Conditions: Soft Tissue Sarcoma
Keywords: Sarcoma Soft tissue
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
This is a single-arm open-label phase Ib/II clinical study assessing the efficacy of concurrent high dose ascorbate in combination with radiotherapy in patients with locally advanced, resectable, high grade sarcomas.

Detailed description:
Phase Ib:

The phase Ib portion of this study is to ensure the safety and tolerability of high dose ascorbate in combination with external beam radiation therapy (EBRT) as assessed by incidence of dose-limiting toxicities (DLT). EBRT will be given at the standard dose for resectable soft tissue sarcomas according to the NCCN sarcoma guidelines.2 Patients will receive 50 Gy over 5 weeks, during which time they will be receiving three times a week IV high dose ascorbate. IV ascorbate infusions will be continued until the end of radiation therapy. Surgery will be performed 4-6 weeks from the end of radiation to allow for adequate tissue healing and resolution of acute toxicities.

Phase 2:

The phase 2 part of the study will provide an estimate of the relative treatment effect of pharmacological ascorbate in combination with preoperative EBRT in subjects with locally advanced, resectable, extremity, trunk or retroperitoneal high grade sarcomas, as measured by pathological response rates.

As above, patients will receive the first dose of pharmacological ascorbate intravenously on day 1 of week 1 provided no reactions are seen to the test dose. This will be followed by 3 times a week dosing at Dose 0 until completion of EBRT. Standard doses of radiation for resectable soft tissue sarcomas according to the NCCN sarcoma guidelines will be administered.2 Patients will receive preoperative radiation at a dose of 50 Gy over 5 weeks starting on week 1 day 1. Subjects will be followed either by clinic visit or phone contact every 12 weeks for approximately 24 months after the end of the treatment phase, at which time the initial survival data and disease recurrence will be assessed.

Arms:
arm 1: Participants will receive radiation therapy over 5 weeks, during which time they will be receiving ascorbate infusions three times a week. Ascorbate infusions will be continued until the end of radiation therapy. Surgery will be performed 4-6 weeks from the end of radiation. arm 2: Participants will receive radiation therapy over 5 weeks, during which time they will be receiving intravenous (IV) ascorbate infusions three times a week. Ascorbate infusions will be continued until the end of radiation therapy. Surgery will be performed 4-6 weeks from the end of radiation.

Interventions: intervention 1: Ascorbate
Intervention descriptions: intervention 1: Phase 1 dose escalation:

75gm IV three times a week

Phase II portion:

75gm IV three times a week if no dose limiting toxicities are experienced in the Phase I portion. Otherwise, ascorbate dose will be deescalated to 62.5 gm IV

Protocol document:
Prot_SAP_000.pdf: 
Version 8 17Novemberl2021 
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Phase 1b/2 Neoadjuvant High Dose Ascorbate with Concurrent 
Preoperative Radiation in Patients with Locally Advanced Soft 
Tissue Sarcomas of Extremity, Trunk and Retroperitoneum  
Coordinating Center: 
Holden Comprehensive Cancer Center – University of Iowa 
*Principal Investigator: 
Varun Monga, MBBS 
Clinical Assistant Professor 
Division of Hematology & Oncology 
Department of Internal Medicine 
University of Iowa Hospitals and Clinics 
C32 G GH 
(319) 384-9497 
varun-monga@uiowa.edu 
 
Co-Investigators: 
 
Mohammed Milhem, MBBS 
Clinical Professor 
Division of Hematology/Oncology 
Department of Internal Medicine C-32 GH 
(319) 356-2324 
mohammed-milhem@uiowa.edu 
Bryan Allen, MD, PhD 
Associate Professor 
Department of Radiation Oncology 
01620 PFP 
(319) 356-3696 
bryan-allen@uiowa.edu  
Benjamin Miller, MD, MS 
Clinical Associate Professor 
Department of Orthopedics 
Carryn Anderson, MD 
Clinical Associate Professor 
Department of Radiation Oncology 
Munir Tanas, MD 
Assistant Professor 
Department of Pathology 
 
 
 


Version 8 17Novemberl2021 
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Statistician: 
Sarah L. Bell, M.S. 
The Holden Comprehensive Cancer Center 
The University of Iowa 
N319 CPHB 
sarah-mott@uiowa.edu  
 
Study Agent: 
Pharmacological ascorbate  
Other Agent(s): 
Standard external beam radiation 
 
Investigational Agent  
IND# 
IND Sponsor  
Ascorbic acid 
137968 
Mohammed Milhem 
 
 
 
 
 
Protocol Version 8 
Protocol Version Date: 17 November  2021 
 
 


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SCHEMA 
Study Timeline Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 1b Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XRT 
Ascorbate IV three 
times weekly 
Screening 
End of Week 5 
End of Week 9, 10, or 11 
Follow up every 12 weeks through 24 months 
Trial dose of IV 
ascorbate & G6PD test 
Complete XRT 
MRI of tumor then Surgery 
Day 1 Week 1 
SCREENING
ENROLLMENT
END OF TREATMENT
SAFETY FOLLOW-UP
END OF STUDY
 
IV Ascorbate 75gm three 
times weekly   
+ 
Radiotherapy starting 
from week 1 
+ 
Surgery 4-6 weeks after 
XRT 
 
 


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SAFETY FOLLOW-UP
Table 1.  
Phase 1b Dose De-escalation Schedule 
 
Number of patients with 
DLT at a given dose level 
Decision Rule 
0 out of 3 
Enter 3 patients at the next higher dose level 
1 out of 3 
Enter up to 3 additional patients at the same dose level.  
• If 0 of these 3 patients experience DLT, proceed to the next 
dose level. 
• If 1 or more of these 3 patients experience DLT, then dose 
escalation is stopped and this dose is declared the 
maximally administered dose. Three (3) additional patients 
will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose.  
≥2 out of 3 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose. Three (3) 
additional patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose.  
 
 
Ascorbate Dose Levels: 
Dose 0 = Ascorbate 75 gm IV three times weekly concurrently with radiation   
Dose -1 = Ascorbate 62.5 gm IV three times weekly concurrently with radiation  
• Initial dose for all = Ascorbate 75gm IV  
Phase 2 Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase II 
 
IV Ascorbate at 
recommended dose three 
times weekly 
+ 
Radiotherapy starting 
from week 1 
+ 
Surgery 4-6 weeks after 
XRT 
END OF TREATMENT
SURVIVAL F-UP
END OF STUDY
SCREENING
ENROLEMENT


Version 8 17Novemberl2021 
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TABLE OF CONTENTS 
1. 
BACKGROUND .................................................................................................................7 
1.1 
Disease Background.................................................................................................7 
1.2 
Ascorbate as an anti-tumor agent .............................................................................7 
1.3 
Clinical Trial Data....................................................................................................9 
1.4 
Radiation Therapy in Sarcoma...............................................................................10 
2. 
REGISTRATION PROCEDURES ...................................................................................10 
3. 
OBJECTIVES ....................................................................................................................10 
3.1 
Primary Objectives.................................................................................................11 
3.2 
Secondary Objectives.............................................................................................12 
4. 
PATIENT SELECTION ....................................................................................................12 
4.1 
Inclusion Criteria ...................................................................................................12 
4.2 
Exclusion Criteria ..................................................................................................14 
5. 
TREATMENT PLAN AND STUDY SCHEMA ..............................................................15 
5.1 
Study Design ..........................................................................................................15 
5.2 
Phase Ib ..................................................................................................................15 
5.3 
Phase 2 ...................................................................................................................16 
5.4 
Study Timeline Schema: ........................................................................................16 
5.5 
Post-consent Screening Procedures .......................................................................17 
5.6 
Concomitant Ascorbate (High-dose Ascorbic Acid) Infusions .............................17 
5.7 
Radiation therapy ...................................................................................................18 
5.8 
General Concomitant Medication and Supportive Care Guidelines ......................21 
5.9 
Criteria for removal from study .............................................................................23 
5.10 
Duration of Follow Up ...........................................................................................23 
6. 
DOSING DELAYS/DOSE MODIFICATIONS/ DOSE LIMITING TOXICITIES .........23 
6.1 
Radiation Therapy ..................................................................................................23 
6.2 
Ascorbate Therapy .................................................................................................23 
6.3 
Dose Limiting Toxicities .......................................................................................24 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................24 
7.1 
Determination of Reporting Requirements ............................................................25 
7.2 
Institutional Review Board reporting requirements ...............................................25 
7.3 
FDA reporting requirements [M.Milhem, sponsor] ...............................................25 
7.4 
Routine Adverse Event Reporting Requirements to DSMC ..................................25 
7.5 
Serious Adverse Event Reporting to DSMC .........................................................26 
8. 
PHARMACEUTICAL INFORMATION – Ascorbic Acid Injection, ASCOR L 500® ..26 
8.1 
Availability ............................................................................................................26 
8.2 
Compatibility .........................................................................................................26 
8.3 
Storage and Stability ..............................................................................................26 
8.4 
Toxicities................................................................................................................27 


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9. 
Correlative and special studies...........................................................................................27 
9.1 
ROS Research blood ..............................................................................................27 
9.2 
Labile Iron Measurements using MRI Imaging (optional) ....................................27 
9.3 
Diffusion Weighted Imaging (optional).................................................................28 
9.4 
Ascorbate levels .....................................................................................................28 
9.5 
Tumor tissue...........................................................................................................28 
10. 
Study Calendar ...................................................................................................................30 
10.1 
Study Procedures ...................................................................................................30 
10.2 
Screening Procedures .............................................................................................32 
10.3 
Post-treatment Evaluations ....................................................................................32 
11. 
MEASUREMENT OF EFFECT........................................................................................32 
11.1 
Pathologic Response ..............................................................................................32 
11.2 
Time to Disease progression (TTP) .......................................................................32 
11.3 
Other Response Parameters ...................................................................................32 
12. 
STATISTICAL CONSIDERATIONS...............................................................................34 
12.1 
Phase Ib ..................................................................................................................34 
12.2 
Phase II...................................................................................................................34 
12.3 
Sample Size/Accrual Rate ......................................................................................34 
13. 
References ..........................................................................................................................35 
 
 
 


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1. BACKGROUND 
1.1 
Disease Background 
Adult soft tissue sarcomas (STS) constitute a wide heterogeneous group of very rare tumors, both 
in terms of histology and biological and clinical behavior. In contrast to major advances in the 
biological understanding of these heterogeneous subtypes, forward progress in the systemic 
treatment of sarcoma has been painstakingly slow. The prognosis of patients with metastatic or 
recurrent disease is poor and most of them will die from tumor progression. Taking into account 
differences in histology subtype, anatomic location of disease and age at disease onset, the overall 
median survival for patients with metastatic STS is approximately one year and only about 10% 
of these patients are alive at five years1.  
Control of localized disease is, therefore, of prime importance as evidenced by the National 
Comprehensive Cancer Network’s (NCCN) current treatment guidelines2. Pisters et al 
demonstrated that histologic grade, depth of location, and positive surgical margins are key 
determinants of STS recurrence.3 However, patients typically present late with local tumor 
extensions into critical adjacent structures, making complete surgical resection with uninvolved 
margins difficult. Preoperative radiotherapy has been shown to significantly improve local disease 
control, functional outcomes and survival in patients with locally advanced STS.4-6 
1.2 
Ascorbate as an anti-tumor agent 
Ascorbate (ascorbic acid, vitamin C, AscH) is one of the early unorthodox therapies for cancer, 
based on two unsupported hypotheses. McCormick postulated that ascorbate protects against 
cancer by increasing collagen synthesis,7,8 while Cameron hypothesized that ascorbate could have 
anti-cancer action by inhibiting hyaluronidase and thereby prevent cancer spread.9 These 
hypotheses were subsequently promoted by Cameron and Pauling.10,11 Cameron and Campbell 
initially published case reports of 50 patients; some seemed to have benefited from high dose 
ascorbate.12 Cameron and Pauling then published results of 100 patients with terminal cancer that 
were given intravenous ascorbate.13 The ascorbate-treated patients were compared to 1000 
retrospective controls with similar disease. Patients who received ascorbate survived on average 
300 days longer than controls.11,13 A prospective study was then conducted that randomized 
patients to ascorbate treatment or palliative therapy. Treated patients had a median survival of 343 
days vs. 180 days for controls.14 Smaller studies have also reported benefits of ascorbate.15,16 
To test “definitively” whether ascorbate was effective, Moertel conducted two randomized 
placebo-controlled studies randomized to oral ascorbate; neither study showed benefit.17,18 
Subsequently, ascorbate therapy was considered ineffective. However, it was not recognized until 
approximately 15 years later that oral and intravenous ascorbate have strikingly different 
pharmacokinetics.19,20 This difference in the administration route is key. Cameron gave patients 
ascorbate intravenously as well as orally, while Moertel’s patients received only oral ascorbate. 
Thus, the issue of ascorbate in cancer treatment needed to be re-examined.  
The evidence for use of ascorbate in cancer treatment falls into two categories: clinical data on 
dose concentration relationships and laboratory data describing potential cell toxicity with high 
concentrations of ascorbate in vitro. Clinical data show that when ascorbate is given orally, fasting 
plasma concentrations are tightly controlled at < 100 µM.21 As doses exceed 200 mg, absorption 
decreases, urine excretion increases and ascorbate bioavailability is reduced.19,21 In contrast, when 
1.25 grams of ascorbate are administered intravenously, concentrations as high as 1 mM are 


