Therapeutic Use of Intravenous Vitamin C in Allogeneic Stem Cell Transplant Recipients
Phase: PHASE2
Conditions: Lymphoid Leukemia, Myeloid Leukemia, Monocytic Leukemia, Myelodysplasia
Sponsor: Virginia Commonwealth University

MCC-17-13299
NCT03613727
Therapeutic Use of Intravenous Vitamin C in Allogeneic Stem Cell Transplant Recipients
12/06/2022

 
 
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MCC Protocol #: MCC-17-13299 
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IND #: 138924 
 
Version Date: 12/06/2022 
REVISION HISTORY 
Revision history is presented in reverse order so that the information pertaining to the most 
current version of the protocol is presented first in this section. 
Version 6, Version Date 12/06/2022 
• 
The version number and date have been updated throughout. 
• 
William B. Clark, MD replaced Gary L. Simmons, DO as sponsor-investigator. 
• 
Study coordination responsibilities were changed from Catherine H. Roberts, PhD to the 
VCU Massey Cancer Center Early Phase Development Department. 
• 
The abbreviation for post office (PO) was removed from all VCU addresses. 
• 
Investigators who have left the study were removed from the cover page. 
Version 5, Version Date 10/20/2020 
• 
The version number and date have been updated throughout. 
• 
The name “Bone Marrow Transplant (BMT) Program” has been changed to “Cellular 
Immunotherapies and Transplant (CIT) Program” throughout. 
• 
Infectious disease marker testing requirements have been updated to reflect current CIT 
Program practices (Section 12). 
Version 4, Version Date 06/12/2019 
• 
The version number and date have been updated throughout.  
• 
On the cover page and throughout the protocol, the term “Principal Investigator” was 
changed to “Sponsor-Investigator.” 
• 
Exploratory endpoints were modified to include newly funded biomarker analyses 
(Sections 3.4.5, 3.4.6, and 13.1.3). 
• 
The window for IV vitamin C administration was defined as every 8 ± 3 hours (Section 
6.1.2). 
• 
The protocol now clearly states that missed doses of vitamin C will not be made up 
(Sections 6.1.3 and 7.1). 
• 
Guidelines for holding vitamin C due to elevated serum creatinine were clarified, and the 
requirement to hold vitamin C for reduced calculated glomerular filtration rate was 
deleted (Section 7.1). 
• 
FDA reporting requirements for adverse events were added to Section 8. 
• 
AE collection instructions were clarified (Section 8.3). 

 
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Version Date: 12/06/2022 
• 
HepB sAB was removed from the list of infectious disease screening titers (Table 4). 
Version 3, Version Date 06/14/2018 
• 
The version number and date have been updated throughout. 
• 
The normal range of vitamin C has been deleted from Section 1.2.1. 
• 
The cutoff for pre-treatment levels of vitamin C in the safety lead-in cohort has been 
clarified as 0.5 mg/dL. 
Version 2, Version Date 04/24/2018 
• 
The version number and date have been updated throughout. 
• 
Dr Ramesh Natarajan has been removed from the cover page as a co-investigator. 
• 
A new schema has been created to reflect the safety lead-in cohort, two-stage design, 
and additional safety and tolerability objective. 
• 
The Table of Contents and List of Tables have been updated. 
• 
The study’s FDA IND number has been added to the cover page and throughout. 
• 
Additional information and references have been added to the rationale (Section 1.2) 
describing vitamin C’s role in immune modulation with possible late effects of early 
treatment. 
• 
A secondary objective (Section 2.2.3) and corresponding secondary endpoint (Section 
3.3.3, Section 13.1.2) have been added to characterize the safety and tolerability of the 
vitamin C regimen by reporting adverse events. 
• 
A safety lead-in cohort of 14 patients has been added to the study design and statistical 
analysis (Section 3.1, Section 13). The safety assessment for this cohort uses the 
existing stopping rules, which are based on severe toxicities and ANC engraftment 
failure. The tables describing the stopping rules have been divided to separate the safety 
lead-in cohort (Table 6) from the phase 2 portion of the trial (Table 7 and Table 8). 
• 
A midpoint efficacy analysis has been added using a Simon’s two-stage design. The first 
stage will consist of 31 patients. The total planned accrual remains 55 patients. The 14 
patients in the safety lead-in cohort will be included in the 31 patients of stage 1 (Section 
3.1, Section 13). 
• 
The list of eligible hematological malignancies has been revised to reduce the 
heterogeneity of the study population (Section 4.1.1). 
• 
Pre-treatment vitamin C testing has been added for the safety lead-in cohort of 14 
patients to confirm deficiency prior to initiating the study regimen (Section 6.1.1, Section 
12). 
• 
The dose of IV vitamin C has been clarified as 16.7 mg/kg every 8 hours (Section 6.1.2). 

 
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Version Date: 12/06/2022 
• 
Standard urinalysis has been added at baseline and weekly through 1 week following 
the last dose of IV vitamin C (Section 6.3, Section 12). 
• 
References to CTCAE version 4.0 have been changed to version 5.0 (Section 8.1.4, 
Section 13.3). 
• 
The description of AE capture has been clarified to ensure that AEs of grade ≥3, 
including lab value AEs of grade ≥3 reflecting renal function, will be recorded as AEs 
(Section 8.4). 
• 
Pharmaceutical information for vitamin C has been amended to clarify the risk of renal 
calculi (Section 9.1). 
• 
The statistical analysis plan now specifies that primary and secondary outcomes will be 
evaluated by comparing to a matched historical cohort (Section 13.1.4). 
Version 1, Version Date 02/20/2018 
Initial submission of the protocol. 
 

 
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TABLE OF CONTENTS 
STUDY SCHEMA ......................................................................................................................... 3 
REVISION HISTORY .................................................................................................................... 4 
TABLE OF CONTENTS ............................................................................................................... 7 
LIST OF FIGURES ....................................................................................................................... 9 
LIST OF TABLES ......................................................................................................................... 9 
LIST OF ABBREVIATIONS ....................................................................................................... 10 
1 
BACKGROUND ........................................................................................................... 11 
1.1 
INTRODUCTION ............................................................................................................... 11 
1.2 
RATIONALE AND PREVIOUS WORK .................................................................................. 12 
1.3 
PROPOSED STUDY ......................................................................................................... 15 
1.4 
POTENTIAL RISKS AND BENEFITS OF THE INVESTIGATIONAL REGIMEN .............................. 15 
1.5 
CORRELATIVE STUDIES .................................................................................................. 15 
2 
OBJECTIVES .............................................................................................................. 16 
2.1 
PRIMARY OBJECTIVE ...................................................................................................... 16 
2.2 
SECONDARY OBJECTIVES ............................................................................................... 16 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................... 16 
3 
STUDY DESIGN .......................................................................................................... 17 
3.1 
GENERAL DESCRIPTION .................................................................................................. 17 
3.2 
PRIMARY ENDPOINT ....................................................................................................... 17 
3.3 
SECONDARY ENDPOINTS ................................................................................................ 17 
3.4 
EXPLORATORY ENDPOINTS ............................................................................................. 17 
4 
PATIENT SELECTION ................................................................................................ 18 
4.1 
INCLUSION CRITERIA ...................................................................................................... 18 
4.2 
EXCLUSION CRITERIA ..................................................................................................... 18 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ............................................... 19 
5.1 
STUDY ENTRY PROCEDURES .......................................................................................... 19 
5.2 
STUDY WITHDRAWAL ...................................................................................................... 19 
6 
TREATMENT PLAN .................................................................................................... 20 
6.1 
STUDY TREATMENT ........................................................................................................ 20 
6.2 
STANDARD HCT MANAGEMENT ...................................................................................... 20 
6.3 
POST-TREATMENT EVALUATION ...................................................................................... 21 
6.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................... 21 
6.5 
FOLLOW-UP PERIOD....................................................................................................... 21 
7 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 21 
7.1 
VITAMIN C ...................................................................................................................... 21 
7.2 
STANDARD SCT TREATMENT .......................................................................................... 22 
8 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .............. 22 
8.1 
DEFINITIONS................................................................................................................... 22 
8.2 
KNOWN AES RELATED TO VITAMIN C .............................................................................. 24 

