21 days for Chemotherapy 
[Gemcitabine and 
Carboplatin] 
28 days for IVC) 
Week 1 
Week 2 
Week 3 
Week 4 
EOT / 
Day of 
Surgery 
Post- 
Surgery / 
EOT 
Follow- 
Up 
Pregnancy 
Follow 
Up 
Long Term 
Follow Up 
Protocol 
Activity 
Eligibility 
Screening 
and 
Baseline 
-28 to 1 
Days 1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
42 days 
(approxi 
mately 6 
weeks) 
after 
surgery/ 
EOT) per 
SOC 
Women: 6 
months 
after EOT 
Men: 3 
months 
after EOT 
(+/- 7 
days) 
1, 3 and 5 
years after 
EOT 
Phone Call to 
check 
pregnancy 
status 
X 
Phone Call or 
visit to check 
health status 
X 

IIT-2019-IVC-GarboGem 
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Abstract 
Objectives and Endpoints (For Correlative / Exploratory Studies Only) 
Sample Collection Instructions (For Correlative / Exploratory Studies Only) 
15  STATISTICAL CONSIDERATIONS 
Sample Size Justification 
 
 
 
Sample collection is REQUIRED for ALL participants. 
 
 
BACKGROUND AND SIGNIFICANCE 
 
We will perform correlative studies to evaluate cell death and apoptosis in response to a single cycle of NAC 
with Vitamin C. Our underlying hypothesis is that Vitamin C will potentiate the action of tumor cell death. 
We will also study biomarkers related to the mechanism of action for Vitamin C as outlined below. 
 
 
Exploratory Objective(s) 
 
Biomarkers for Cell death, IVC related biomarkers and cellular outcome biomarkers will be evaluated in 
tumor samples at initial resection and radical cystectomy. 
 
Exploratory Endpoint(s) 
Tumor samples will be collected at initial resection and at cystectomy for evaluation of generally used cellular 
outcome markers, as well as markers for IVC specific mechanism, via the IRB approved BCa tumor bank 
(Taylor PI). Acetylated tubulin levels and transferrin receptor levels in tumor samples will be detected as IVC 
related markers. SLC23A2 (SVCT2, vitamin C tissue receptor) will be assessed for drug uptake. We will use 
TUNEL staining as a measure of cell death and Ki67 as a measure of cell proliferation. This aim will generate 
information for future studies in reflective and predictive biomarkers in a larger clinical trial. 
 
 
Samples to include tumor tissue, blood and urine will be collected at the time of entry into the study as well as 
at the time of surgery under the IRB approved KUMC Bladder Cancer Longitudinal Biorepository for 
Development of Novel Therapeutics/Biomarkers (PI: John Taylor III, MD, MS, IRB#: STUDY00141546, Appendix 
C). Samples will be stored in Wahl Hall East 3019. 
 
 
 
Simon's two-stage minimax34 will be used. Pathologic downstaging to non-invasive disease <pT2 is reported 
as approximately 15% with cystectomy alone. Therefore, the null hypothesis that the true response rate of 
downstaging is 0.15 will be tested against a one-sided alternative. Typically, with effective NAC (for cisplatin 
eligible cases) we might expect 30% of subjects to respond with downstaging to non-invasive disease. 
Although we do not know exactly what to expect with this regimen, we will therefore use 0.30 as our 
CORRELATIVE / EXPLORATORY STUDIES 

IIT-2019-IVC-GarboGem 
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Description Of Statistical Methods 
General Approach 
Analysis Of Primary Objective 
Analysis Of Secondary Objective(s) 
desirable rate of response. In the first stage of the trial, 13 subjects will be accrued. If there are 1 or fewer 
responses in these 13 subjects, the study will be stopped for futility. In other words, 2 or more responses will 
be required to move to the second stage. In the first stage, we are looking for evidence of futility. If we do 
not have early evidence of futility. 8 additional subjects will be accrued for a total of 21. The null hypothesis 
will be rejected if 5 or more responses are observed in 21 subjects, which we will take as evidence that this 
treatment should be studied further. This design yields a type I error rate of .21 and power of 79% when the 
true response rate is 0.30. We feel this increased type I error rate is warranted by the pilot nature of this 
study, given that success of this study will be used to justify a larger study and estimate its power. With this 
design, the probability of early termination if the null hypothesis is true is approximately 0.39. The 
Department of Urology performs ~100 cystectomies per year with an anticipated 30-40 patients being either 
cisplatin ineligible or decline cisplatin based NAC. We do not foresee recruitment problems and fully expect 
to fulfill enrollment goals in the timeframe of the trial. However, due to funding considerations, only the first 
stage will be completed during the 1 year timeframe. Then, we anticipate further funding will be available to 
complete the analyses described in this protocol. 
 