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achieved. Some clinicians have infused more than 10 grams of ascorbate in cancer patients and 
achieved plasma concentrations of 1 to 5 mM.22 Thus, it is clear that intravenous administration of 
ascorbate can yield very high plasma levels, while oral treatment does not.  
Pharmacologic ascorbate concentrations have been shown to selectively kill many cancer cell 
types. Chen et al. measured cell death in 10 cancer and 4 normal cell types using 1-hour exposures 
to pharmacological ascorbate.23 Normal cells were unaffected by 20 mM ascorbate whereas 5 
cancer cell lines had EC50 values of < 4 mM, a concentration achievable by intravenous 
administration. In addition, cell death was independent of metal chelators, but dependent on 
formation of H2O2.24 H2O2 generation was dependent on ascorbate concentration, incubation 
time; [H2O2] displayed a linear increase with [AscH] and it increased as a quadratic function of 
ascorbate radical, ascorbate being an electron donor to O2 to form superoxide and, eventually, 
H2O2.  
When ascorbate is infused intravenously the resulting pharmacologic concentration will distribute 
rapidly into the extracellular water space.25 In vivo, Chen and colleagues demonstrated that 
intravenous injection of ascorbate (0.25-0.5 mg/g body weight) increased baseline concentrations 
of ascorbate in the blood and extracellular fluid to > 8 mM as well as increased formation of 
H2O2.26 More recent studies have demonstrated that intraperitoneal doses of 4 g/kg ascorbate 
resulted in blood concentrations of 40 mM; tumor extracellular fluid increased to peaks of 20 mM 
for up to 3 hours.21 Our data demonstrate that pharmacologic doses of ascorbate are cytotoxic to 
sarcoma cell lines and that it enhances radiation therapy sensitivity in vitro (Figure 1). 
Additionally, we also showed that intraperitoneal administration of high dose ascorbate in 
combination with radiation inhibits orthotopic sarcoma growth and decreases tumor size in mice 
without causing an associated toxicity in vivo (Figure 2). Combined, these studies provide a 
foundation for pursuing pharmacologic ascorbate as a prooxidant agent in cancer therapy and 
specifically in sarcoma.27 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 Demonstrates that sarcoma cell 
lines, fibrosarcoma (HT1080) and synovial 
sarcoma (SW-872), are sensitive to 
increasing doses of pharmacological 
ascorbate. Cells were treated with 
increasing doses of ascorbate for 1 hour 
followed by clonogenic cell survival 
analysis. 


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Ascorbate-mediated cell death has been shown to be due to H2O2 generation, via ascorbate radical 
formation, with ascorbate as the electron donor.23,24,26 When ascorbate is infused intravenously the 
resulting pharmacologic concentration distributes rapidly in the extracellular water space.26 Thus, 
pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, should 
generate ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate 
concentrations in whole blood generate little detectable ascorbate radical and no detectable 
H2O2.18 This can be accounted for by efficient and redundant H2O2 catabolic pathways in whole 
blood relative to those in media or extracellular fluid. Thus, ascorbic acid administered 
intravenously in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the 
extracellular milieu, but without H2O2 accumulation in blood.  
1.3 
Clinical Trial Data 
In a Phase I trial of intravenous ascorbic acid in patients with advanced malignancy the high-dose 
intravenous ascorbic acid was well tolerated when administered to patients. Adverse events and 
toxicity were minimal at all dose levels. Ascorbic acid concentrations reached up to 25 mmol/L in 
patients who received ascorbic acid of 1.5 g/kg. Of the 24 patients in the study, only 4 recorded 
minor adverse events including headache, dizziness and diarrhea.28  In another phase I trial using 
pharmacological ascorbate concurrently with gemcitabine in patients with locally advanced and 
Figure 2 Pharmacological ascorbate 
selectively sensitizes fibrosarcoma tumors 
to radiation in an orthotopic murine 
xenograft model. An orthotopic 
fibrosarcoma model was utilized by 
injecting 1×106 HT-1080 cells into the 
dermis of the right rear flank of athymic 
nude female mice. Once tumors were 
established, therapy was initiated with 
daily ascorbate (4 g kg−1 or sodium 
chloride control; IP) in combination with 
12 Gy IR in 2 fractions (days 2 and 4) (A) 
Tumor volume measurements (points +/- 
error) fitted with a logistical regression 
(line) for mice treated with daily ascorbate 
in combination with radiation (B) Overall 
survival in mice treated with ascorbate in 
combination with radiation. Mice were 
sacrificed when any tumor dimension 
reached 1.5 cm. NED=no evidence of 
macroscopic disease at end of experiment. 
(C) Mouse weight in mice treated with 
ascorbate in combination with radiation. 
For each treatment group, n = 8 mice. 


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metastatic pancreatic cancer conducted at University of Iowa Hospitals and Clinics, 9 patients 
received treatment. Individual doses between 50 to 125 g per infusion were given for maintenance 
of 350 mg/dL level in plasma. 75-g dose yielded peak plasma levels ranging between 320 and 630 
mg/dL. No dose limiting toxicities or serious adverse events were reported.29  
A phase I study of adding ascorbate to standard therapy in glioblastomas and NSCLC was initiated 
in 2013.30 Subjects were assigned to high-dose ascorbate dose cohorts for the concomitant portion 
of therapy. Dose cohorts ranged from 15g to 87.5g. During the adjuvant phase, subjects underwent 
interpatient dose escalation to achieve a targeted plasma ascorbate level of 350 mg/dL. Subjects 
received high-dose ascorbate during the adjuvant phase for up to 6 cycles. To date, 5 subjects have 
been enrolled in the recommended phase 2 dose of 87.5g. Treatment was well-tolerated with minimal 
adverse events. No subject experienced a grade 3 or greater hematologic or non-hematologic 
toxicity. The only adverse events associated with ascorbate were grade 1 dry mouth, grade 1 chills, 
and grade 2 hypertension. Dry mouth is transient and ends shortly after infusion. Grade 1 chills are 
infusion related, most likely due to the volume of fluid infused. Grade 2 hypertension occurs in some 
subjects during infusion, again most likely due to the volume of fluid infused.30    
1.4 
Radiation Therapy in Sarcoma 
The benefits of combination therapy with radiation and surgery in significantly improving local 
control in STS patients are well documented. Preoperative radiotherapy has been shown to 
significantly improve local disease control, functional outcomes and survival in patients with 
locally advanced STS4-6. Recent review of literature indicates that about 10% of patients will have 
≥ 95% tumor necrosis, and about 25% will achieve ≥ 80% tumor necrosis following preoperative 
radiation therapy alone.31,32  Further review indicates that only those patients who achieve ≥ 95% 
tumor necrosis with preoperative radiation have improved local and distant control as well as 
overall survival.32 Despite its reported benefits, radiotherapy is associated with a high rate of 
complications and significant functional morbidity. O’Sullivan et al compared preoperative versus 
postoperative external beam radiation (EBRT) for resectable extremity STS.  Long term follow up 
revealed no statistical difference in local control and cause specific survival, however, preoperative 
radiotherapy was associated with a significantly higher rate of acute wound complications (35% 
vs. 17%, p = 0.01) and a lower rate of late Grade 2– 4 fibrosis (32% vs. 48%, p = 0.07).33,34 Multiple 
retrospective reviews have similarly found high rates of acute wound complications in sarcoma 
patients ranging from 25% to 44%.35-38 These reported high rates of acute and late toxicities 
support the need for additional research to improve the safety profile of neoadjuvant radiotherapy. 
In addition, there is need to improve efficacy of the radiation treatments to achieve higher rates of 
tumor necrosis, and, to ensure resection of the tumor with clear margins for successful organ 
preserving treatment of sarcoma. 
2. REGISTRATION PROCEDURES 
NA; Single Institution study.  
3. OBJECTIVES 
 


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OBJECTIVES 
ENDPOINTS 
Primary 
 
Phase 1b: To determine the 
safety and tolerability of 
neoadjuvant ascorbate in 
combination with preoperative 
EBRT as assessed by incidence 
of dose-limiting toxicities (DLT) 
in subjects with locally advanced 
high grade soft tissue sarcomas 
of extremity, trunk and 
retroperitoneum.  
 
Phase 2: To estimate the 
efficacy of neoadjuvant 
ascorbate and radiotherapy as 
assessed by the pathological 
complete response rates (pCR) 
in subjects with locally advanced 
high grade soft tissue sarcomas. 
For this study, pCR will be 
defined as ≥ 95% tumor necrosis 
following concurrent radiation 
therapy and ascorbate. 
 
Incidence of Dose Limiting Toxicities. 
 
 
 
 
 
 
 
 
 
 
pCR rate- the proportion of subjects with pathologic 
tumor necrosis > 95%. 
Secondary 
 
Time to disease progression 
(local or distant recurrence) 
 
 
Overall response rate (ORR) pre 
op as measured by RECIST 1.1 
or a later tool for monitoring 
disease progression.  
 
 
Overall survival rate (OS) at 2  
Years 
 
 
To grade radiation related skin 
toxicity overlying the tumor 
 Time from first day of study treatment to first 
documented disease progression. 
 
 
The proportion of subjects with a complete or partial 
response. 
 
 
 
 
Time from first day of study treatment to death due to 
any cause.  Survival will be estimated at 2 years. 
 