 
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8.3 
RECORDING AES, SAES, AND UPS ................................................................................. 24 
8.4 
TIME PERIOD AND GRADE OF AE CAPTURE ..................................................................... 24 
8.5 
AES REQUIRING EXPEDITED REPORTING ........................................................................ 24 
8.6 
EXPEDITED REPORTING PROCEDURES FOR SAES, AND UPS ........................................... 26 
9 
PHARMACEUTICAL INFORMATION ......................................................................... 27 
9.1 
VITAMIN C GENERAL INFORMATION ................................................................................. 27 
9.2 
PARENTERAL VITAMIN C (ASCOR L 500) ......................................................................... 28 
9.3 
VITAMIN C TABLETS ........................................................................................................ 29 
10 
MEASUREMENT OF EFFECT .................................................................................... 30 
10.1 
ENGRAFTMENT ............................................................................................................... 30 
10.2 
LENGTH OF RELAPSE-FREE/GVHD-FREE SURVIVAL AND SURVIVAL ................................. 30 
10.3 
RELAPSE FROM REMISSION ............................................................................................ 30 
10.4 
GVHD STAGING AND GRADING ....................................................................................... 30 
11 
CORRELATIVE STUDIES ........................................................................................... 32 
11.1 
PARTICIPATION IN CORRELATIVE STUDIES ....................................................................... 32 
11.2 
PROCESSING AND DISTRIBUTION OF BLOOD SAMPLES ..................................................... 32 
11.3 
BLOOD SAMPLES FOR CORRELATIVE STUDIES ................................................................. 32 
11.4 
LABELING FOR BLOOD SAMPLES ..................................................................................... 32 
11.5 
PROCESSING AND ANALYSIS OF BLOOD SAMPLES ........................................................... 33 
12 
STUDY CALENDAR .................................................................................................... 33 
13 
STATISTICAL CONSIDERATIONS ............................................................................ 36 
13.1 
STATISTICAL METHODS .................................................................................................. 36 
13.2 
SAMPLE SIZE AND POWER DETERMINATION .................................................................... 36 
13.3 
SAFETY CRITERIA FOR LEAD-IN PHASE AND PHASE 2 PORTIONS OF THE TRIAL ................ 37 
14 
DATA AND SAFETY MONITORING ........................................................................... 40 
14.1 
STUDY TEAM .................................................................................................................. 40 
14.2 
MONITORING AND AUDITING ............................................................................................ 40 
15 
REGULATORY COMPLIANCE AND ETHICS ............................................................ 40 
15.1 
ETHICAL STANDARD ....................................................................................................... 40 
15.2 
REGULATORY COMPLIANCE ............................................................................................ 40 
15.3 
INSTITUTIONAL REVIEW BOARD ....................................................................................... 41 
15.4 
INFORMED CONSENT PROCESS ...................................................................................... 41 
15.5 
PATIENT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ......................... 41 
16 
DATA HANDLING AND RECORD KEEPING ............................................................. 42 
16.1 
DATA MANAGEMENT RESPONSIBILITIES ........................................................................... 42 
16.2 
SOURCE DOCUMENTS .................................................................................................... 42 
16.3 
CASE REPORT FORMS AND DATA COLLECTION ................................................................ 42 
16.4 
STUDY RECORD RETENTION ........................................................................................... 42 
17 
REFERENCES ............................................................................................................. 43 

 
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LIST OF FIGURES 
Figure 1. CRP Levels and SOFA Scores Lower with Parenteral Ascorbic Acid Compared to 
Placebo ....................................................................................................................................... 13 
Figure 2. Vitamin C Deficient Levels at Baseline Up Until Day +60 from HCT ........................... 14 
Figure 3. cfDNA Levels Elevated in Transplant Recipient .......................................................... 15 
 
LIST OF TABLES 
Table 1. Expedited Reporting Requirements .............................................................................. 26 
Table 2. GVHD Staging .............................................................................................................. 31 
Table 3. GVHD Grading .............................................................................................................. 31 
Table 4. Study Calendar – Screening/Pretreatment Requirements ............................................ 34 
Table 5. Study Calendar – Treatment and Follow-Up ................................................................. 35 
Table 6. Number of Observed ANC Engraftment Failures and Toxic Events (Measured 
Separately for Each Toxicity Outcome) Needed to Stop Trial During Safety Lead-In Given 
Accrued Sample Size .................................................................................................................. 38 
Table 7. Number of Observed Toxic Events (Measured Separately for Each Toxicity Outcome) 
Needed to Stop Phase 2 Portion of Trial Given Accrued Sample Size ....................................... 39 
Table 8. Number of Observed ANC Engraftment Failures Needed to Stop Phase 2 Portion of 
Trial Given Accrued Sample Size ............................................................................................... 39 
 

 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
twice per day 
BMT 
bone marrow transplant 
BP 
blood pressure 
cfDNA 
cell-free deoxyribonucleic acid 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CIT 
Cellular Immunotherapies and Transplant 
CRF 
case report form 
CRP 
C-reactive protein 
CTCAE v5.0 
Common Terminology Criteria for Adverse Events Version 5.0 
cGVHD 
chronic graft versus host disease 
ddCD3 
donor-derived CD3+ (cell count) 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DSMC 
Data Safety and Monitoring Committee 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
GVHD 
graft versus host disease 
HCT 
hematopoietic cell transplant 
HLA 
human leukocyte antigen 
HSC 
hematopoietic stem cells 
IBW 
ideal body weight 
LPS 
lipopolysaccharide 
MAC 
myeloablative conditioning 
MCC-VCUHS 
Massey Cancer Center-Virginia Commonwealth University Health System 
MRD 
matched related donor 
MUD 
matched unrelated donor 
NRM 
non-relapse mortality 
PBSC 
peripheral blood stem cells 
PO 
by mouth 
RIC 
reduced intensity conditioning 
RNS 
reactive nitrogen species 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SCT 
stem cell transplantation 
TBI 
total body irradiation 
TRM 
transplant-related mortality 
ULN 
upper limit of normal 
UP 
unanticipated problem 
URD 
unrelated donor 
VCU 
Virginia Commonwealth University 
VOD 
veno-occlusive disease 
WBC 
white blood cell 
WCBP 
woman of childbearing potential 
 
 
 
 
 
 
 