 
 
Simon's two-stage minimax34 design will be used. For this design, we defined a response as downstaging to 
non-invasive disease. During the first year, only 13 subjects for the first stage will be accrued. Then, we 
anticipate further funding will be available to complete the analyses described in this protocol. Assuming a 
successful first stage (2 or more responses), we will accrue a total of 21 subjects. Descriptive statistics will be 
calculated and provided for all data collected (I.e. demographic and study specific measures). These will 
include the mean, median, standard deviation, and histograms for all quantitative values, and frequency 
tables for categorical values. Additionally, the informed consent rate wand adverse event rates will be 
calculated and 95% confidence intervals generated to provide valuable information for any future study. 
 
The null hypothesis of a response rate of just 0.15 will be considered rejected if 5 or more responses are 
observed, albeit with a type I error rate of 0.21. However, this type I error rate is justified as the primary 
purpose of this study is to gather preliminary data for a larger, randomized trial, as well as getting some 
indication as to whether or not such a trial seems warranted. The response rate will also be calculated and a 
95% confidence interval generated. 
 
QOL, as measured by FACT-BI will be reported using summary statistics (mean, median, standard deviation) 
for each time point (at enrollment, just prior to cystectomy, and post-cystectomy). DFS will be evaluated at 1 
and 3 years and DSS will be evaluated at 5 years using the Kaplan-Meier method. Survival curves and median 
survival time will be reported. 

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STUDY STOPPING RULES 
16  ASSESSMENT OF SAFETY 
Specification Of Safety Parameters 
 
 
 
Assess Mediators of Cancer Cells’ Responses to IVC. As described in Preliminary Data, upregulated TfR and 
SVCT2 expression have been proposed to increase cancer cells susceptibility to ascorbate treatment, by 
increasing cellular liable iron pool and ascorbate uptake.13,27 We will collect tumor specimens from all 
participants at initial resection and at cystectomy via the IRB approved BCa tumor bank. For measurement of 
TfR and SVCT1/2 expression levels, qRT-PCR will be used for detecting mRNA expression levels in snap frozen 
tumor tissues. Immunofluorescence or immunohistochemistry assay will be utilized using OCT embedded 
frozen tissues. The expression levels will be given numerical H scores (0-300) by pathologist review, defined 
as sum of staining intensity (0, 1, 2, 3) multiplied by percentage of positive stained cells. The results from 
those who respond to IVC treatment will be compared to non-responders. 
 
 
Based on a Simon 2-Stage Design, toxicity and efficacy will be evaluated after the first 13 subjects are 
enrolled on this study, prior to enrolling additional subjects. 
If > 20% subjects have Grade 3 or 4 toxicity probably related or directly related to iv Vitamin C, we will hold 
the study for analysis of toxicity. 
 
 
 
 
Analyses will be performed for all participants having received at least one dose of study drug / one 
administration of therapy. 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting and 
toxicity assessment. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
Information and links regarding CTCAE version 5.0 can be found at the CTEP website: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site: 
https://view.officeapps.live.com/op/view.aspx?src=https://ctep.cancer.gov/protocolDevelopment/electronic_ 
applications/docs/CTCAE_v5.0.xlsx 
 
The investigators in this study will use this document for assessing and reporting of adverse events. 
Analysis Of Exploratory Objective(s) 

IIT-2019-IVC-GarboGem 
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Page 51 of 75 
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Text below in italics is verbatim from “Guidance for Industry and Investigators. Safety Reporting 
Requirements for INDs and BA/BE Studies”, issued December 2012 by U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologics 
Evaluation and Research. The guidance may be retrieved from: 
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351. 
pdf?source=govdelivery 
 
Adverse Event [21 CFR 312.32(a)] 
An adverse event means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
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 in combination with another drug) and with any route of administration, formulation, or dose, 
including an overdose. 
 
Suspected Adverse Reaction [21 CFR 312.32(a)] 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event. For the purposes of safety reporting, ‘reasonable possibility’ means there is 
evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug. 
 