 
Incidence of radiation related skin toxicity by grade 


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OBJECTIVES 
ENDPOINTS 
 
To measure labile iron using T2* 
imaging sequence on MRI pre 
and post ascorbate treatments 
and compare with serum iron 
measurements 
 
To evaluate diffusion weighted 
imaging sequences on MRI in 
pre and post treatment tumors 
 
Changes in labile iron and serum iron from pre to 
post-treatments 
 
 
 
 
Changes in diffusion weighted imaging sequence 
from pre-to post-treatment 
 
3.1 
Primary Objectives 
Phase 1b: To determine the safety and tolerability of neoadjuvant ascorbate in combination with 
preoperative EBRT as assessed by incidence of dose-limiting toxicities (DLT) in subjects with 
locally advanced high grade soft tissue sarcomas of extremity, trunk and retroperitoneum.  
Phase 2: To estimate the efficacy of neoadjuvant ascorbate and radiotherapy as assessed by the 
pathological complete response rates (pCR) in subjects with locally advanced high grade soft tissue 
sarcomas. For this study, pCR will be defined as ≥ 95% tumor necrosis following concurrent 
radiation therapy and ascorbate. 
3.2 
Secondary Objectives 
- Time to disease progression (local or distant recurrence) 
- Overall response rate (ORR) pre op as measured by RECIST 1.1 or a later tool for 
monitoring disease progression.  
- Overall survival rate (OS) at 2 years 
- To grade radiation related skin toxicity overlying the tumor as compared to historical 
controls  
- To measure labile iron using T2* imaging sequence on MRI pre and post ascorbate 
treatments and compare with serum iron measurements 
- To evaluate diffusion weighted imaging sequences on MRI in pre and post treatment 
tumors and correlate it with necrosis and survival  
4. PATIENT SELECTION 
4.1 
Inclusion Criteria  
4.1.5 Subject or subject’s legally acceptable representative has provided informed consent. 
4.1.6 Histologically confirmed diagnosis of locally advanced soft tissue sarcoma of extremity, 
trunk or retroperitoneum that is unresectable with clear wide margins, for which 
preoperative radiotherapy is considered appropriate. 
• Including metastatic (stage IV) disease for which radiotherapy and surgical resection 
of the primary tumor are indicated. 
4.1.7 Patients with locally recurrent sarcoma after surgery alone are eligible for enrollment if 


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other inclusion criteria are met. 
4.1.8 Patient does not have histologic subtypes: GIST, Desmoid, Ewing sarcoma, bone 
sarcomas and Kaposi sarcoma 
4.1.9 Age ≥18 years.  
4.1.10 Patients with history of non-melanomatous skin cancer, in situ carcinoma, or low-risk 
prostate cancer can be enrolled. 
4.1.11 ECOG performance status ≤1. 
4.1.12 Tolerate one test dose (15g) of ascorbate.  
4.1.13 Patient must have measurable disease: 
• Tumor size at least ≥ 5 cm in the longest diameter as measured by CT scan or MRI 
for which radiation is feasible and indicated. 
 
 


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4.2 
Exclusion Criteria 
4.2.1 Inadequate organ function within 21 days of Day 1 of study as defined by:  
• Hemoglobin < 9.0 g/dL 
• Absolute neutrophil count (ANC) </= 1500 per mm3  
• Platelet count </= 100,000 per mm3 
• Total bilirubin >/= 1.5 × ULN. Subjects with direct bilirubin < ULN with total 
bilirubin levels > 1.5 X ULN will not be excluded.  
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN 
• Alkaline phosphatase > 2.5 × ULN 
• PT (or INR) and PTT (or aPTT) >/= 1.5 × ULN 
• Creatinine > 2.0 × ULN 
4.2.2 G6PD (glucose-6-phosphate dehydrogenase) deficiency 
4.2.3 Prior history of two episodes of symptomatic oxalate kidney stones within last year. 
4.2.4 Prior radiation therapy in excess of 20 Gy to the site of the current diagnosis of sarcoma. 
No overlap with prior radiation fields in excess of 20 Gy is allowed. 
4.2.5 Prior history of receiving pharmacological ascorbate.  
4.2.6 Patients actively receiving insulin therapy AND needing daily fingerstick for glucose 
monitoring.  
4.2.7 Concurrent, clinically significant, active malignancies within two years of study 
enrollment. 
4.2.8 Female subjects who are pregnant or breast-feeding, or planning to become pregnant 
during study treatment and through 3 months after the last dose of study treatment. 
4.2.9 Female subjects of childbearing potential or male subjects who are unwilling to use 2 
highly effective methods of contraception during study treatment and through 3 months 
after the last dose of study treatment.  
4.2.10 Currently receiving treatment in another invasive investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or drug study(s). 
4.2.11 Patients who are on the following drugs and cannot have a drug substitution:  flecainide, 
methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbic acid may 
affect urine acidification and, as a result, may affect clearance rates of these drugs. 
4.2.12 Known CNS disease, except for treated brain metastasis: Treated brain metastases are 
defined as having no evidence of progression or hemorrhage after treatment and no ongoing 
requirement for dexamethasone, as ascertained by clinical examination and brain imaging 
(MRI or CT) during the screening period.  Anticonvulsants (stable dose) are allowed.  
Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery 
(RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the 
treating physician.  Patients with CNS metastases treated by neurosurgical resection or brain 
biopsy performed within 3 months prior to Day 1 will be excluded 
4.2.13 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ascorbate  


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4.2.14 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
4.2.15 Known HIV-positive and hepatitis B & C individuals. High-dose ascorbate acid is a 
known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs  
4.2.16 Patients who are on warfarin and cannot have a drug substitution or who decline the drug 
substitution.   
5. TREATMENT PLAN AND STUDY SCHEMA 
5.1 
Study Design 
This is a single-arm open-label phase Ib/II clinical study assessing the efficacy of concurrent high 
dose ascorbate in combination with radiotherapy in patients with locally advanced, resectable, high 
grade sarcomas, as measured by pathological response rates. Patients will be treated with three 
times weekly IV ascorbate concurrently with radiation therapy. Surgery will be performed 4-6 
weeks from the end of radiation therapy to allow for resolution of acute toxicities per current 
standard of care. 
5.2 
Phase Ib 
The phase Ib portion of this study is to ensure the safety and tolerability of high dose ascorbate in 
combination with EBRT as assessed by incidence of dose-limiting toxicities (DLT). Although this 
combination has been shown to be safe and well tolerated in GBM, this combination has not been 
studied in sarcoma patients.  EBRT will be given at the standard dose for resectable soft tissue 
sarcomas according to the NCCN sarcoma guidelines.2 Patients will receive 50 Gy over 25 fractions 
for extremity and trunk sarcomas or 45 – 50.4 Gy in 28 fractions for retroperitoneal sarcomas, during 
which time they will be receiving three times a week IV high dose ascorbate. IV ascorbate infusions 
will be continued until the end of radiation therapy. Surgery will be performed 4-6 weeks from the 
end of radiation to allow for adequate tissue healing and resolution of acute toxicities. 
Ascorbate will be dosed at an initial dose of 75gm IV three times a week concurrently with 
radiation therapy provided patient tolerated the test dose of ascorbate during screening without any 
reactions. Initially 3 patients will be entered at the Dose 0 for ascorbate and be monitored at this 
three times a week dose until surgery when safety issues will be addressed. Otherwise, ascorbate 
dose will be deescalated and dose -1 will be explored as outlined. For this protocol DLT will be 
defined as an attributed adverse event (definite, probable or possible) that meets the criteria 
(Section 6.3). 
Table 1.  
Phase 1b Dose De-escalation Schedule 
Number of Patients with DLT  
at a Given Ascorbate Dose 
Decision Rule 
> 2 
Dose level will be declared toxic. 
If this is the lowest dose level, stop the study due to 
excessive toxicity; otherwise enter three additional 
patients at the next lowest dose level. 
< 1 out of 3 
Enter three more patients at this dose level. 
< 1 out of 6 
This is the recommended dose for the subsequent Phase2. 


Version 8 17Novemberl2021 
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Ascorbate Dose Levels 
Dose 0 
Ascorbate 75 gm IV three times weekly concurrently with radiation   
Dose -1 
Ascorbate 62.5 gm IV three times weekly concurrently with radiation 
 
• Initial dose for all = Ascorbate 75gm IV  
5.3 
Phase 2 
The phase 2 part of the study will provide an estimate of the relative treatment effect of 
pharmacological ascorbate in combination with preoperative EBRT in subjects with locally 
advanced, resectable, extremity or retroperitoneal high grade sarcomas, as measured by 
pathological response rates.    
As above, patients will receive the first dose of pharmacological ascorbate intravenously on day 1 
of week 1 provided no reactions are seen to the test dose. This will be followed by 3 times a week 
dosing (= 15 doses total) at Dose 0 until completion of EBRT. Standard doses of radiation for 
resectable soft tissue sarcomas according to the NCCN sarcoma guidelines will be administered.2 
Patients will receive preoperative radiation at a dose of 50 Gy over 25 fractions  for extremity and 
trunk sarcoma or 45 to 50.4 Gy in 28 fractions for retroperitoneal sarcomas starting on week 1 day 
1. Subjects should be followed either by clinic visit or phone contact every 12 weeks (+/- 4 weeks) 
for approximately 24 months after the end of the treatment phase, at which time the initial survival 
data and disease recurrence will be assessed. Details as per study calendar (Section 10). 
5.4 
Study Timeline Schema:  
 
 
 
 
 
 
 
 
 
 
 
Phase 1b schema: 
 
 
 
 
 
 
 
 
 
 
 
XRT 
Three times aweek IV 
ascorbate 
Screening 
End of Week 5 
End of Week 9, 10 or 11 
Follow up every 12 weeks through 24 months 
Test dose of IV ascorbate 
& G6PD test 
Complete XRT 
MRI of tumor then Surgery 
Day 1 Week 1 
SCREENING
ENROLLMENT
END OF TREATMENT
SAFETY FOLLOW-UP
END OF STUDY
 
IV Ascorbate 75gm three 
times weekly for 5 weeks  
+ 
Radiotherapy starting 
from week 1 
+ 
Surgery 4-6 weeks after 
XRT 
 
 


Version 8 17Novemberl2021 
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SAFETY FOLLOW-UP
Phase 2 schema: 
 
 
 
 
 
 
 
 
 
 
 
 
5.5 
Post-consent Screening Procedures 
If subjects fail the G6PD or test doses of ascorbate, they are considered a screen failure. 
• G6PD test (off-site test, so draw immediately). If subject has a prior G6PD test, this can 
be used as G6PD levels do not fluctuate (i.e., there is no window for this test). 
• One test dose of 15g of ascorbate.  A physician must review the patient's medication list 
against the list of medications prohibited on this trial prior to the test dose of ascorbate. 
5.6 
Concomitant Ascorbate (High-dose Ascorbic Acid) Infusions 
5.6.1 Participant dose. All patients will receive a standard ascorbate dose of 75 gm given over 
120 minutes 
5.6.2 Administration. Based on subject tolerance; infusion rate should not exceed 500 mL/hour 
without consulting with physician. Recommended infusions times are as follows (Table 1) 
but may be adjusted for subject comfort. Changes in infusion rates should be recorded. 
5.6.3 Initiation. Start the week prior to chemoradiation with one 15-g infusion. This is the test 
dose. 75 gm dosing begins week 1 of radiation therapy. If the participant fails the 15g test 
dose it is not considered dose limiting toxicity. 
5.6.4 Schedule. Scheduled three times weekly during chemoradiation;.  
5.6.5 Duration. Subjects will continue with therapy until the end of standard radiation therapy 
or if any criteria of removal are met (Section 5.7) 
5.6.6 Dose modifications. Provided in Section 6.2 
Table 1. Recommended Infusion Times for Pharmacological Ascorbate †   
Ascorbate dose  
(500 mg / mL) 
Total volume* 
Osmolarity 
(mOsm/L)§ 
Infusion Time 
 
15g (30 mL) 
 
250 mL 
 
681 
 
30 minutes 
 
75g (150 mL) 
 
1000 mL 
 
851.7 
 
120 minutes 
 
62.5 g (125 mL) 
 
1000 mL 
 
709 
 
120 mins 
† Provided by Drug Information Center at the University of Iowa, July 2011 
*  Sterile water for injection only. Do not use D5W 
§  Theoretical calculations provided by Drug Information Center; targeted osmolarity range is 500 – 900 mOsm/L 
 
Phase II 
IV Ascorbate at 
recommended dose three 
times weekly 
+ 
Radiotherapy starting 
from week 1 
+ 
Surgery 4-6 weeks after 
XRT 
END OF TREATMENT
SURVIVAL F-UP
END OF STUDY
SCREENING
ENROLEMENT 