 
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1 BACKGROUND 
1.1 Introduction 
Approximately 20,000 hematopoietic cell transplants (HCT) are performed in the United 
States each year (Pasquini MC. 2014 CIBMTR Summary Slides). Myeloablative allogeneic 
HCT remains the only potential cure for leukemia, lymphoma, and hematopoietic disorders, 
however, it is associated with a high risk of morbidity and mortality. Myeloablative 
conditioning (MAC) refers to the necessary chemotherapy and/or radiation regimen used in 
stem cell transplant to eliminate residual leukemia/lymphoma and condition the host for the 
incoming graft of hematopoietic stem cells (HSC).  
Non-relapse mortality (NRM), defined as mortality from complications of HCT but not tumor 
relapse, is usually from graft versus host disease (GVHD), infection, or organ failure. NRM 
after allogeneic HCT is influenced by type of donor (related vs. unrelated), conditioning 
chemotherapy doses, and co-morbidities of the recipient. In a study reported by Sorror et 
al, 2-year NRM in myeloablative allogeneic HCT was 14% to 41% based on patient 
comorbidities (1). In a recent clinical trial (BMTCTN 0901) comparing conditioning 
chemotherapy regimens of different intensities in acute myelogenous leukemia (AML), the 
overall NRM was 16% at 18 months (2).  
HCT after myeloablative conditioning has several associated toxicities such as 
pancytopenia, mucositis, interstitial pneumonitis, hepatic sinusoidal obstruction 
syndrome/veno-occlusive disease (SOS/VOD), and sepsis. These HCT toxicities are 
induced by MAC and are characterized by endothelial injury and a pro-inflammatory state 
with elevated inflammatory cytokines such as IL-1 and tumor necrosis factor-alpha (TNF-α) 
(3). The inflammatory response increases antigen presenting cell (APC) activity presenting 
minor histocompatibility antigens to T-cells resulting in acute GVHD in 35-50% of HCT 
recipients. Acute GVHD is a leading risk factor for chronic GVHD which is present in 40-
70% of all HCT (3). GVHD, infection, and organ failure as a consequence of HCT 
contributes to NRM after allogeneic HCT. The one-year NRM at Virginia Commonwealth 
University (VCU) in 2014-2015 was 10-20% for patients receiving HLA-matched related 
donor grafts (MRD) and 20 - 40% in those with unrelated donor grafts (MUD) (4, 5).  
The NRM risk, mediated by inflammation, endothelial injury, and GVHD, may be mitigated 
by an agent such as vitamin C which has several beneficial effects in patients with sepsis-
associated acute inflammation including reduction in endothelial injury, hemodynamic 
instability, organ dysfunction and markers of inflammation (6). These effects are partly 
mediated by reduction in reactive oxygen species (ROS), an important consequence of 
both sepsis and high-dose chemoradiotherapy (7). We have demonstrated at our institution 
that patients’ pre-HCT are deficient in vitamin C and remain deficient out to Day +60 
following HCT (8).  
This phase 2 trial will evaluate the efficacy of parenteral vitamin C in myeloablative 
allogeneic HCT patients. We hypothesize that mitigating the pro-inflammatory effects of 
HCT with early administration of vitamin C to restore normal blood levels will improve the 
outcomes of patients undergoing HCT by attenuating mucositis, endothelial and organ 
injury, as well as GVHD and will result in a reduction in the risk of transplant-related 
mortality.  

 
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1.2 Rationale and Previous Work 
Myeloablative HCT utilizes a combination of chemotherapy dose intensity and donor  
T cell-mediated graft versus leukemia effect to achieve long-term freedom from disease 
progression in patients with recurrent hematological malignancies. This combination 
results in a pro-inflammatory state that resembles severe sepsis. The tissue damage 
results in secretion of pro-inflammatory cytokines IL-1 and tumor necrosis factor alpha 
(TNF-α), and the net effect is acute GVHD (9). Immunosuppression administered to 
prevent GVHD increases the risk of both relapse, as well as opportunistic infections, 
contributing to the observed high non-relapse mortality following allogeneic HCT. Evidence 
of the deleterious impact of the pro-inflammatory state comes from biomarker studies using 
ferritin and C-reactive protein (CRP) as well as cytokines IL-1 and TNF-α, which have 
been validated as predictors of outcomes after myeloablative allogeneic HCT. A review of 
the patients transplanted at VCU has found that elevated ferritin (>2020 G/dL) was 
associated with an increased risk for GVHD and inferior survival in patients transplanted 
for myeloid malignancies (4).  
CRP produced by hepatocytes downstream of IL-6 is widely used as a reliable surrogate 
marker of inflammation (10). After allogeneic HCT, the elevation of CRP has been shown 
to be associated with transplant-related mortality (11). In a study by Fuji et al., the 
correlation between the pre-engraftment CRP value and subsequent clinical events was 
analyzed to test whether high CRP reflected the degree of tissue damage because of the 
conditioning regimen, infections, and allogeneic immune reactions and/or inflammation, all 
of which could contribute to subsequent GVHD and NRM. They found that CRP > 15 
mg/dL was associated with a significant increase in GVHD and decreased overall survival  
post-allogeneic HCT (12). Another marker of tissue damage, cell-free DNA (cfDNA), is 
released as a result of cell necrosis or apoptosis and has been studied as a biomarker in 
severe sepsis (13). In a retrospective, observation study of 80 patients with severe sepsis 
in the intensive care unit (ICU), cfDNA had a sensitivity of 88% and specificity of 94% for 
predicting mortality in the ICU (13). Systemic release of TNF-α during pre-HCT 
conditioning is highly predictive for occurrence of acute GVHD and related complications 
and one-year transplant-related mortality in patients receiving allogeneic HCT (14, 15). 
Vitamin C’s pleotropic effect on the inflammatory process was demonstrated by Molina et 
al who stimulated lymphocytes with lipopolysaccharide (LPS) followed by treatment with 
vitamin C. Vitamin C reduced the reactive oxygen species and the production of  
pro-inflammatory cytokines TNF-α and IFN-γ, as well as increasing the anti-inflammatory 
cytokine IL-10. Also, glutathione (GSH) and G6PDH enzymes were increased in this study 
supporting the role of vitamin C as anti-oxidant (16). 
The endothelial injury syndromes such as microangiopathy, VOD of the liver, diffuse 
alveolar hemorrhage, engraftment syndrome, and capillary leak syndrome are a major 
cause of NRM after allogeneic HCT. Further, biomarkers of endothelial injury such as 
thrombomodulin show a close relationship with GVHD (17). Tatekawa et al., generated a 
novel diagnostic system for transplant related complications from endothelial injury by 
analyzing 188 adult patients who received allogeneic HCT and found that the peripheral 
blood levels of biomarkers angiopoietin 2 (ANG2), CRP, D-dimer, and thrombomodulin at 
the onset were associated with transplant related complications with endothelial cell 
damage (18). These may then also serve as important biomarkers for endothelial injury 
and potentially its response to vitamin C therapy in the setting of HCT, as proposed in the 
MCC-17-132999 study. 