Suspected adverse reactions are the subset of all adverse events for which there is a reasonable possibility 
that the drug caused the event. Inherent in this definition, and in the requirement to report suspected adverse 
reactions, is the need for the sponsor to evaluate the available evidence and make a judgment about the 
likelihood that the drug actually caused the adverse event. 
 
Unexpected [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is 
not required or available, is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application… “Unexpected,” as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the Particular drug under investigation. 
 
This definition relies entirely on a listing of the adverse events or suspected adverse reactions in the 
investigator brochure…as the basis for determining whether newly acquired information generated from 
clinical trials or reported from other sources is unexpected. This means that events not listed for the Particular 
drug under investigation in the investigator brochure are considered “unexpected” and those listed are 
considered “expected.” When new adverse event information is received, it is the sponsor’s responsibility to 
determine whether the event is “unexpected” for safety reporting purposes. 
Definition Of Adverse Events (AE) 

IIT-2019-IVC-GarboGem 
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Relationship To Study Agent 
Serious [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator 
or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the patient or patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or patient at immediate risk of death. It does not 
include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death 
 
 
Factors to be considered in assessing the relationship of the adverse event to study drug include: 
 
• 
The temporal sequence from study drug administration: The event should occur after the study drug 
is given. The length of time from study drug exposure to event should be evaluated in the clinical 
context of the event. 
• 
Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-challenge): 
participant’s response after drug discontinuation (de-challenge) or participants response after study 
drug re-introduction (re-challenge) should be considered in the view of the usual clinical course of 
the event in question. 
• 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the context of the 
natural history and course of the disease being treated and any other disease the participant may 
have. 
• 
Concomitant medication or treatment: The other drugs the participant is taking or the treatment the 
participant receives should be examined to determine whether any of them may be suspected to 
cause the event in question. 
• 
The pharmacology and pharmacokinetics of the study drug: The pharmacokinetic properties 
(absorption, distribution, metabolism and excretion) of the test drug(s), coupled with the individual 
participant’s pharmacodynamics should be considered. 
 
Attribution is the relationship between an adverse event or serious adverse event and the study treatment. 

IIT-2019-IVC-GarboGem 
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Reporting Procedures 
Adverse Event Reporting 
Recording Adverse Events And Documentation In CRIS 
Attribution will be assigned as follows: 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Definite – The AE is clearly related to the study treatment. 
 
 
 
 
Information for adverse events, whether reported by the participant, directly observed, or detected by 
physical examination, laboratory test or other means, will be collected, recorded, followed and reported in 
the study Case Report Form (CRF) as described in the following sections. 
 
ALL adverse events experienced by participants will be collected and reported as follows: 
 
• 
Adverse events will be collected and reported] from the time of signing consent, during screening, then 
from Day 1 of study treatment and/or procedure, throughout the study, and up to and including day 30 
after the last dose of study drug and/or last study procedure. 
 
• 
SERIOUS adverse events that meet the definition(s) of a serious adverse event will be collected and 
reported from Day 1 of study treatment and/or procedure, and up to and including day 30 after the last 
dose of study drug and/or last study procedure. 
 
Participants who experience an ongoing adverse event related to a study procedure and/or study medication 
beyond 30 days will continue to be contacted by a member of the study team until the event is resolved, 
stabilized, or determined to be irreversible by the Sponsor -investigator. 
 
Study participants should also be instructed to report any new serious post-study event(s) that might 
reasonably be related to participation in this study. 
 
Medical conditions/diseases, or cancer related symptoms present before starting study treatment are 
considered adverse events only if they worsen after initiation of study drug. 
 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms, or require therapy. In this case they will be recorded on the Adverse Events CRF, along with the 
associated signs, symptoms or diagnosis. 
 
 
All expected and unexpected adverse events and serious adverse events occurring after the participant has 
signed the informed consent will be reported as described previously in this document, and must be fully 
recorded in the participant’s case record form. 

IIT-2019-IVC-GarboGem 
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Serious Adverse Event Reporting 
Summary Of Expedited Serious Adverse Event Reporting 
 
All AEs and SAEs regardless of causality must be entered in the KU implementation of Velos eResearch; at KU, 
called the Comprehensive Research Information System (CRIS). Unexpected and expected adverse events 
must be entered within 5 days and include: new unexpected adverse events; worsening baseline conditions; 
clinically significant laboratory findings; disease-related signs and symptoms that were not present at 
baseline, and any event of findings that the Investigator feels is clinically significant. 
 