Version 8 17Novemberl2021 
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5.7 
Radiation therapy  
External beam radiation therapy will be given at the standard dose for resectable soft tissue 
sarcomas according to the NCCN sarcoma guidelines.2 Patients with extremity and trunk STS will 
receive 50 Gy over 25 fractions  and those with retroperitoneal STS will receive 45 to 50.4 Gy in 
28 fractions, during which time they will be receiving three times weekly IV ascorbate until the 
end of radiation therapy. Surgery will be performed 4-6 weeks from the end of radiation to allow 
for adequate tissue healing and resolution of acute toxicities. 
Radiation therapy for this protocol is as per currently used standard pre-operative radiation therapy at 
the University of Iowa even for non-protocol patients. Selected guidelines from previously conducted 
Radiation Therapy Oncology Groups (RTOG) studies are briefly summarized for this protocol. 
5.7.1 Preoperative Radiation therapy (3D-CRT or IMRT). Either 3D conformal 
radiotherapy or intensity modulated radiation therapy may be utilized for adequate tumor 
coverage and to meet the dose constraints for critical normal structures. 
5.7.2 Radiation treatment planning scans and immobilization. CT scans with patient in a 
stable and comfortable position will be used for planning. MRI scans are optional and may 
be used for co-registration with CT for tumor localization as needed. VacLoc or other 
immobilization devices can be used for immobilization. 
5.7.3 Target volumes and treatment field (Extremity Sarcoma): 
Gross Target Volume (GTV): Outline of the tumor as seen on CT or CT/MRI fusion.  
Clinical Target Volume (CTV): CTV = GTV plus 4 cm margins in the proximal and distal 
directions. However, the margin can be reduced if it extends beyond the compartment, the 
field can be shortened to include the end of a compartment. The radial margin from the 
lesion should be 1 cm. It can be reduced in areas confined by the fascial barrier or bone or 
skin surface as per standard of care and treating radiation oncologist’s discretion. 
Planning Target Volume (PTV): Include CTV and error of setup and organ motion. 
Typically PTV includes CTV plus 0.5 - 1 cm in all dimensions. Final PTV is usually GTV 
+ 5 cm longitudinal and 2 cm radial, except where restricted by the compartment end, 
fascia, bone or skin surface as per standard of care and treating radiation oncologist’s 
discretion. 
Use of bolus on the skin surfaces is optional as needed. Where applicable biopsy scars 
should be bolused with appropriate thickness specific to the energy of the photon beam. 
5.7.4 Target volumes and treatment field (Retroperitoneal/Trunk Sarcoma): 
Gross Target Volume (GTV): Outline of the tumor as seen on CT or CT/MRI fusion. 
Clinical Target Volume (CTV): 4D-CT imaging should be performed for tumors above 
the iliac brim to assess for possible tumor motion associated with respiration.  The CTV is 
generated by expanding the different respiratory phases GTV (ITV) by 1.5 cm 
symmetrically.  The margin can be reduced if it extends beyond the retroperitoneal 
compartment into bone, kidney, or liver.  If tumor extends through inguinal canal, an 
additional 3cm can be added distally as per standard of care and treating radiation 
oncologist’s discretion. 
 
 


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Planning Target Volume (PTV): Include CTV and error of setup and organ motion. PTV 
expansions are typically CTV plus 0.5 - 1 cm in all dimensions.  Final PTV is typically 
ITV + 2 cm symmetrically as confined to the retroperitoneal compartment as per standard 
of care and treating radiation oncologist’s discretion.   
5.7.5 Dose Specifications: 
A dose of 50 Gy in 25 daily fractions for extremity STS and 45 to 50.4 Gy in 28 fractions 
for retroperitoneal STS will be prescribed to the planning target volume (PTV) using linear 
accelerator and megavoltage photon beams with energies of 6MV or greater.  
For retroperitoneal/intra-abdominal sarcomas, a dose-painted simultaneous integrated 
boost (SIB) to total dose of 57.5 Gy in 25 fractions is allowed in select cases. A 
postoperative EBRT boost is discouraged. 
Prescribed dose should cover > 90% of the PTV. More than 95% of the PTV should receive 
> 95% of the prescribed dose. No more than 20% of the PTV will receive ≥ 110% 
prescription dose. 
5.7.6 Precautions and Dose Constraints for critical structures: 
Radiation dose to normal tissues should be kept within the accepted normal tissue 
tolerances. Every effort should be made to: 
a) Avoid treating the full circumference of an extremity;  
b) Avoid treating anus, urogenital tract, perineum and genitalia; if the tumor is close to 
these structures, typically less than 50% volume of the anus and vulva should receive 
30 Gy; less than 50% volume of the testis should receive 3 Gy, if the patient prefers to 
reserve fertility;  
c) Avoid treating the lung, through use of appropriate shielding and treatment planning; 
less than 20% of the lungs should receive 20 Gy (V20); 
d) Avoid dose maximums in areas where surgical scars will be placed; this may require 
reviewing treatment plans with the surgeon; 
e) If possible, avoid treating skin over areas commonly traumatized to full dose (e.g., the 
elbow, knee, shin, femoral neck). 
f) If possible, less than 50% of any joints (including shoulder, elbow and knee) should 
receive 50 Gy.  
g) Less than 50% of kidney volumes should receive 18 Gy.  
h) No more than 50% of normal weight-bearing bone within the radiation field should 
receive 50 Gy except when the tumor invades the bone or when there is circumferential 
involvement of the tumor more than a quarter of the bone or when the bone will be 
resected in a subsequent surgical resection after radiation. 
For any other normal tissue structures, no radiation dose more than the established TD5/5 
limit should be given.  
5.7.7 Image Guidance and Verification Devices 
Portal films or conebeam CT images should be used for target localization and alignment. 
Daily cone beam CT will be preferred and dose from daily cone beam should be included 


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in the final dosimetry. 
 
 


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21 
5.7.8 Simultaneous Integrated Boost 
A simultaneous integrated boost to a total dose of 57.5 Gy in 25 fractions is allowed for 
patients in whom the surgeon feels a margin negative resection will be difficult to 
achieve. The boost volume is defined as the high-risk retroperitoneal margin jointly 
identified by the surgeon and treating radiation oncologist. In this scenario, no further 
postoperative boost is allowed. 
 
5.7.9 Postoperative Radiotherapy Boost  
An External Beam or Brachytherapy boost can be given at the discretion of the radiation 
oncologist. If deemed necessary, the boost volume would include the positive tumor 
margin (residual tumor) plus a margin of 1 cm. Boost treatment should be delivered within 
2 weeks following surgery or after adequate wound healing has occurred. 
The target volume for postoperative radiotherapy will be the residual tumor bed as defined 
by the surgical and pathological findings.  
5.7.10 External Beam Radiotherapy 
Postoperative external beam boost dose is 16 Gy in 8 fractions (once a day) for microscopic 
disease and 20 Gy in 10 fractions for gross residual disease providing normal tissue is 
spared (likely requires a biologic or synthetic tissue spacer).  
5.7.11 Anticipated Radiation Therapy Adverse Events  
Acute: Wound complications of any grade are expected to develop in about one third of 
patients. Other common radiation adverse events include: fatigue, regional alopecia, 
diarrhea, skin erythema and desquamation within the treatment fields, and reduction in 
blood counts. 
Long-term: Common long-term treatment adverse events include: lymphedema of the 
extremity receiving radiation and surgery, subcutaneous fibrosis, and joint stiffness. Much 
less common radiation adverse events include bowel injury, osteoradionecrosis, and bony 
fracture in the radiation field. There also is a risk of secondary malignancy occurring in the 
irradiated field.  
5.8 
General Concomitant Medication and Supportive Care Guidelines 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, etc., when appropriate. The reason(s) for treatment, dosage, and the dates of treatment 
should be recorded.  
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care. All prescription and nonprescription 
concomitant medication administered up to 28 days prior to enrollment, on an ongoing basis at 
enrollment, as well as changes in such concomitant medication, and any new concomitant 
medication taken while the subject is on study, should be recorded up to 30 days after the last dose 
of ascorbate. 
5.8.1 Antiemetics. Use Zofran (ondansetron) with caution as this medication may be less 
effective when used with ascorbate. Prefer alternative agents such as prochlorperazine 
5.8.2 Fluid intake. Subjects will be encouraged to maintain adequate hydration to decrease the 
risk of nephrolithiasis. Those unable to maintain oral hydration should be considered for 


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supplemental IV hydration per institutional care guidelines.  
5.8.3 For diabetics, be aware high-dose ascorbate can provide false results for finger-stick 
glucose readings. This effect is dose dependent but can last up to 6h post-infusion. 
Serum/plasma tests are not affected.39 
 
 


Version 8 17Novemberl2021 
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5.9 
Criteria for removal from study  
Treatment with pharmacological ascorbate may be discontinued if any one of the following criteria 
is met: 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• Progressive disease as determined by the investigator 
• A female subject becomes pregnant or fails to use 2 highly effective methods of 
contraception (for those subjects who are able to conceive).  
• A female subject breast feeds while on study treatment. 
• A male subject fails to use a highly effective method of contraception  
5.10 
Duration of Follow Up 
Post-operatively subjects should be followed either by clinic visit or phone contact every 12 ± 4 
weeks for approximately 2 years from the end of enrollment, to assess for survival, and disease 
recurrence. Surveillance imaging and clinical assessment to assess for disease recurrence will be 
as per NCCN guidelines. 
6. DOSING DELAYS/DOSE MODIFICATIONS/ DOSE LIMITING TOXICITIES 
6.1 
Radiation Therapy 
6.1.1 Dose modification - Radiation therapy dose will not be modified. 
6.1.2 Treatment delay - Will only occur for reasons of safety due to intercurrent illness or 
medical conditions that in the judgment of the radiation oncologist forbid delivery of 
radiation therapy. 
6.1.3 Interruptions or delays of greater than three days should be discussed with the study’s 
principal investigator and documented 
6.2 
Ascorbate Therapy  
6.2.1 Dose reductions – As per Table 1 (below) if there is a DLT (Section 5.6) 
Table 1.  
Phase 1b Dose De-escalation Schedule 
Number of Patients with DLT  
at a Given Ascorbate Dose 
Decision Rule 
> 2 
Dose level will be declared toxic. 
If this is the lowest dose level, stop the study due to 
excessive toxicity; otherwise enter three additional 
patients at the next lowest dose level. 
< 1 out of 3 
Enter three more patients at this dose level. 
< 1 out of 6 
This is the recommended dose for the subsequent Phase2. 


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Ascorbate Dose Levels 
Dose 0 
Ascorbate 75 gm IV three times weekly concurrently with radiation   
Dose -1 
Ascorbate 62.5 gm IV three times weekly concurrently with radiation 
 
• Initial dose for all = Ascorbate 75gm IV  
6.2.2 Test/retest. If an unexpected adverse event is observed, the treating physicians may 
withhold ascorbic acid for up to 2 calendar weeks to determine if the effect diminishes or 
resolves entirely. Considering the nature and severity of the event, if reasonable ascorbic 
acid should then be continued to determine if the event again presents. This will function 
as a test for causality.  
6.2.3 Dose delays. Due to holidays or inclement weather, doses may be delayed by up to one 
week with physician and PI approval. Reason for treatment delay should be noted in the 
study chart.  
6.3 
Dose Limiting Toxicities 
Definitions of dose-limiting toxicity: 
Toxicity will be evaluated according to CTCAE version 5.0. DLT will be defined as any of the 
following ascorbate related toxicity or related to the combination of pharmacologic ascorbate and 
radiation therapy during treatment and up to 28 days after the first pharmacologic ascorbate 
infusion:  
• Infection grade 4 
• SAE per 21CFR312.21 with an attribution of possible, probable, or definite to ascorbate 
• Grade 3 diarrhea or nausea/vomiting despite maximal support 
• Any grade 3/4 or greater hematologic or non-hematologic toxicity not explainable by 
another cause in the opinion of the principal investigator, with the exceptions of:  
o Expected radiation related skin toxicity of any grade. 
o Brief (< 1 week) grade 3 fatigue. 
If unexpected DLT occurs, ascorbate administration should be delayed until the DLT has resolved 
to at least CTCAE version 5.0 grade 1 or baseline and future dose be reduced to dose level -1 as 
per table 1. If dosing is delayed by more than 4 weeks due to the occurrence of unexpected adverse 
event or if a patient already dose reduced to level -1 (62.5 gm/dose) experiences another DLT that 
is considered related to ascorbate, then the subject should be taken off study. 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
This study will also be monitored by internal oversight specialists at the University of Iowa. The 
Data and Safety Monitoring Plan of the Holden Comprehensive Cancer Center provides standard 
operating procedures to monitor all clinical cancer trials at the UIHC. All investigator-initiated 
trials are automatically monitored by the Data and Safety Monitoring Committee (DSMC). A 
detailed data and safety monitoring plan for this study is provided (Appendix). This study has been 
assigned as a risk level 4 as it utilizes an investigator sponsored IND.  
 