 
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High-dose vitamin C has been used in patients with septic shock to reduce inflammatory 
state. Nathens et al used parenteral vitamin C dosed at 1 gram every 8 hours combined 
with oral vitamin E for 28 days in 594 surgically critically ill patients and found a statistically 
significantly lower incidence of acute lung injury and multiple organ failure (19). In a phase 
1 clinical trial performed at VCU, Fowler and colleagues found that high-dose parenteral 
vitamin C (200 mg/kg/24hours) was safe to administer with no adverse events and was 
effective at reducing inflammation in patients with severe sepsis. All patients with severe 
sepsis had below normal serum vitamin C levels. Patients treated with parenteral vitamin C 
had a significant rise in serum vitamin C compared to placebo (6). To assess the effects of 
parenteral vitamin C on inflammation they assessed organ function in severe sepsis by the 
sequential organ failure scores (SOFA), and inflammatory biomarkers, CRP, procalcitonin 
and thrombomodulin. CRP and SOFA levels decline with both low and high doses of 
parenteral vitamin C compared to placebo (Figure 1). Thrombomodulin levels remained 
stable compared to placebo, which trended upward (6). Given the significant immune 
modulatory and anti-inflammatory effects of parenteral vitamin C in patients with septic 
shock demonstrated in the above-referenced studies, we have hypothesized that IV 
ascorbic acid in BMT patients undergoing myleoablative allogeneic SCT will impact not 
only early conditioning-induced complications such as mucositis, sepsis, VOD, and acute 
lung injury, but also modulate immune reconstitution and ameliorate remote events such 
as acute and chronic GVHD. This will likely have a salutary effect on immune reconstitution 
as well as diminishing the likelihood of severe late opportunistic infections, resulting in 
improved survivability of myeloablative allogeneic SCT. 
Patients undergoing myeloablative HCT are deficient in vitamin C, as reported by Nannya 
et al who found blood levels of vitamin C were normal before HCT, but deficient by Day 0 
and remained low throughout the following 28 days with lowest levels at Day 14. In the 
same study, ferritin (a biomarker of inflammation) increases inversely as vitamin C declines 
(20). A similar state of vitamin C deficiency has been observed in transplant recipients 
conditioned with MAC at VCU. The pleiotropic anti-inflammatory effects of vitamin C make 
it an attractive intervention in HCT, which is a pro-inflammatory state that physiologically 
resembles severe sepsis. 
 
 
Figure 1. CRP Levels and SOFA Scores Lower with Parenteral Ascorbic Acid Compared to 
Placebo 
There are multiple studies supporting the role of vitamin C augmenting hematopoiesis, 
which may reduce time to engraftment and minimize blood product transfusions in patients 
undergoing HCT. In preclinical trials, vitamin C has been shown to have an effect on  

 
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TET-2, T cell development, and responsiveness to growth factors. There is evidence that 
tissue injury and inflammation in the early weeks following SCT affects late endpoints such 
as GVHD and immune reconstitution (21), which in turn affect the likelihood of NRM. The 
profound impact of early milieu on late outcomes is also borne out by our group’s work, 
which has demonstrated that the magnitude and rate of early lymphoid recovery following 
SCT modulates the risk of GVHD developing at remote times (22-24). 
1.2.1 Preliminary Data 
In a VCU prospective study, plasma vitamin C levels were measured at baseline 
and on Days 0, 14, 30, and 60 post-transplant in HCT recipients with MAC. To date, 
15 patients have been studied: 4 underwent autologous and 11 allogeneic HCT. The 
results of the vitamin C levels are illustrated in Figure 2. The mean plasma vitamin C 
level was low at 40.8 μmol/L (±18.4) at baseline, falling to 27.3 μmol/L (±14.1) at 
Day 0 (p < 0.05, compared with baseline), and reaching nadir at 21.5 μmol/L (± 
13.8) on Day 14 (p <0.05 compared with baseline) post-HCT. Plasma vitamin C 
levels recovered to 34.2 μmol/L (± 20.5) at Day 30 and subsequently to 37.2 μmol/L 
(± 27.9) at Day 60 (p < 0.05 compared with Day 14). Of the patients studied, none 
maintained normal vitamin C levels throughout the study period and 13/15 
developed significantly deficient vitamin C levels of < 28 μmol/L. Patients with 
severe mucositis tended to have lower vitamin C levels at Day 14. These patients 
also had cfDNA levels measured, and as can be seen in Figure 3, elevated cfDNA 
during the conditioning phase of HCT and throughout the 60 days after HCT (n=15). 
This is consistent with tissue injury sustained during conditioning prior to HCT.  
 
Figure 2. Vitamin C Deficient Levels at Baseline Up Until Day +60 from HCT 
 

 
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Figure 3. cfDNA Levels Elevated in Transplant Recipient 
1.3 Proposed Study 
In the MCC-17-13299 trial, we will attempt to determine the effect of parenteral vitamin C 
administered for 2 weeks beginning on Day +1 followed by oral vitamin C beginning on 
Day +15 and continuing through Day +180 on NRM at one year following myeloablative 
allogeneic HCT. Other transplant interventions and supportive care, transfusions, and 
infection prophylaxis will be applied per the VCU CIT Program’s standard procedures. 
1.4 Potential Risks and Benefits of the Investigational Regimen 
1.4.1 Potential Benefits 
Vitamin C is water-soluble and acts as an anti-oxidant and anti-inflammatory 
indicated for the prevention and treatment of scurvy. The anti-inflammatory effect of 
vitamin C and endothelial protection will potentially result in less GVHD, NRM, 
incidence and severity of mucositis, VOD, and infections. Its parenteral 
administration is desirable for patients with acute deficiency or those whose 
absorption of orally ingested vitamin C is uncertain. 
1.4.2 Potential Risks 
Too rapid infusion of intravenous vitamin C solution may cause temporary faintness 
or dizziness. Other side effects include nausea, vomiting, heartburn, and stomach 
cramps.  
Previous clinical studies in patients with severe sepsis receiving parenteral vitamin 
C did not have any adverse events. During the 96-hour infusion period, no patients 
were withdrawn due to study-related adverse events (ie, hypotension, tachycardia, 
hypernatremia, or nausea/vomiting). 
1.5 Correlative Studies  
Blood samples will be collected for the following purposes: 
• 
To determine the effect of parenteral vitamin C on levels of vitamin C in the blood  

 
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4 PATIENT SELECTION 
4.1 Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible to participate in the 
study. 
4.1.1 Any of the following hematological malignancies: 
• 
Acute lymphoblastic leukemia 
• 
Acute myelogenous leukemia 
• 
Chronic myelogenous leukemia 
• 
Myelodysplasia 
4.1.2 Candidate for HCT 
Note: Patients with or without previous myeloablative autologous transplant are 
eligible. 
4.1.3 HLA-matched stem cell donor, either related (6/6 or 5/6 loci matched) or unrelated 
(8/8 or 7/8 loci matched) 
4.1.4 Stem cell graft from either bone marrow or peripheral blood 
4.1.5 Negative serology for HIV 
4.1.6 Age ≥ 18 to < 78 years of age 
4.1.7 Karnofsky Performance Status of 70-100% 
4.1.8 Women who are not postmenopausal or have not undergone hysterectomy must 
have a documented negative serum pregnancy test per standard MCC-VCUHS CIT 
Program guidelines 
4.1.9 Ability to understand and the willingness to sign a written informed consent 
document 
Note: The consent form must be signed and dated prior to initiation of SCT 
preparative treatments. 
4.2 Exclusion Criteria 
A patient who meets any of the following exclusion criteria is ineligible to participate in the 
study. 
4.2.1 Known allergy to vitamin C 
4.2.2 Inability to swallow oral medication 
4.2.3 Known or suspected malabsorption condition or obstruction 
4.2.4 G6PDH deficiency 