Documentation must be supported by an entry in the participant’s file. A laboratory test abnormality 
considered clinically significant(e.g., causing the participant to withdraw from the study, requiring treatment 
or causing apparent clinical manifestations, or judged relevant by the investigator, should be reported as an 
adverse event). Each event should be described in detail along with start and stop dates, severity, 
expectedness, relationship to investigational product, action taken and outcome. 
 
 
For serious adverse events, the clinical research site will follow local IRB policies and procedures 
 
All SAEs regardless of causality must be entered into CRIS within 24 hours. Entering the event into CRIS will 
send an automatic email to the KUCC Regulatory team. 
 
Follow-up source documentation is required within 5 days. 
Send all supporting documents with a cover sheet to: 
KUCC DSMC 
Email: kucc-dsmc@kumc.edu 
 
 
Relationship to 
Study Drug 
IRB 
CRIS 
(KU DSMC and PI) 
FUNDER 
Unexpected 
SAE/AESI 
Related 
Per local IRB 
reporting policy 
24 hrs 
24 hrs 
Unexpected 
SAE/AESI 
Not-related 
Per local IRB 
reporting policy 
24 hrs 
24 hrs 
Expected 
SAE/AESI 
Related 
Per local IRB 
reporting policy 
24 hrs 
24 hrs 
Expected 
SAE/AESI 
Not-related 
Per local IRB 
reporting policy 
24 hrs 
24 hrs 

IIT-2019-IVC-GarboGem 
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Reporting Of Pregnancy 
17  DATA AND SAFETY AUDITING AND MONITORING 
DSMC Oversight And Monitoring Plan 
 
 
 
The University of Kansas Cancer Center Regulatory Affairs Department is delegated by the Sponsor- 
Investigator to report any IND safety report any suspected adverse reaction that is both serious and 
unexpected. Before submitting this report, the sponsor-investigator needs to ensure that the event meets all 
three of the definitions contained in the requirement: 
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected 
If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited 
IND safety report. 
 
The following reports require expedited reporting. 
• 
unexpected fatal or life-threatening adverse experiences associated with the use of the drug 
are to be reported by telephone or fax no later than 7 calendar days after initial receipt of 
the information [21 CFR 312.32©(2)] 
• 
any adverse experience associated with the use of the drug that is both serious and 
unexpected is to be reported in writing no later than 15 calendar days after initial receipt of 
the information [21 CFR 312.32(c)(1)] 
 
 
 
Any pregnancy occurring on study must be reported as an adverse event. 
 
In the unlikely event pregnancy occurs, pregnancy outcomes will not be followed. 
 
 
 
The multidisciplinary KUCC Data and Safety Monitoring Committee (DSMC) is charged with overseeing the 
monitoring of participant safety, conduct and scientific progress of research protocols, and the validity and 
integrity of the data for clinical trials. The KUCC DSMC has the authority to require amendments, suspend, or 
terminate any research activities that fall within its jurisdiction, and can institute other appropriate actions as 
needed to protect participant safety. 
 
The study will be audited by the DSMC at appropriate intervals, no less than those assigned by the KUCC 
Protocol Review and Monitoring Committee (PRMC), to assure compliance to GCP and to assess the data 
quality and study integrity. 
 
This trial will also be monitored by CTO Clinical Site Managers, which will occur as described in a separate 
monitoring plan for the trial. 
Submitting IND Safety Reports To FDA 

IIT-2019-IVC-GarboGem 
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Data Management 
Safety Review And Oversight Requirements 
Serious Adverse Event 
Review Of Serious Adverse Event Rates 
Study Safety And Progress 
The investigator and staff are expected to cooperate and provide all relevant study documentation in detail 
at each site visit on request for review. The study monitor will have direct access to source data for data 
verification. Data verification will be conducted by comparing the data entered into the CRFs with source 
data 
 
 
Web-based eCRFs will be used to collect patient data in this study. All eCRFs and resulting data will be 
developed and maintained in a manner consistent with currently available regulations and guidance 
pertinent to the use of computerized systems in clinical trials. All Sponsor, Sponsor designees, and study-site 
users of the eCRF system will be trained prior to the use of the system. A complete review of source 
documentation and safety data will be conducted at each monitoring visit for verification that all information 
recorded in the eCRF accurately reflects the data recorded in the subject's source documents. 
 
 
 
Serious adverse events that require expedited reporting will be reviewed by the DSMC Chair or designee who 
will determine if immediate action is required. If determined to be necessary by the DSMC, all participating 
sites will be notified of the event and any resulting action within one working day of this determination. 
 