 


Version 8 17Novemberl2021 
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7.1 
Determination of Reporting Requirements 
The clinical research team is responsible for collecting and recording the research data. As these 
results are collected, all toxicities and adverse events will be identified and reported to the principal 
investigator (PI). The principal investigator (PI) will determine final relationship of the event to 
the investigational product (ascorbate): 
• 
Grade 1 and 2 events do not require attributions assigned. 
• 
Grade 3 and higher adverse events require attribution assigned to ascorbate.  
Toxicity will be graded according to NCI’s Common Toxicity Criteria (CTCAE v5 ). The principal 
investigator will have final responsibility for determining the attribution of toxicity as it is related 
to the investigational product.  
7.2 
Institutional Review Board reporting requirements 
Adverse events that meet criteria of both serious and attributed (possible, probable, or definite) to 
the study agent. Thus: 
• Serious adverse events only 
• Attributable to ascorbate (i.e., drug related) 
• Report to the IRB via HawkIRB within 10 business days of event 
7.3 
FDA reporting requirements [M.Milhem, sponsor] 
Adverse events meeting the criteria of serious, unexpected, and attributed (possible, probable, or 
definite) to ascorbate must be reported by the sponsor or the sponsor’s appointed designee to the 
FDA: 
• Serious adverse events only [21 CFR 312.32] 
• Attributable to ascorbate with a causal relationship (possible, probable, or definite)  
• Unexpected, as defined by the FDA: “…not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed; or, if an investigator 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, as amended.” 
To help the sponsor meet these reporting requirements, all serious adverse events that are 
unexpected and attributed to study drug must be reported to the sponsor within 1 business day. 
This coincides with SAE reporting requirements for the DSMC. 
7.4 
Routine Adverse Event Reporting Requirements to DSMC 
An adverse event (AE) is defined in the CTEP, NCI Guidelines [2005] as “any unfavorable and 
unintended sign (including a clinically significant abnormal laboratory finding), symptom or 
disease temporally associated with the use of a medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probably or definite).” 
Routine adverse events are captured in OnCore, the clinical trials management system, for review 
and assessment by the P.I., sponsor, medical monitor, and DSMC.  
 
 


Version 8 17Novemberl2021 
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7.5 
Serious Adverse Event Reporting to DSMC 
For any experience or condition meeting the definition of a serious adverse event (SAE; 
21CFR312.32), from the first day of study treatment and typically continue through the 30 day 
follow-up period after treatment is discontinued.  
Investigators must report to the DSMC any SAE, regardless of attribution to study drug. SAEs 
must be reported via an OnCore SAE Report within 1 business day of learning of the event.  
An adverse event is considered serious if it results in ANY of the following outcomes:   
• 
Death 
• 
A life-threatening adverse event  
• 
An adverse event that results in inpatient hospitalization OR prolongation of 
existing hospitalization for ≥ 24 hours  
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. (21 
CFR 312.32; ICH E2A and ICH E6). 
8. PHARMACEUTICAL INFORMATION – ASCORBIC ACID INJECTION, ASCOR L 
500® 
8.1 
Availability 
IND 137968 allows ascorbate to be obtained through McGuff Pharmaceuticals (Santa Ana, 
CA). Their product Ascor L 500® is now a commercially available injection available in 
sterile single-use 50 mL vials containing 25 g of ascorbic acid (500 mg/mL).  
8.2 
Compatibility 
Ascorbate is considered a CYP4503A4 inhibitor.40 Therefore close monitoring of subjects 
who may be concomitantly receiving CYP3A4 substrates with narrow therapeutic indexes 
for toxicities is required. A table of CYP3A4 substrates, inhibitors, and inducers is 
provided in the Appendix. Ascorbate may decrease plasma/blood concentrations of 
substrates (Appendix B, tables 1, 2, and 3). Ascorbate may increase CYP3A4 induction 
(Appendix B, Table 4).  
8.3 
Storage and Stability 
Unopened vials of are stable until the expiration date indicated on the package when stored 
between 2° – 8°C (36°–46°F). Protect from light and store in the carton until time of use. 


Version 8 17Novemberl2021 
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8.4 
Toxicities 
9. DIARRHEA, NAUSEA AND/OR VOMITING, KIDNEY STONES, DRY 
MOUTH/THIRST, HEADACHE, ABDOMINAL PAIN, FATIGUE, FACIAL 
FLUSHING, SWEATING, WEAKNESS, INJECTION SITE IRRITATION, AND 
FAINT/DIZZY (AFTER RAPID INFUSION), AND HYPERTENSION THAT MAY 
REQUIRE MEDICATION HAVE BEEN REPORTED. CORRELATIVE AND 
SPECIAL STUDIES  
9.1 
ROS Research blood 
Research blood for future use will be drawn at: 
• Baseline prior to test dose of ascorbate  
• Prior to XRT dose 1  
• Week 3 of radiation therapy prior to XRT dose  
• After last fraction of radiation therapy (≤60 minutes of completing that fraction) 
• End of study visit which will be ~ 1 month of completing ascorbate therapy 
 
The specimen should be placed on ice immediately after the draw and carried to Spitz lab. 
Time point 
Ascorbate level  
(4 cc green top)  
ROS (6cc pink)      Immuno  (6cc  pink)  
Test Dose 
pre 
pre 
pre 
W1D1 
30 min post Ascorbate 
pre XRT dose  
NA 
W3D1 
30 min post Ascorbate 
pre XRT dose  
NA 
W5 
30 min post last 
Ascorbate dose 
≤ 60 min post last  
fraction of XRT  
30 min post last Ascorbate 
dose (or can be drawn with 
ROS after last fraction of 
XRT) 
30 Day post last 
Ascorbate 
NA 
yes 
yes 
 
9.2 
Labile Iron Measurements using MRI Imaging (optional) 
Pharmacological ascorbate’s mechanism of action is hypothesized to involve changes in labile iron 
pools within the tumor. The presence of labile iron and/or iron containing metalloproteins is 
necessary to oxidize ascorbate and eventually lead to the generation of hydrogen peroxide, thereby 
increasing tumor cell oxidative stress. In vitro laboratory studies demonstrate treating GBM and 
non-small cell lung cancer (NSCLC) cells with high doses of ascorbate increases labile iron 
pools.30 Additionally, chelating (e.g., removing) iron from tissue culture media reduces 
pharmacological ascorbate toxicity to tumor cells. 
MRI imaging will be done only for extremity sarcoma subjects prior to ascorbate treatment as a 
pre-scan control (at diagnosis) and will be done at  60 minutes +/- 30 minutes)and 4 hours post 
ascorbate treatment (in radiation oncology suite during week 3) as it has been seen that ascorbate 
levels tend to peak between 1 and 2 hours after injection.30 Imaging studies will be conducted on 


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a GE 1.5T/3T MRI scanner using appropriate anatomical coils.  Images will be acquired using a 
T2* fast gradient-echo, multi-echo pulse sequence with short echo time (~6 ms) and repetition 
time ~25 ms which has shown to be beneficial in previous studies involving iron overload 
measurements in the liver and heart.41,42  Image analysis will initially be done using a region of 
interest approach in which the tumor region will be contoured and then analyzed using a mono-
exponential decay of the T2* relaxation time.  This image analysis has been shown by Positano, 
et. al 42 to be clinically acceptable and more clinically relevant. Serum iron, transferrin saturation, 
total iron binding capacity and ferritin levels will be obtained to evaluate if they correlate with 
responses and T2* imaging findings.     
This series will be done at three time points – baseline (as part of simulation in radiation oncology 
suite or as part of diagnostic MRI if it is being done), week 3 and end of study (as part of diagnosis). 
The imaging in week 3, done in the radiation oncology suite, is centered around that day’s 
ascorbate infusion. Contrast is not allowed for these sequences and will not be ordered. The 
following MRI should be ordered to be completed on the same day: 
9.2.1 Contrast.  No contrast is to be used (oral or IV) 
9.2.2 Scheduling. The infusional T2* is scheduled in week 3. The other time points are at RT 
simulation and end of treatment study (diagnostic) 
9.2.3 Pre-infusion (week 3). A pre-infusion T2* MR series will be obtained. This will contain 
both the T2* and also axial imaging for reference.  
9.2.4 Post-infusion (week 3). 30 to 90 minutes within the end-of-infusion, a second T2* / axial 
series will be obtained. This should be obtained prior to the day’s radiation therapy. 
9.2.5 4h post-infusion (week 3). The last T2* / axial series will be done approximately 4h 
after the end-of-infusion (± 60 minutes). 
9.3 
Diffusion Weighted Imaging (optional) 
Addition of functional diffusion-weighted MRI (DW-MRI) to standard anatomic and postcontrast 
MRI greatly facilitates interpretation of response to therapy43,44. After radiation therapy, new 
enhancement alone can be seen which may be a result of vascular disruption rather than histologic 
response. Hence should be interpreted carefully. Although currently not a standard clinical trial 
endpoint, DW-MRI appears to be a promising as a quick, noninvasive tool showing excellent 
reproducibility for apparent diffusion coefficient measurements, which reflect tumor cellularity 
and microarchitecture in STS. However, the relationship of these MRI parameter changes with 
clinical outcomes has not yet been validated. Hence we intend to evaluate this MRI sequence which 
is currently acquired routinely for imaging brain tumors and stroke. This sequence will be added 
to the planning MRI acquired in radiation oncology prior to starting radiation therapy treatment 
and will be compared to the DWI sequence acquired pre-operatively. 
9.4 
Ascorbate levels 
Serum ascorbate levels will be drawn at screening, 30 mins post at week 1 day 1, as well as 30 
mins  post  week 3 Day 1 and 30 min post  last infusion in week 5. This is being done to ensure a 
target serum level of 20 mM is reached during treatment. 
9.5 
Tumor tissue  
A part of the resected tumor (1 x 1 inch) specimen together with the surrounding normal tissue 
will be testing for immune markers such as CD4, CD8, T regulatory cells. MDSCs and 


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macrophages. Flash frozen tissue will be subjected to T2 * imaging testing to determine labile iron 
concentrations in comparison to the surrounding normal tissue. Molecular testing including next 
generation testing may be performed on the paraffin embedded tissue specimens. Optional pre- 
treatment tumor biopsies will be taken from approximately 5 subjects total and immune markers 
will be compared between pre and post treatment tissue in the immunology lab. 
 