 
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4.2.5 Uncontrolled viral, fungal, or bacterial infection 
4.2.6 Active meningeal or central nervous system disease 
4.2.7 Alternative HCT including haplo-identical and umbilical cord transplants 
4.2.8 Non-myeloablative conditioning defined as TBI < 2 cGy 
4.2.9 Pregnancy or breastfeeding 
4.2.10 Medical, psychological, or social condition that, in the opinion of the investigator, 
may increase the patient’s risk or limit the patient’s adherence with study 
requirements 
5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Study Entry Procedures 
5.1.1 Required Pre-Registration Screening Tests and Procedures 
Refer to the study calendar in Section 12 for the screening tests and procedures 
that are required prior to registration. 
5.1.2 Study Enrollment 
The following are needed for patient registration: 
• Completed, signed, and dated eligibility checklist 
• Signed and dated consent form 
The patient’s initial enrollment data (eg, demographics, consent, eligibility, on study) 
will be entered into the OnCore database before treatment begins. 
5.2 Study Withdrawal 
A patient will be removed from the study for any of the following reasons: 
• 
Consent withdrawal for study treatment and study procedures 
• 
If, in the opinion of the investigator, it is in the best interest of the patient to do so 
• 
The study has been closed by the Sponsor-Investigator 
The reason for withdrawal from the study and the date the patient was removed from the 
study must be documented in the source documents and OnCore database. 

 
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6 TREATMENT PLAN 
6.1 Study Treatment  
6.1.1 Safety Lead-In Cohort 
For the initial safety lead-in cohort of 14 patients, vitamin C deficiency will be 
confirmed by a standard clinical pathology laboratory blood test before the first dose 
of parenteral vitamin C (see Sections 12 and 13.3). Safety lead-in patients with 
confirmed vitamin C levels of 0.5 mg/dL or less (20) may proceed on study 
treatment. 
6.1.2 Planned Vitamin C Regimen 
All study patients will receive the following vitamin C regimen: 
• 
Parenteral vitamin C 50 mg/kg/day divided in 3 doses beginning on post-
transplant Day +1 and continuing through Day +14; each dose (16.7 mg/kg) 
given in 50 mL of 5% dextrose and water over 30 minutes every 8 ± 3 hours  
• 
After completion of the parenteral vitamin C doses, oral vitamin C 500 mg twice 
each day beginning on Day +15 and continuing until Day +180 
The vitamin C regimen will continue as described above even if the vitamin C levels 
are found to be within normal range at the time of testing (refer to Section 6.3 for 
testing time points). 
6.1.3 Missed Doses 
Missed doses of IV vitamin C will not be made up (see Section 7.1). 
Patients will be instructed to take a missed dose of oral vitamin C on the same day, 
as soon as they remember, and to not take more than 2 doses of vitamin C on the 
same day to make up for doses that were missed on the previous day. 
6.1.4 Monitoring Patient Adherence (Oral Vitamin C Regimen) 
Following hospital discharge, patients will be instructed to bring any unused supply 
of vitamin C to visits with their study team. 
Patient reports of self-administration and review of unused medication will be used 
to assess the patient’s compliance with the oral vitamin C regimen. 
6.2 Standard HCT Management 
Other than the vitamin C regimen (Section 6.1) and the collection of blood samples for the 
correlative studies (Section 11), all pre- and post-transplant assessments, examinations, 
procedures, and treatment required for patients undergoing HCT will be carried out 
according to the standard approach of the MCC-VCUHS CIT Program.  

 
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6.3 Post-Treatment Evaluation 
• 
All patients will undergo standard blood tests for vitamin C and CRP at baseline, on 
transplant day 0, and at post-transplant days +14, +30, and +100. 
• 
All patients will undergo a standard urinalysis at baseline and weekly through 1 week 
following the last dose of IV vitamin C. 
• 
All patients will have blood samples collected for thrombomodulin, TNF-α, and cfDNA 
assays at baseline, on transplant day 0, and at post-transplant days +14, +30, and 
+100. 
• 
Relevant and disease-specific restaging studies will be performed per standard 
procedures of the MCC-VCUHS CIT Program following transplantation or earlier if 
clinically indicated. 
6.4 General Concomitant Medication and Supportive Care Guidelines 
Standard transplant-related supportive medications, other than vitamin C, may be 
administered at the investigator’s discretion. 
6.5 Follow-Up Period 
The patient’s follow-up status will be recorded in the source documents and the CRFs. 
Study follow-up will be conducted as follows: 
6.5.1 Evaluation of Adverse Events (AEs) 
Patients will continue to be evaluated for AEs until 6 months post-transplant. 
6.5.2 Non-Relapse Mortality 
Follow-up for NRM will continue for one year following transplantation per standard 
post-transplant procedures or until relapse or death, whichever occurs first. 
6.5.3 Survival 
Patients will be followed for survival for 2 years. 
7 DOSING DELAYS/DOSE MODIFICATIONS 
7.1 Vitamin C 
During days 1-14, IV vitamin C will be held in patients who develop a serum creatinine of 
>2.0 mg/dL and resumed once serum creatinine is ≤ 2.0 mg/dL. Missed doses will not be 
made up.  
During days 15-180, if a patient has a serum creatinine level of > 2.0 mg/dL definitely, 
probably, or possibly related to vitamin C (Section 8.1.8), the patient will be instructed not 
to take their oral vitamin C until the serum creatinine level is ≤ 2.0 mg/dL. Missed doses 
will not be made up. 

 
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7.2 Standard SCT Treatment 
There are no study-required dosing delays or dose modifications for any of the agents 
included in the SCT preparatory, GVHD prophylaxis, infection prophylaxis, or 
transplantation regimens. Dose modifications and delays, if needed for patient support and 
safety, will be per investigator discretion. 
8 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
8.1.2 Suspected Adverse Reaction (SAR) 
A SAR is any AE for which there is a reasonable possibility that the drug caused the 
AE. “Reasonable possibility” means that there is evidence to suggest a causal 
relationship between the drug and the AE. 
An AE with an attribution of possible, probable, or definite (Section 8.1.8) is a SAR. 
8.1.3 Serious AE (SAE) or Serious SAR (SSAR) 
An AE or SAR is considered “serious” if, in the view of the investigator, it results in 
any of the following outcomes: 
• 
death, 
• 
a life-threatening AE or SAR (An AE or SAR is considered “life-threatening” if, in 
the view of the investigator, its occurrence places the patient at immediate risk 
of death. It does not include an AE or SAR that, had it occurred in a more severe 
form, might have caused death.), 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
Planned inpatient hospitalizations are exempt from SAE reporting. Events 
that prolong hospitalization beyond the expected period of time and otherwise 
meet reporting criteria are, however, subject to SAE reporting requirements. 
• 
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 

 
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judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
8.1.4 Unexpected SAR 
A SAR 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, is not consistent with the risk 
information described in the prescribing information. 
“Unexpected” as used in this definition, also refers to SARs 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 drug under investigation. 
8.1.5 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
• 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the patient population being studied; 
• 
related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
suggests that the research places patients or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
8.1.6 AE Description and Grade 
The descriptions and grading scales found in the revised Common Terminology 
Criteria for Adverse Events version 5.0 (CTCAE v5.0) will be utilized for AE 
reporting. 
8.1.7 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. Refer to Section 8.2 regarding expected 
AEs. Unexpected AEs are those AEs occurring in one or more patients participating 
in the study, the nature, severity, or frequency of which is not consistent with either: 
• 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) the protocol-related documents, such as 
the IRB-approved research protocol and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts; or 