 
Once per month, serious adverse event rates will be monitored by the DSMC Coordinator. If any study site 
has had 2 or more of the same SAE reported within one month, or more than 6 of the same SAE in 6 months, 
the DSMC will review summaries of SAEs, and discuss events in detail with the PI. The DSMC chair or designee 
determines whether further action is required. The sponsor-investigator, in collaboration with the DSMC 
Coordinator ensure that collaborating investigators and IRBs for all participating sites are notified of any 
resulting action. 
 
 
An overall assessment of toxicities as described in the protocol is reviewed at DSMC meetings. This review 
enables DSMC committee members to assess whether significant risks are occurring that would warrant 
study suspension/closure or protocol amendment. 
 
The DSMC is an autonomous committee. However, its actions are communicated to other committees 
engaged in oversight of clinical research at KUCC. The PI is responsible for forwarding all DSMC letters, 
including those recommending continuation of the study, to the IRB and PRMC. DSMC recommendations for 
modifications to the trial are forwarded to the Deputy Director of KUCC. The PI is notified of this 
recommendation, and is expected to alert all collaborating investigators about the DSMC action. At this time 
the PI may appeal the Committee’s decision to the Deputy Director of KUCC or their designee. The Deputy 
Director of the KUCC or their designee will notify the PI if he/she concurs with the DSMC’s recommendation, 
including suspension or closure. 

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Protocol Review And Amendments 
19  ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
Ethical Standard 
Informed Consent Process 
 
 
 
 
This protocol, the proposed informed consent and all forms of participant information related to the study 
(e.g., advertisements used to recruit participants) and any other necessary documents must be submitted, 
reviewed and approved by a properly constituted IRB. 
 
Any changes made to the protocol must be submitted as amendments and must be approved by the IRB prior 
to implementation. Any changes in study conduct must be reported to the IRB. The sponsor- Investigator will 
disseminate protocol amendment information to all study team members. 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
 
 
 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good and sound 
research practice: 
 
1. State laws 
2. ICH Consolidated Good Clinical Practice: Guidelines (E6) 
3. US Code of Federal Regulations (CFR) governing clinical study conduct and ethical principles that have 
their origin in the Declaration of Helsinki 
 
With attention to the following specific regulations: 
 
a. Title 21 Part 50 – Protection of Human Subjects 
b. Title 21 Part 56 – Institutional Review Boards 
c. Title 21 Part 312 – Investigational New Drug Application Responsibilities of Sponsors and 
Investigators 
4. Institutional research policies and procedures: 
 
 
 
Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient information 
for participants to make an informed decision about their participation in this study. The formal consent of a 
participant, using the IRB approved consent form, must be obtained before the participant is involved in any 
study-related procedure. The consent form must be signed and dated by the participant or the participant’s 
legally authorized representative, and by the person obtaining the consent. The participant must be given a 
18  REGULATORY CONSIDERATIONS 

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20  DATA HANDLING AND RECORD KEEPING 
Data Collection And Management Responsibilities 
Study Records Retention 
Protocol Deviations 
copy of the signed and dated consent document. The original signed copy of the consent document must be 
retained in the medical record or research file. 
 
 
 
Case report forms (CRFs) will be completed for each participant enrolled and registered on this study. All 
CRFs will be customized per this study, in order to emphasize completeness and accuracy. The medical chart 
and any other clinical worksheets, procedural reports, etc. will be the source documentation of data captured 
into the study database. 
 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information enables 
the study to be fully documented and the study data to be subsequently verified. Original source documents 
supporting entries in the case report forms include but are not limited to hospital records and clinic charts, 
laboratory and pharmacy records, ECG, signed ICFs, participant diaries and pathology reports. All study- 
related documents must be retained for the maximum period required by applicable federal regulations and 
guidelines or institutional policies. 
 
 
It is understood that deviations from the protocol should be avoided, except when necessary to eliminate an 
immediate hazard to a research participant. All deviations must be reported to the IRB according to the local 
reporting policy. 

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Appendix A: Performance Status 
 
 
 
 
 
 
 
21  APPENDICES 

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The FACT-BL questionnaire will be maintained in this study as a separate, stand alone document. 
Appendix B: Quality Of Life Questionnaire(s) 

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Appendix C: Bladder Cancer Longitudinal Biorepository Protocol – IRB Approved HSC # 
STUDY00141546 

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