 


Version 8 17Novemberl2021 
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10. STUDY CALENDAR  
10.1 
Study Procedures 
 
Screenb 
Treatmenta 
Off 
treatment 
and end 
of studyc 
Follow 
Upd 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
(+ 1wkj) 
H & P 
X 
X 
 
X 
 
X 
 
 
Tumor biopsy (optional) 
Xb 
 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
X 
X 
Clinical MRI/ Staging CT     
X 
 
 
 
 
 
X 
Xe 
Pregnancy testk (urine) 
X 
 
 
 
 
 
 
 
G6PD 
X 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
CBC w/diff  
X 
 
 
X 
 
X 
 
 
PT/INR, PTT & uric acid 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight, BSA 
X 
 
 
 
 
 
X 
 
Vitals (BP, pulse)m 
X 
X 
x 
X 
x 
X 
X 
 
Comprehensive metabolic panel 
(CMP)  
X 
X 
 
X 
 
X 
X 
 
Ascorbate infusion 
Xi 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
Blood for ascorbate levelsf 
X 
X 
 
X 
 
X 
 
 
ROS Research bloodg   
X 
X 
 
X 
 
X 
X 
 
Immunology research labg 
X 
 
 
 
 
X 
X 
 
Iron Panel including ferritinh 
X 
 
 
 
 
 
X 
 
T2* /QSM and DWI MR imaging 
sequences (optional) 
X 
 
 
X 
 
 
X 
 
Adverse Events &Con Meds 
 
 
X 
X 
X 
X 
X 
 
a 
study day 1 is defined as radiation therapy day 1 (i.e., fraction 1). 
b 
screening labs, history, and physical must be obtained ≤ 28d from d1. G6PD may be obtained at any time prior to 
test dose.  MRI/CT obtained ≤ 28d from d1 (RT sim is acceptable). Pregnancy test per institutional guidelines. 
Optional tumor biopsy can be done anytime before week 1 dosing.  
c 
includes both off-treatment evaluation  and study completion.  Study completion requires a final study dictated 
visit 4 to 6 weeks after the last dose of ascorbate. Follow at least monthly until resolution of all ascorbate related 
adverse events. 
d 
approx every 3 months (every 12 weeks [+/- 4 weeks]) for overall survival through passive chart review, phone 
call or scheduled follow-up visit for 2 years   
e 
Imaging as per standard of care for site specific sarcomas 
f  
4cc green-top Na-Heparin tube. Draw pre-infusion at 15g dose, then 30 min post-infusion: week 1 day 1 , week 
3 and last infusion of week 5 
g 
6cc pink-top EDTA tube. Draw pre infusion The specimen should be placed on ice immediately after draw and 
carried to the lab   
h 
At time of screening and end of study 
i 
Test dose of 15 g intravenously once G6PD levels confirmed to be adequate.  A physician must review the 
patient's medication list against the list of medications prohibited on this trial prior to the test dose of ascorbate.   
j 
In case of radiation treatment delays due to holidays  
k 
±7 days prior to day 1  


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m Blood pressure should be obtained before and after (≤ 15 min EOI) ascorbate infusion   
 
 


Version 8 17Novemberl2021 
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10.2 
Screening Procedures 
Procedures to be completed within 28 days prior to first treatment (day 1) (unless otherwise noted). 
• Informed consent 
• Review of eligibility criteria- 
• Recording of medical history and concomitant medications 
• Physical exam (including weight) 
• ECG 
• Vital signs (blood pressure, temperature, pulse and respirations) 
• Radiographic imaging (chest, abdomen, and pelvis and all other sites of disease)  
• Imaging of primary tumor site 
Laboratory Assessments 
Procedures to be completed within 28 days prior to enrollment 
• CBC w/diff  
• CMP and uric acid 
•  PT/INR, PTT., Urine pregnancy test for females of childbearing potential within 7 days 
of W1D1 
10.3 
Post-treatment Evaluations 
Following surgical resection of primary tumor, patients will be followed as per NCCN guidelines 
for approximately 2 years for survival data and disease recurrence. 
11. MEASUREMENT OF EFFECT 
11.1 
Pathologic Response  
4 to 6 weeks after the end of neoadjuvant therapy, patients will undergo resection of the treated 
tumor. The SOC pretreatment biopsy and all the resected tumor samples will be reviewed by the 
same pathologist.  
The percentage of post treatment tumor necrosis must be documented. The primary end point for 
this study is pathologic complete response (pCR), and is defined as ≥ 95% tumor necrosis 
following concurrent radiation therapy and ascorbate  
Treatment effect on the resected overlying skin tissue will be graded and recorded (to be done by 
the pathologist). This will be compared with historical controls.   
Additional immunohistochemical studies will be performed as determined by the pathologist. 
11.2 
Time to Disease progression (TTP) 
TTP is defined as the time from Enrollment until objective tumor progression including local and 
distant recurrences. 
11.3 
Other Response Parameters 
The following response assessment guidelines may be amended during the course of the study if 
changes are made to the current RECIST Guidelines or if a new disease assessment tool becomes 
available.  


Version 8 17Novemberl2021 
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Response Measurement Criteria:  
Measurements of the tumor in its largest dimension should be obtained at baseline and at the end 
of the treatment phase, prior to surgical resection.  
Response criteria should be by RECIST v 1.1. 
• Complete response is the disappearance of all target lesions. 
• Partial response is a 30% decrease in the sum of the longest dimensions of the target 
lesions, relative to baseline. 
• Progressive disease is an increase of 20% or more in the sum of the longest dimension of 
target lesions 
• Stable disease is a decrease in the tumor size of < 30% or an increase of < 20%. 
• Antitumor response by pathologic assessment will be performed on the resected tumors. 
Pathologic assessment will be performed per institutional guidelines.  
• The percent of tumor necrosis and the percent of tumor-infiltrating lymphocytes will be 
documented. 
• Complete pathological response will be considered ≥ 95% pathologic tumor necrosis. 
Radiologic response will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
 
 


Version 8 17Novemberl2021 
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12. STATISTICAL CONSIDERATIONS 
12.1 
Phase Ib 
The primary objective of the Phase Ib portion of this study is to confirm the current standard dose 
of intravenous ascorbate, 75 gm, utilized in patients diagnosed with pancreatic cancer also 
receiving concurrent chemo radiation is safe within this population of sarcoma patients being 
treated concurrently with pre-operative radiation. Up to six (6) patients will be recruited to the 
standard dose, 75 grams administered intravenously 3 times a week during radiation therapy (5 
weeks). If at most 1 out of 6 patients experience a DLT, the standard dose will be considered safe. 
If 2 or more patients experience a DLT, the next cohort of patients will be assigned to dose level -
1. The recommended phase II dose (RP2D) will be defined as the highest dose level for which at 
most 1 out of 6 patients experience a DLT.   
12.2 
Phase II 
The primary objective of the Phase II portion of this study is to evaluate the proportion of patients 
with pathologic tumor necrosis ≥95%. Previous literature indicates approximately 10% of patients 
will achieve ≥95% tumor necrosis with pre-operative radiation therapy alone. A sample size of 25 
patients achieves 81% power to detect a difference of 20% (from 10% to 30%) using a one-sided 
binomial exact test. The target significance level is 0.05 and the achieved level is 0.03. If 6 or more 
patients achieve ≥95% tumor necrosis, the treatment will be deemed worthy of further 
investigation. For secondary objectives, time to disease progression and overall survival will be 
estimated using the Kaplan-Meier method. Estimated survival probabilities will be plotted and 
medians reported, along with 95% confidence intervals. To identify differences in wound 
complication and Grade 3-4 dermatitis rates relative to historical controls, binomial point estimates 
and 95% exact confidence intervals will be reported. Mixed effects regression models will be used 
to estimate changes in labile iron and diffusion imaging sequences on MRI pre and post treatment.   
12.3 
Sample Size/Accrual Rate 
The Phase I portion of this study is expected to require 6 evaluable patients (min 6, max 12). 
Patients treated in Phase Ib at the RP2D will also be included in the Phase II portion. Additional 
evaluable patients will be accrued for a total of 25 patients treated at the RP2D. The anticipated 
accrual rate is 2 patients per month who would meet inclusion criteria.  
 
 
 


Version 8 17Novemberl2021 
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Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA 
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12. Cameron E, Campbell, A: The orthomolecular treatment of cancer. II Clinical trial of 
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13. Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: 
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of the National Academy of Sciences of the United States of America 75:4538-42, 1978 
 
14. Cameron E, Campbell, A:: Innovation vs. quality control: an ‘unpublishable’ clinical 
trial of supplemental ascorbate in incurable cancer Med Hypotheses 36:185-189, 1991 
 
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‘spontaneous’ regressions, in response to high dose ascorbic acid therapy. A report on 
subsequent progress. Oncology 48:495-497, 1991 
 
16. Murata A, Morishige, F, Yamaguchi, H: Prolongation of survival times of terminal 
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Suppl 23:103-113, 1982 
 
17. Creagan E, Moertel, CG, O’Fallon, JR, Schutt, AJ, O’Connell, MJ, Rubin, J, Frytak, S: 
Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced 
cancer: A controlled trial. N Engl J Med 301:687-690, 1979 
 
18. Moertel C, Flemin, TR, Creagan, ET, Rubin, J, O’Connell, MJ, Ames, MM: : High-
dose vitamin C versus placebo in the treatment of patients with advanced cancer who 
have had no prior chemotherapy. A randomized double-blind comparison. N Engl J 
Med 312:137-141, 1985 
 
19. Levine M, Conry-Cantilena, C, Wang, Y, Welch, RW, Washko, PW, Dhariwal, KR, 
Park, JB, Lazarev, A, Graumlich, JF, King, J, Cantilena, LR. : Vitamin C 
Pharmacokinetics in healthy volunteers: Evidence for a recommended dietary 
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20. Padayatty SJ, Levine, M: Reevaluation of vitamin C in cancer treatment: emerging 
evidence, open minds and serendipity. J. Amer. Coll. Nutr. 19:423-425, 2000 
 
21. Graumlich J, Ludden, TM, Conry-Cantilena, C, Cantilena, Jr LR, Wang, Y, Levine, M: 
Phamacokinetic model fo ascorbic acid in healthy male volunteers during depletion and 
repletion. Pharm Res 14:1133-1139, 1997 
 
22. Riordan N, Riordan, HD, Meng, X, Li, Y, Jackson, JA: Intravenous ascorbate as a 
tumor cytotoxic chemotherapeutic agent. Med Hypotheses 44:207-213, 1995 
 
23. Chen Q, Espey, MG, Krishna, MC, Mitchel,l JB, Corpe, CP, Buettner, GR, Shacter, E, 
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Action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA 
102:13604-13609, 2005 
 
24. Chen Q, Espey, MG, Sun, AY, Lee, JH, Krishna, MC, Shacter, E, Choyke, PL, Pooput, 
C, Kirk, KL, Buettner, GR, Levin, M.: Ascorbic acid in pharmacologic concentrations: 
a pro-drug for selective delivery of ascorbate radical and hydrogen peroxide to 
extracellular fluid in vivo Proc Natl Acad Sci USA 104:8749-8754, 2007 
 
25. Padayatty S, Sun, H, Wang, Y, Riordan, HD, Hewitt, SM, Katz, A, Wesley, RA, 
Levine, M. : Vitamin C pharmacokinetics: implications for oral and intravenous use. 
Annals of Internal Medicine 140:533-537, 2004 
 
26. Chen Q, Sun, AY, Espey, MG, Levine, M: Ascorbic acid as a pro-oxidant therapeutic 
agent in cancer. Free Radical Biology and Medicine 43:S52, 2007 
 
27. Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al: Redox active metals and H2O2 
mediate the increased efficacy of pharmacological ascorbate in combination with 
gemcitabine or radiation in pre-clinical sarcoma models. Redox Biol 14:417-422, 2018 
 
28. Hoffer LJ, Levine M, Assouline S, et al: Phase I clinical trial of i.v. ascorbic acid in 
advanced malignancy. Annals of oncology : official journal of the European Society for 


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Medical Oncology / ESMO 19:1969-74, 2008 
 
29. Welsh JL, Wagner BA, van't Erve TJ, et al: Pharmacological ascorbate with 
gemcitabine for the control of metastatic and node-positive pancreatic cancer 
(PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol 71:765-
75, 2013 
 
30. Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al: O2- and H2O2-Mediated 
Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and 
GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell 31:487-500.e8, 2017 
 
31. Canter RJ, Martinez SR, Tamurian RM, et al: Radiographic and histologic response to 
neoadjuvant radiotherapy in patients with soft tissue sarcoma. Ann Surg Oncol 
17:2578-84, 2010 
 
32. Shah D, Borys D, Martinez SR, et al: Complete pathologic response to neoadjuvant 
radiotherapy is predictive of oncological outcome in patients with soft tissue sarcoma. 
Anticancer Res 32:3911-5, 2012 
 
33. O'Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative 
radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359:2235-
41, 2002 
 
34. Davis AM, O'Sullivan B, Turcotte R, et al: Late radiation morbidity following 
randomization to preoperative versus postoperative radiotherapy in extremity soft tissue 
sarcoma. Radiother Oncol 75:48-53, 2005 
 
35. Cannon CP, Ballo MT, Zagars GK, et al: Complications of combined modality 
treatment of primary lower extremity soft-tissue sarcomas. Cancer 107:2455-61, 2006 
 
36. Cheng EY, Dusenbery KE, Winters MR, et al: Soft tissue sarcomas: preoperative 
versus postoperative radiotherapy. J Surg Oncol 61:90-9, 1996 
 