 
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• 
The expected natural progression of any underlying disease, disorder, or 
condition of the patient(s) experiencing the AE and the patient’s predisposing 
risk factor profile for the AE. 
8.1.8 AE Attribution 
• 
Definite – The AE is clearly related to the study intervention. 
• 
Probable – The AE is likely related to the study intervention. 
• 
Possible – The AE may be related to the study intervention. 
• 
Unlikely – The AE is doubtfully related to the study intervention. 
• 
Unrelated – The AE is clearly NOT related to the study intervention. 
8.2 Known AEs Related to Vitamin C 
Too rapid infusion of intravenous vitamin C solution may cause temporary faintness or 
dizziness. Other side effects include nausea, vomiting, heartburn, diarrhea, and stomach 
cramps.  
8.3 Recording AEs, SAEs, and UPs 
All recordable AEs per protocol (defined in Section 8.4), all SAEs, and all UPs will be 
recorded in MCC’s OnCore Clinical Trial Management System. In most cases, it is 
acceptable to record only the highest grade of a toxicity occurring during a particular study 
segment when an event has serial fluctuations in grade over time. 
SAEs will be entered into the OnCore SAE domain. UPs will be entered into the OnCore 
Deviations domain. An SAE that is both an SAE and a UP will be entered in both domains. 
For all SAEs, a corresponding entry should be made in the routine AE record to match the 
event entries in the SAE domain. Additionally, events related to stopping criteria will be 
entered in OnCore as an event of special interest. 
8.4 Time Period and Grade of AE Capture 
AEs ≥ grade 3 regardless of expectedness or attribution will be recorded for study 
tabulation and analysis beginning on Day 0 and continuing until Day 180. Toxicity 
assessments will include a review of all toxicities experienced during each assessment 
period. The highest grade of each relevant toxicity during that period will be recorded. 
Exception: Cytopenias and changes in electrolytes will not be recorded. Only clinical 
events and lab values reflecting renal function (eg, creatinine, urinalysis results) will be 
recorded as AEs. 
8.5 AEs Requiring Expedited Reporting 
All patients in this study will be receiving potentially toxic preparative therapy, therefore, 
significant regimen-related toxicity is anticipated, ie, expected AEs. 
8.5.1 Expedited Reporting Requirements 

 
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All grade 3, 4, and 5 unexpected AEs regardless of attribution will be reported in an 
expedited manner from the first dose of vitamin C (on Day 1) until post-transplant 
Day 180. (Refer to Section 8.5.2 for AEs that should NOT be considered 
unexpected.) 
8.5.2 Expedited Reporting Exceptions 
The following ≥ grade 3 toxicities/events are expected AEs: 
• 
All laboratory abnormalities regardless of grade 
• 
Hospitalization including hospitalization for the transplant procedure 
• 
Infection 
• 
GVHD 
• 
Graft failure 
• 
Progression or relapse 
• 
Death 
• 
Adverse events that are commonly observed after hematopoietic cell 
transplantation including diarrhea, hematuria, hemorrhage, hypoxia, sepsis, 
mental status changes, pneumonitis, anemia, minor bleeding episodes (eg, 
epistaxis), hepatic VOD, renal insufficiency, blood clots, and thrombotic 
microangiopathy 

 
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9 PHARMACEUTICAL INFORMATION 
Refer to the current FDA-approved prescribing information for the pharmaceutical 
information for all of the agents used in the management of patients enrolled on the study. 
Information regarding vitamin C is outlined in this section.  
9.1 Vitamin C General Information 
9.1.1 Description 
The chemical name of vitamin C is L-ascorbic acid. The molecular formula is 
C6H8O6. It occurs as white or slightly yellow crystals or powder. 
9.1.2 Availability and Ordering 
All study vitamin C will be ordered and dispensed by MCC Investigational Drug 
Services. 
9.1.3 Agent Accountability 
MCC Investigational Drug Services will retain records of the inventory and 
disposition of study vitamin C. 
9.1.4 Agent Destruction and Return 
At the conclusion of the study, any unused study vitamin C will be destroyed 
according to institutional policies. 
9.1.5 Contraindications 
Administration of vitamin C is contraindicated in patients with a known allergy to 
vitamin C or any other ingredient used in the formulation. 
9.1.6 Drug Interactions 
Acidification of the urine by ascorbic acid may cause precipitation of cysteine, urate 
or oxalate stones (renal calculi) and will alter the excretion of certain other drugs 
administered concurrently.  
Large doses interfere with the anticoagulant effect of warfarin.  
Ascorbic acid has on occasion been used as a specific antidote for symptoms 
resulting from interaction between ethanol and disulfiram (Antabuse®). It may be 
expected that the concurrent administration of high doses of vitamin C could 
interfere with the effectiveness of disulfiram given to patients to encourage 
abstention from alcohol. 
Because ascorbic acid is a strong reducing agent, it interferes with numerous 
laboratory tests based on oxidation-reduction reactions. Diabetics taking more than 
500 mg of ascorbic acid daily may obtain false readings of their urinary glucose test. 
No exogenous ascorbic acid should be ingested for 48 to 72 hours before amine-

 
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dependent stool occult blood tests are conducted because false negative results 
may occur. 
9.1.7 Adverse Reactions 
The most common adverse events associated with high intake of vitamin C are 
gastrointestinal events, including nausea, vomiting, heartburn, abdominal cramps, 
and diarrhea. As stated in Section 9.1.6, there is also a risk of renal calculi. 
9.2 Parenteral Vitamin C (Ascor L 500) 
9.2.1 How Supplied 
Ascor L 500 (Ascorbic Acid Injection, USP) is a sterile, nonpyrogenic solution of 
ascorbic acid prepared with the aid of sodium bicarbonate in water for injection. 
Each mL contains 500 mg of ascorbic acid, and edetate disodium 0.025% (w/v). It 
also contains sodium bicarbonate and may contain sodium hydroxide to aid in 
preparation and pH adjustment. The pH is 5.5-7.0. It contains no bacteriostat, 
antimicrobial agent, or added buffer. Ascor L 500 (ascorbic acid for injection, USP), 
500 mg/mL, is available in trays of twenty-five, 50 mL, sterile, pharmacy bulk bottles, 
containing no preservative.  
9.2.2 Storage Requirements 
Protect from light. Store in refrigerator at 2°– 8°C (36°– 46°F). Do not allow to stand 
at room temperature before use. Failure to follow this caution may lead to excessive 
pressure inside the vial. 
9.2.3 Stability 
All vials of Ascor L 500 are labeled with a “Best Use” date. 
9.2.4 Route of Administration 
Intravenous. 
9.2.5 Warnings and Precautions 
Pain and swelling at the site of injection have been reported in some patients. 
Excessively rapid intravenous injection may result in temporary faintness or 
dizziness. Since high internal pressure may develop on long storage, precautions 
should be taken when withdrawing the solution from the vial. Do not administer 
unless solution is clear and container is intact. Discard unused portion. 
Usage in pregnancy: Pregnancy Category C (in doses greater than the RDA). 
Animal reproduction studies have not been conducted with ascorbic acid injection. It 
is not known whether ascorbic acid injection can cause fetal harm when 
administered to a pregnant woman or can affect reproductive capacity. High doses 
of vitamin C taken during pregnancy have been reported to cause scurvy in infants 
removed from this environment at birth.  

 
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Nursing mothers: Ascorbic acid is excreted in breast milk. Caution should be 
exercised when ascorbic acid injection is administered to a nursing woman, and 
excessive doses should be avoided. 
9.3 Vitamin C Tablets 
9.3.1 How Supplied 
Vitamin C for oral consumption is available in tablets containing 500 mg vitamin C 
each. 
9.3.2 Storage Requirements 
Vitamin C tablets may be stored at room temperature. 
9.3.3 Stability 
Containers of vitamin C tablets are labeled with an expiration date. 
9.3.4 Route of Administration 
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10 MEASUREMENT OF EFFECT 
10.1 Engraftment 
Hematopoietic engraftment is defined as both of the following: 
• 
Recovery from post-transplant cytopenia with an absolute neutrophil count  
of ≥ 0.5 x 109 /L for 3 consecutive measurements or ≥ 1.0 x 109 /L for 1 day; and 
• 
Platelet count of ≥ 20 x 109 /L for 7 days without transfusion. 
10.2 Length of Relapse-Free/GVHD-Free Survival and Survival 
All study patients including those removed from the treatment protocol will be followed for 
survival every 3 months. 
• 
Length of relapse-free/GVHD-free survival is measured from transplant to relapse, 
GHVD diagnosis, death, or time of last contact, censoring for patients alive and  
relapse-free/GVHD-free at the time of last contact. 
• 
Length of survival is measured from transplant to death or time of last contact, 
censoring for patients alive at time of last contact. 
10.3 Relapse from Remission 
10.3.1 Lymphoma (Hodgkin Lymphoma, Non-Hodgkin Lymphoma, and T-Cell Lymphoma) 
In patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or T-cell lymphoma, 
25% or greater increase in involved lymph nodes and histologically documented 
relapse at another site will be indicative of relapse or PET scanning with an SUV >4. 
10.3.2 Leukemia (Acute and Chronic Myeloid and Lymphoid) and Myelodysplasia 
Patients with acute leukemia will be considered as having relapsed if there is an 
increase in blast count to beyond 5% or recurrent cytogenetic abnormalities or 
molecular aberration defined by an abnormal FISH or PCR. 
10.3.3 Myelofibrosis  
Re-emergence of clonal hematopoiesis or increased blasts in circulation in the 
presence of recipient chimerism, with or without persistent marrow fibrosis. 
10.3.4 Multiple Myeloma 
In patients with multiple myeloma, disease relapse will be defined by increase in the 
plasmacytosis to greater than 5% plasma cells and/or 25% or greater increase in 
paraproteinemia, appearance of new extramedullary disease, or appearance of new 
skeletal disease. 
10.4 GVHD Staging and Grading 
Acute GVHD will be graded according to the CIBMTR acute GVHD system. The staging 
and grading criteria for GVHD are outlined on Table 2 and Table 3. 

 
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11 CORRELATIVE STUDIES  
11.1 Participation in Correlative Studies 
Plans for the correlative studies are described in Section 1.5. Participation in the 
correlative studies using collected blood samples is mandatory. 
11.2 Processing and Distribution of Blood Samples 
Samples for vitamin C and CRP will be processed and analyzed in the VCUHS clinical 
pathology laboratory. 
The laboratory of Ramesh Natarajan, PhD, will receive, process, and store blood samples 
for TNF-α, TM, and cfDNA studies. 
11.3 Blood Samples for Correlative Studies 
Blood samples will be collected for the planned correlative studies at the following time 
points: 
• 
Baseline (before beginning conditioning) 
• 
Day 0 
• 
Day +14  
• 
Day +30 
• 
Day +100  
Approximately 4 mL will be collected in each of three tubes at each time point: one tube for 
vitamin C, one tube for CRP, and one tube to be processed and stored for TNF-α, TM, and 
cfDNA studies. 
11.4 Labeling for Blood Samples 
Blood samples for vitamin C and CRP testing should be labeled in accordance with the 
standard practice of the VCUHS clinical pathology laboratory. 
Each blood sample collected for storage and future analysis should be labeled as follows: 
• 
Study number 
• 
Patient study identification number 
• 
Date of sample collection 
• 
Time of sample collection 
• 
Study time point 

 
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11.5 Processing and Analysis of Blood Samples 
Testing and analysis will be as follows: 
11.5.1 Vitamin C  
Serum levels of vitamin C will be measured according to standard practices of the 
VCUHS clinical pathology laboratory. 
11.5.2 C-Reactive Protein (CRP) 
Plasma/serum levels will be measured using by high sensitivity C-reactive protein 
(hsCRP) assay. The assay will be performed by ELISA using the Human C-Reactive 
Protein/CRP Quantikine ELISA Kit (R&D Systems, catalog # DCRP00). 
11.5.3 Tumor Necrosis Factor-Alpha (TNF-α)  
TNF- α levels in plasma/serum will be quantified using a Human TNF-alpha 
Quantikine ELISA Kit according to manufacturer’s instructions (R&D Systems, 
catalog # DTA00C). 
11.5.4 Thrombomodulin (TM) 
Plasma levels will be quantified using an ELISA kit (IMUBIND; American 
Diagnostica Inc., Stamford, Connecticut, USA). 
11.5.5 Cell-Free DNA (cfDNA) 
The levels of cf-DNA in human serum/plasma will be quantified using the Invitrogen 
Quant-iT PicoGreen dsDNA assay kit according to the manufacturer’s instructions 
(Life Technologies, Grand Island, NY). Fluorescence intensity will be measured on a 
SpectraMax Gemini XPS microplate reader with excitation at 490 nm and emission 
at 525 nm, with 515 nm emission cutoff filter (Molecular Devices, Sunnyvale, CA). 
12 STUDY CALENDAR 
Required assessments, tests, examinations, administration of the vitamin C regimen, and 
collection of blood samples for correlative studies are outlined on Table 4 and Table 5. 
 
 
 

 
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13 STATISTICAL CONSIDERATIONS 
13.1 Statistical Methods 
13.1.1 Primary Endpoint 
The primary outcome in this study is non-relapse mortality (NRM) at one year. 
13.1.2 Secondary Endpoints (with measurement type) 
• 
Time to engraftment (in days) 
• 
Acute GVHD (days to positive diagnosis: time-to-event; positive diagnosis: 
categorical) 
• 
AEs of grade ≥ 3 possibly, probably, or definitely related to the vitamin C 
regimen (counts by event type) 
13.1.3 Exploratory Endpoints 
• 
Chronic GVHD (days to positive diagnosis: time-to-event; positive diagnosis: 
categorical) 
• 
Overall survival 
• 
Relapse-free/GVHD-free survival 
• 
Levels in blood over time of vitamin C and exploratory biomarkers 
13.1.4 Statistical Analysis 
The primary and secondary outcomes will be compared between the study cohort 
and a historical cohort matched for age, donor type, and diagnosis. The NRM rate 
will be compared to the historical 35% rate (see Section 13.2 below) using a one-
sided exact binomial test. Time-to-event outcomes (time to engraftment, acute and 
chronic GVHD, and overall and relapse-free survival) will be graphically represented 
with a Kaplan-Meier step-function and will be assessed for associations with serum 
vitamin C levels and patient demographic measurements using a Cox Proportional 
Hazards model. Associations between blood levels of vitamin C and other 
exploratory endpoints will be estimated using Spearman rank correlation 
coefficients. 
13.2 Sample Size and Power Determination 
The sample size and power are calculated based on Simon’s two-stage minimax design, 
which minimizes the expected maximum sample size under the alternative hypothesis. The 
previous 2 years at VCU have seen an ~15% NRM rate in MRD patients and an ~40% 
NRM rate in MUD patients. Given that MRDs comprise ~25% of total transplantations and 
MUDs comprise ~75%, we then assume an overall 35% NRM rate. The null hypothesis 
that the NRM rate is 35% will be tested against a one-sided alternative. In order to achieve 
80% power (with 5% significance) to declare an NRM of 20% significantly smaller than the 