37. San Miguel I, San Julian M, Cambeiro M, et al: Determinants of toxicity, patterns of 
failure, and outcome among adult patients with soft tissue sarcomas of the extremity 
and superficial trunk treated with greater than conventional doses of perioperative high-
dose-rate brachytherapy and external beam radiotherapy. Int J Radiat Oncol Biol Phys 
81:e529-39, 2011 
 
38. Devisetty K, Kobayashi W, Suit HD, et al: Low-dose neoadjuvant external beam 
radiation therapy for soft tissue sarcoma. Int J Radiat Oncol Biol Phys 80:779-86, 2011 
 
39. Ma Y, Sullivan GG, Schrick E, et al: A convenient method for measuring blood 
ascorbate concentrations in patients receiving high-dose intravenous ascorbate. J Am 
Coll Nutr 32:187-93, 2013 
 
40. van Heeswijk RP, Cooper CL, Foster BC, et al: Effect of high-dose vitamin C on 
hepatic cytochrome P450 3A4 activity. Pharmacotherapy 25:1725-8, 2005 
 
41. Positano V, Pepe A, Santarelli MF, et al: Standardized T2* map of normal human heart 
in vivo to correct T2* segmental artefacts. NMR Biomed 20:578-90, 2007 
 
42. Positano V, Salani B, Pepe A, et al: Improved T2* assessment in liver iron overload by 
magnetic resonance imaging. Magn Reson Imaging 27:188-97, 2009 


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43. Dudeck O, Zeile M, Pink D, et al: Diffusion-weighted magnetic resonance imaging 
allows monitoring of anticancer treatment effects in patients with soft-tissue sarcomas. 
J Magn Reson Imaging 27:1109-13, 2008 
 
44. Messiou C, Bonvalot S, Gronchi A, et al: Evaluation of response after pre-operative 
radiotherapy in soft tissue sarcomas; the European Organisation for Research and 
Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) and 
Imaging Group recommendations for radiological examination and reporting with an 
emphasis on magnetic resonance imaging. Eur J Cancer 56:37-44, 2016 
 
 
 
 


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PROTOCOL APPENDIX A: Performance status criteria 
 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 


Version 8 17Novemberl2021 
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PROTOCOL APPENDIX B: CYP3A4 INTERACTION TABLE 
 
CYP3A4 INTERACTION TABLE  
(Ascorbate may decrease the plasma/blood concentrations of substrates) 
Drugs with strikeout text are antiretroviral drugs that are not allowed for use on this study. 
* 3A4 substrate & inhibitor; # 3A4 substrate & inducer 
abiraterone 
acetaminophen 
ado-trastuzumab  
alfentanil 
alfuzosin 
aliskiren 
alitretinoin 
almotriptan 
alprazolam 
ambrisentan 
amiodarone* 
amitriptyline 
amlodipine 
amprenavir 
apixaban 
aprepitant* 
aripiprazole 
armodafinil# 
artemether 
asenapine 
astemizole 
atazanavir* 
atorvastatin 
avanafil 
axitinib 
beclomethasone 
bedaquiline 
benzphetamine 
bexarotene  
bisoprolol 
boceprevir 
bortezomib 
bosentan# 
bosutinib 
brentuximab 
bromazepam 
bromocriptine 
budesonide 
buprenorphine 
buspirone 
busulfan 
cabazitaxel 
cabozantinib 
caffeine 
canagliflozin 
carbamazepine# 
cevimeline 
chlordiazepoxide 
chloroquine 
chlorpheniramine 
ciclesonide  
cilostazol 
cinacalcet 
cisapride  
citalopram 
clarithromycin* 
clindamycin 
clobazam 
clomipramine 
clonazepam 
clopidogrel 
clorazepate 
clozapine 
cobicistat* 
cocaine 
codeine 
colchicine 
conivaptan* 
crizotinib 
cyclobenzaprine 
cyclophosphamide 
cyclosporine* 
dantrolene 
dapsone 
darifenacin 
darunavir 
dasatinib 
delavirdine* 
desogestrel  
dantrolene 
dexamethasone# 
dexlansoprazole 
dextromethorphan 
diazepam 
diclofenac 
dienogest 
dihydroergotamine 
diltiazem* 
disopyramide 
docetaxel 
dofetilide 
dolasetron 
domperidone 
donepezil 
doxorubicin 
dronedarone 
droperidol 
dutasteride 
efavirenz*# 
eletriptan 
elvitegravir 
enzalutamide 
eplerenone 
ergoloids 
ergonovine 
ergotamine 
erlotinib 
erythromycin* 
escitalopram 
esomeprazole 
estazolam 
estradiol 
estradiol valerate 
estrogens 
eszopiclone 
ethinyl estradiol 
ethosuximide 
etonogestrel 
etoposide 
etravirine 
everolimus 
exemestane 
felbamate 
felodipine 
fentanyl 
fesoterodine 
fexofenadine 
finasteride 
fingolimod 
flunisolide 
flurazepam 
flutamide 
fluticasone 
fosamprenavir* 
fosaprepitant 
fulvestrant 
galantamine 
gefitinib 
granisetron 
guanfacine 
haloperidol* 
hydrocodone 
hydrocortisone 
ifosfamide 
iloperidone 
imatinib* 
imipramine 
indacaterol 
indinavir* 
irinotecan 
isosorbide dinitrate 
isosorbide 
mononitrate 


Version 8 17Novemberl2021 
41 
CYP3A4 INTERACTION TABLE  
(Ascorbate may decrease the plasma/blood concentrations of substrates) 
Drugs with strikeout text are antiretroviral drugs that are not allowed for use on this study. 
* 3A4 substrate & inhibitor; # 3A4 substrate & inducer 
isradipine 
itraconazole* 
ivacaftor 
ixabepilone 
ketamine 
ketoconazole* 
lansoprazole  
lapatinib 
lercanidipine 
letrozole 
levonorgestrel 
lidocaine* 
linagliptin 
lomitapide 
loperamide  
lopinavir 
loratadine 
losartan 
lovastatin 
lumefantrine 
lurasidone 
maraviroc 
marijuana 
medroxyprogesterone 
mefloquine 
meloxicam 
mestranol 
methadone 
methylergonovine 
methylprednisolone 
miconazole* 
midazolam 
mifepristone 
mirabegron 
mirtazapine 
modafinil 
mometasone 
montelukast 
nateglinide 
nefazodone* 
nelfinavir* 
nevirapine# 
nicardipine* 
nifedipine 
nilotinib 
nimodipine 
nisoldipine 
nitrendipine 
norethindrone 
norgestrel 
nortriptyline 
omeprazole 
ondansetron 
ospemifene 
oxybutynin 
oxycodone 
paclitaxel 
paliperidone 
palonosetron 
pantoprazole 
paricalcitol 
paroxetine 
pazopanib 
perampanel 
perphenazine 
pimozide 
pioglitazone 
pomalidomide 
ponatinib 
prasugrel 
prednisolone 
prednisone  
primaquine 
progesterone/ 
progestins 
propafenone 
propranolol 
quazepam 
quetiapine 
quinidine*  
quinine 
rabeprazole 
ramelteon 
ranolazine 
regorafenib 
repaglinide 
rifabutin# 
rilpivirine 
risperidone 
ritonavir* 
rivaroxaban 
roflumilast 
romidepsin 
ruxolitinib 
salmeterol 
saquinavir* 
saxagliptin 
selegiline 
sertraline 
sibutramine 
sildenafil 
silodosin 
simvastatin 
sirolimus 
sitagliptin 
solifenacin 
sorafenib 
sufentanil 
sunitinib 
tacrolimus 
tadalafil 
tamoxifen 
tamsulosin 
telaprevir 
telithromycin* 
temsirolimus 
teniposide 
terfenadine 
testosterone  
tetracycline* 
theophylline 
tiagabine 
ticagrelor 
ticlopidine 
tinidazole 
tipranavir 
tofacitinib 
tolterodine 
tolvaptan 
topotecan 
toremifene 
tramadol 
trazodone 
triazolam 
trimethoprim 
trimetrexate 
trimipramine 
ulipristal 
vandetanib 
vardenafil 
vemurafenib  
venlafaxine 
verapamil* 
vilazodone 
vinblastine 
vincristine 
vinorelbine 
vismodegib 
voriconazole 
warfarin 
zaleplon 
zileuton 
ziprasidone 
zolpidem 
zonisamide 
zopiclone 
 
 


Version 8 17Novemberl2021 
42 
 
References:  
1. Lexi-comp On-line. Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. (accessed 
1/16/15) 
2. Pharmacist’s Letter/Prescriber’s Letter. Cytochrome P450 Drug Interactions. October 2013. 
3. P450 Drug Interaction Table. Indiana University Department of Medicine Division of Clinical 
Pharmacology.  http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
4. Hansten and Horn’s Drug Interactions Analysis and Management. Facts and Comparisons. 2014 
 
 
UIHC Drug Information Center: 1/15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 8 17Novemberl2021 
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APPENDIX D: DATA AND SAFETY MONITORING PLAN 
Type of Clinical Trial: 
 Investigator-initiated (UI/HCCC) 
 Investigator-initiated, participating site 
 Pilot study 
 Phase I 
 Phase I/II 
 Phase II 
 Phase III 
 Compassionate-use/Expanded Access  
 Interventional Treatment 
 Interventional Non-Treatment 
 Non-Interventional 
 
Study risk-level:  
 Level 1—low risk of morbidity or death, * <1% of death or any adverse event  
 Level 2—risk of death* <1% or any adverse event 1% – 5%  
 Level 3—risk of death* 1% – 5% or grade 4 – 5 SAE 1% – 5%  
 Level 4—risk of death* >5% or grade 4 – 5 SAE >5%  
 Drugs being used on a “compassionate” basis  
* Risk of death” refers specifically to 100-day treatment-related mortality 
___________________________ 
Reporting and Monitoring Requirements:  
All institutional investigator initiated trials (IITs), regardless of assigned risk level are subject to 
routine DSMC monitoring activities which may include but are not limited to review of signed 
consent documents, eligibility and adverse event reporting.  
All institutional IITs have the following reporting requirements as part of their DSMP: 
• Register all subjects in HCCC’s Clinical Trial Management System, OnCore 
• Document Adverse Events  
• Document protocol deviations  
• Provide an annual progress report to the DSMC via OnCore data export 
Selected monitoring strategy based on risk-level: 
Risk Level 4 
Interventional treatment trials involving investigational agents or devices with a risk of death* 
(>5% or grade 4 – 5 SAE >5%), e.g. all investigator initiated INDs, most Phase I/II trials, gene 
therapy, gene manipulation or viral vector systems high-risk clinical procedures if performed 
solely for research purposes.  The use of a new chemical or drug for which there is limited or no 
available safety data in humans. 
 
 


Version 8 17Novemberl2021 
44 
Study Safety Review 
An independent study monitor and/or the DSMC Chair (or designee), will review study data 
(provided by the PI/available in OnCore) and communicate with the PI at least biannually.  A copy 
of this communication will be forwarded to the DSMC and PRMC Chairs.   
Additional Reporting Requirements:  
- A scanned copy of the completed eligibility checklist, with screening information and PI 
signature, will be attached in OnCore for ongoing review by DSMC staff.  
- Serious adverse events will be entered directly into an OnCore SAE report by the research 
team.  OnCore will send an automatic notification to the DSMC Chair/acting Chair and staff 
for review.  
- The DSMC utilizes a risk-based monitoring approach.  The trial's research records will be 
monitored at minimum twice per year.  Monitoring may be done more frequently depending 
on the protocol, risks to subjects, reported serious/adverse events, patient population and 
accrual rate.   Records for a minimum of 25% of subjects will be monitored for the entire 
study.    
Monitoring will involve the following: 
• review eligibility of patients accrued to the study, 
• check for the presence of a signed informed consent, 
• determine compliance with protocol’s study plan, 
• determine whether SAEs are being appropriately reported to internal and external 
regulatory agencies,  
• compare accuracy of data in the research record with the primary source documents, 
• review investigational drug processing and documentation, 
• assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
Routine Adverse Event Reporting 
For non-serious Adverse Events, documentation must begin from the time the subject signs the 
informed consent document and continue through the 30-day follow-up period after the last dose 
of study drug. 
Collected information should be recorded in the electronic/Case Report Forms (eCRF/CRF) for 
that subject. A description of the event, its severity or toxicity grade (according to NCI’s Common 
Toxicity Criteria (CTCAE)), onset and resolved dates (if applicable), and the relationship to the 
study drug should be included. Documentation should occur in real time. The principal investigator 
has final responsibility for determining the attribution of the event as it is related to the study drug. 
Serious Adverse Event Reporting 
For any experience or condition that meets the definition of a serious adverse event (SAE), 
recording of the event must begin after signing of the informed consent and continue through the 
30 day follow-up period after treatment is discontinued.  
Investigators must report to the DSMC any serious adverse events (SAE), whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64). SAEs must be 
reported via an OnCore SAE Report within 24 hours of learning of the event.  
 