 
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hypothesized null NRM of 35%, we will accrue 31 patients in stage 1 and an additional 24 
patients in stage 2 (provided the trial is not stopped early for futility). At the end of stage 1, 
if there are 11 or more NRMs in the 31 stage 1 patients, the study will be stopped for 
futility. Otherwise, 24 additional patients will be accrued for a total of 55. The null 
hypothesis will not be rejected if 14 or more NRMs are observed in the total 55 patients. 
We anticipate a 32% screen failure rate, leading to a recruitment target of 81 subjects 
(VCU sees ~5 eligible MRD/MUD patients per month). The number of MUD patients will be 
limited to 80%. 
The population evaluable for the primary endpoint includes all patients who receive at least 
one dose of IV vitamin C and who have a known survival status at one year. Patients who 
are enrolled to the study but do not receive any IV vitamin C or who are lost to follow up at 
one year will be replaced. 
13.3 Safety Criteria for Lead-In Phase and Phase 2 Portions of the Trial 
Early stopping criteria based on severe toxicities and ANC engraftment failure will be used 
to ensure patient safety in both the safety lead-in cohort and the phase 2 portion of the 
trial.  
The following toxic events as defined per CTCAE v5.0 will be counted separately toward 
the stopping rules in Table 6 and Table 7: 
• 
Grade 4 mucositis (any site) 
• 
Any grade 4 renal toxicity 
• 
Any grade 4 hepatobiliary toxicity 
• 
Grade 4 respiratory failure 
• 
Grade 4 sepsis 
13.3.1 Safety Lead-in Cohort 
The stopping rules for the initial safety phase are based on both the five toxic events 
listed above and ANC engraftment failure occurring with 30 days following 
transplant. The safety phase and the overall study will be stopped if either of the 
conditions stated for toxic events or ANC engraftment failure in Table 6 below are 
met. Both stopping rules are based on a one-sided exact binomial test with right-
tailed significance level of α=0.05 for sample sizes 4 to 14. For the toxic events the 
assumed null proportion is 0.30 for each of the five toxicities listed above, while for 
ANC engraftment failure the assumed null proportion of 0.10.  
After enrollment to the safety lead-in cohort has been completed, accrual to the 
study will be temporarily suspended until all patients have completed toxicity and 
engraftment assessments through 30 days post-transplant. These assessments will 
be reviewed by study monitors and the Data and Safety Monitoring Committee 
(DSMC, Section 14.2). If the DSMC concludes that the reported toxicities and 
engraftment meet safety criteria to continue, the study will reopen to accrual. 

 
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14 DATA AND SAFETY MONITORING  
14.1 Study Team 
The study team minimally consists of the sponsor-investigator, the co-investigators, the 
study coordinator, the clinical research associate, and the study biostatistician. While 
patients are on treatment, the sponsor-investigator and the study coordinator will meet at 
least monthly and will meet at least quarterly with the study biostatistician to review study 
status. This review will include, but not be limited to, reportable AEs and UPs and an 
update of the ongoing study summary that describes study progress in terms of the study 
schema. All meetings including attendance are documented. 
14.2 Monitoring and Auditing  
14.2.1 MCC Compliance Office 
Compliance specialists in the MCC Compliance Office will provide ongoing 
monitoring and auditing for this study.  
14.2.2 Data and Safety Monitoring Committee (DSMC) 
The study will be reviewed by the MCC DSMC initially according to the risk level 
specified by the MCC Protocol Review and Monitoring Committee (PRMC) and then 
according to a schedule based on study status and quality indicators. The DSMC 
will review reports provided by the sponsor-investigator/study team and the MCC 
Compliance Office focusing on data integrity and patient safety.  
15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (US National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research, April 18, 1979). 
15.2 Regulatory Compliance 
This study will be conducted in compliance with: 
• 
The protocol 
• 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 
(IND Application); and 45 CFR 46 Subparts A (Common Rule), B (Pregnant Women, 
Human Fetuses and Neonates), C (Prisoners), and D (Children) 

 
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15.3 Institutional Review Board 
The VCU IRB, which is registered with the Office for Human Research Protections, will 
review and provide approval for the protocol, the associated informed consent document, 
material that will be provided to participating patients, and any recruitment material. Any 
amendments to the protocol, consent form, or other materials will also be approved by the 
IRB. 
15.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Discussion of risks and possible benefits of this therapy will be provided to the patients and 
their families. IRB-approved consent forms describing the study interventions, study 
procedures, and risks are given to the patient and written documentation of informed 
consent is required prior to starting intervention/administering study product.  
The patient will be asked to read and review the document. Upon reviewing the document, 
the investigator will explain the research study to the patient and answer any questions 
that may arise. The patient will sign the informed consent document prior to any 
procedures being done specifically for the study. The patients should have the opportunity 
to discuss the study with their surrogates or think about it prior to agreeing to participate. 
Patients may withdraw consent at any time throughout the course of the trial. A copy of the 
informed consent document will be given to patients for their records. The rights and 
welfare of the patients will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
15.5 Patient Confidentiality and Access to Source Documents/Data 
Patient confidentiality is strictly held in trust by the participating investigators and their staff. 
This confidentiality includes the clinical information relating to participating patients, as well 
as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor-investigator. 
The sponsor-investigator will allow access to all source data and documents for the 
purposes of monitoring, audits, IRB review, and regulatory inspections. 
The study monitor or other authorized representatives of the sponsor-investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 

 
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16 DATA HANDLING AND RECORD KEEPING 
16.1 Data Management Responsibilities 
The sponsor-investigator is responsible for: (i) the overall conduct of the investigation;  
(ii) ongoing review of trial data including all safety reports; and (iii) apprising participating 
investigators of any UPs. Participating investigators are responsible for reporting SAEs and 
UPs as required in Section 8. 
Any laboratory conducting correlative studies must maintain the laboratory records and 
documentation (laboratory notebooks, laboratory protocols, print-outs, recordings, 
photographs, etc). 
16.2 Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic 
test reports, etc) are maintained in the patient’s clinical file. Source documents for the 
correlative studies are maintained in the laboratory conducting the study. 
16.3 Case Report Forms and Data Collection 
MCC OnCore data management will provide standard and study-specific electronic case 
report forms (eCRFs) to capture all the information required by the protocol. The eCRFs 
will be approved by the study team to ensure the most effective data acquisition.  
The investigator(s) and study coordinator(s) must maintain source documents for each 
patient in the study. All information on the eCRFs will be traceable to the source 
documents, which are generally maintained in the patient’s file.  
All eCRFs should be completed and available for collection within a timely manner, 
preferably no more than 14 days after the patient’s visit. 
16.4 Study Record Retention 
As applicable, study records will be maintained a minimum of 6 years beyond: (i) the 
publication of any abstract or manuscript reporting the results of the protocol; (2) the 
submission of any sponsored research final report; or (iii) submission of a final report to 
clinicaltrials.gov. 

 
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