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45 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization OR prolongation of existing 
hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
 
Study Stopping and Pausing Rules 
The study will pause enrollment and stop treatment for all participants if any of the 
following events occur pending submission to Regulatory Agencies and review by the  
DSMC and IRB who will determine if the study may resume: 
• 
Any event of treatment related death in a study subject 
 
FDA Reporting Requirements (for Sponsor-Investigators)  
It is the responsibility of the IND sponsor-investigator to comply with IND safety reporting as set 
forth in the Code of Federal Regulations, Section 312.32. This responsibility includes providing 
an annual IND report to the FDA.  
All IND safety reports must be submitted on Form 3500A  and be accompanied by Form 1571. 
The type of report (initial or follow-up) should be checked in the respective boxes on Forms 3500A 
and 1571. See Instructions for completing Form 3500A.  Please note all instance of UIHC, 
location, and faculty / staff should be redacted from supporting documentation and the 3500A. 
The submission must be identified as: 
• “IND safety report” for 15-day reports, or 
• “7-day IND safety report” for unexpected fatal or life-threatening suspected adverse 
reaction reports, or 
• “Follow-up IND safety report” for follow-up information. 
For detailed explanation of the above definitions, requirements, and procedures related to IND 
application safety reports and the responsibilities of IND applications sponsors with regard to such 
reporting, refer to Guidance for Industry and Investigators: Safety Reporting Requirements for 
INDs and BA/BE Studies (PDF - 227KB) 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
• Treatment regimen (dosing frequency, combination therapy) 


Version 8 17Novemberl2021 
46 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known (grading the event per 
CTCAE) 
• Supportive laboratory results and diagnostics 
• Sponsor-Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Data Monitoring and Management  
Subject Registration 
All studies that undergo PRMC review and/or utilize HCCC Clinical Research Services (CRS) 
resources are required to register subjects in OnCore. Each subject registration includes the 
following: 
• The subject’s IRB approved (version date) consent form and the date of their consent.  
• Date of eligibility and eligibility status (eligible, not eligible) 
• On study date and subject’s disease site (and histology if applicable) 
• On treatment date (if applicable)  
All subject registration information is expected to be entered into OnCore within 2 (two) business 
days after the subject’s study visit.  
Subject Data 
For HCCC investigator initiated trials, research staff are responsible for entering subject study data 
(data collection) into OnCore electronic case report forms (eCRFs). These eCRFs must be 
approved by the PI and statistician prior to study activation to ensure sufficient and necessary data 
acquisition. All information entered into eCRFs will be traceable to the source documents which 
are generally maintained in the subject’s file.  
eCRF data entry needs to be timely and should be entered into OnCore as soon as possible but no 
later than 14 (fourteen) business days after the subject’s visit, including adverse events, tumor 
measurements, administration of study medication, concomitant medications, labs, and vitals. 
Physical exam assessments must be entered no later than 14 (fourteen) business days following 
completion of the physician’s clinic note in the medical record.  
Timely data entry facilitates remote monitoring of data, allows the data to progress appropriately 
through the data cleaning process, and helps prevent a backlog of data queries. 
Forms Monitoring 
OnCore eCRF data are monitored on a routine basis (dependent on accrual) to ensure all data are 
entered completely, accurately, and within time requirements outlined above. The assigned DSMC 
monitor will coordinate and complete the data monitoring review. When the time comes to monitor 
a study (based on patient accrual and assigned risk level of trial) the monitor arranges for a 
selection of cases to be reviewed from among the subjects registered in OnCore.  As part of the 
forms monitoring process, the assigned monitor will issue queries via OnCore (linked to the eCRF) 
to resolve missing, incomplete, and/or incorrect information. A member of the research team is 
expected to respond to these monitoring queries within 14 (fourteen) business days.  
The monitoring process can often identify misunderstandings or deficiencies in the written, 
research protocol requirements earlier in the study process and thereby improve data quality and 


Version 8 17Novemberl2021 
47 
reduce rework.  
Final Reports 
A summary of each subject’s data record is continually available to the PI, research staff, and 
DSMC from OnCore’s Biostat Console. The availability of this information is a valuable tool for 
the preparation of final reports and manuscripts as well as ongoing deficiency reports. 

ICF_001.pdf: 
FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 1 of 11 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
Phase 1b/2 Neoadjuvant High Dose Ascorbate with Concurrent Preoperative 
Radiation in Patients with Locally advanced Soft Tissue Sarcomas of Extremity, Trunk and 
Retroperitoneum 
 
Principal Investigator: 
Varun Monga, MBBS 
 
Research Team Contact: 
Teena Davis-Vandaele, RN   319-467-5834 
 
Other Research Team Members: Mohammed Milhem, MBBS; Deborah Parr, PA-C; Michele 
Freesmeier, PA-C 
This consent form describes the research study to help you decide if you want to participate.  This form 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights as a research subject.   
• If you have any questions about or do not understand something in this form, you should ask the 
research team for more information.   
• You should discuss your participation with anyone you choose such as family or friends.   
• Do not agree to participate in this study unless the research team has answered your questions and you 
decide that you want to be part of this study.  
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study.  We are inviting you to participate in this research study because you have 
sarcoma in one of your extremities, your trunk or in the retroperitoneum that can’t be removed by 
surgery and you are a candidate for preoperative radiation therapy. 
The purpose of this research study is to see if high dose ascorbate (Vitamin C) in combination with 
radiation therapy will reduce the size of your tumor.  We hope that high doses of ascorbate together with 
radiation therapy will work better in killing the cancer cells, than either treatment alone. 
High dose ascorbate is not approved by the U.S. Food and Drug Administration for any cancer.  It is 
considered investigational for patients with locally advanced soft tissue sarcoma of the extremity, trunk 
and retroperitoneum, which means that it has not been approved by the U.S. Food and Drug 
Administration. The combination of high-dose ascorbate and radiation therapy has been shown to be 
safe and well tolerated in patients with glioblastoma multiforme, but has not been studied in patients 
with sarcoma. 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 35 people will take part in this study conducted by investigators at the University of 
Iowa.   


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 2 of 11 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last for approximately 5 years.  You will 
receive treatment with ascorbate three times a week for 5 weeks.  You’ll also receive radiation therapy 
during the same 5 weeks.  Each visit will last from 2 - 4 hours.  After your treatment has finished, you 
will have follow up visits according to recommended standard of care, for about 5 years. 
WHAT WILL HAPPEN DURING THIS STUDY? 
COVID-19 Pandemic Adjustments 
Due to the coronavirus pandemic (COVID-19), your doctors or study nurses may choose to skip some 
research-only tests. These tests are not for safety and do not impact your well-being. These are: 
• 
Ascorbate levels 
• 
Research blood sampling for biomarkers (how the ascorbate affects your body) 
• 
Research-MR imaging (T2*) 
You can also decline to have these tests done if you would prefer to reduce your time at UIHC.  
Normally, you would have your MRIs and blood tests performed at UIHC for this study. However, due 
to the pandemic, your doctor may want to you to have these tests done elsewhere. If so, the tests results 
will be sent to UIHC and reviewed by your cancer doctors. They will also be added to your UIHC 
medical record. 
Before you begin the study treatment 
You will need to have some tests done to find out if you can continue to be in the study. Some of these 
tests are part of regular cancer care and may be done even if you do not join the study treatment. If you 
have had some of them recently, they may not need to be repeated. This is up to your doctor. 
• 
Medical history 
• 
Physical examination including vital signs. 
• 
Electrocardiogram (ECG) to check the function of your heart. 
• 
Blood will be taken to determine blood counts, kidney function, liver function, electrolyte levels, 
and levels of an enzyme in your blood called G6PD. The result of the G6PD test will be added to 
your medical record. 
• 
Pregnancy test (if you are a woman of child-bearing potential). The results of this test will also be 
added to your medical record. 
• 
CT scan of the chest, abdomen and pelvis. The CT scans done during this study are considered 
standard of care.  
• 
MRI of your arms and/or legs if your tumor is located there. 
• 
You will have blood drawn for research labs prior to the test dose of ascorbate to check the 
oxidative stress markers in your blood.   
• 
An optional MRI may be done if your tumor is in your extremities and if you agree.  This is a 
research-only procedure done to see if a new type of MRI will be useful in planning for radiation 
therapy treatment.   There will be a place at the end of this consent form to let us know if you 
agree to this MRI.   


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 3 of 11 
• 
A 15 gram test dose of ascorbate via IV infusion will be administered. If you do have a serious 
side effect or a significant medical event in the opinion of the study doctor, you will not continue 
in the study.  Your study doctor will let you know if you are unable to continue in the study. 
• 
If you agree, we would like to take an optional tumor biopsy from you at this time, in order to 
compare the immune markers on your tumor from before treatment is started to samples we take 
after you receive treatment. To perform the biopsies, ultrasound will be used to guide a needle into 
the tumor which will be used to remove a core sample of the tumor. These biopsies will be used 
for only for research, they will not contribute to decisions about your care. You do not have to 
agree to this optional biopsy to participate in this study,  Please initial your choice below: 
 
_______ Yes, I agree to allow a biopsy of my tumor to be collected prior to receiving any study drug, 
to be used on this study as well stored for future research.  
 
_______ No, I do not want to participate in the pre treatment biopsy 
 
High dose ascorbate may interfere with finger-stick blood glucose readings. If you are using a finger-stick 
glucometer, you must discuss this with the study doctor. You may not be able to participate in this study. 
During your study treatment 
If the tests show you can proceed, you will begin receiving treatment. 
• 
You will have blood drawn weekly during the 5 weeks of treatment to check your blood counts, 
kidney function, liver function and electrolyte levels.  You will also have blood drawn for research 
labs during weeks 1, 3 and 5 as well as when you’ve finished treatment.   
• 
Physical examinations (including vital signs such as blood pressure and pulse) will be done during 
visits at weeks 1, 3 and 5.   
• 
You will receive ascorbate infusions three times a week for 5 weeks.  You’ll also receive radiation 
therapy daily, Monday – Friday, during the same 5 weeks. 
• 
At various points throughout the study visit you will be asked about changes in your health and/or 
use of medications.  
• 
Three optional MRIs may be done if your tumor is in your extremities and if you agree.  These 
would be done at the following times: 
o During screening as part of your planning in radiation oncology or as part of a diagnostic MRI 
if that is being done (listed above in the list of tests done before you begin study treatment). 
o During week 3 of treatment. 
o At the end of the study. 
After your study treatment 
• 
You will have a follow-up appointment in the Holden Comprehensive Cancer Center 4 to 6 weeks 
after your final ascorbate treatment.  
• 
Follow up appointments will be scheduled to see how you are doing, according to the standard of 
care, for about 5 years or until progression of your cancer is seen.  


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 4 of 11 
Tissue/Blood/Data Storage for Future Use  
As part of this study, we are obtaining blood samples from you.  We would like to study your blood 
samples in the future, after this study is over.  Your sample, information, and/or data may be placed in a 
central repository or other national repositories sponsored by the National Institutes of Health or other 
Federal agencies. If this happens, it may be stripped of identifiers (such as name, date of birth, address, 
etc).  Other qualified researchers who obtain proper permission may gain access to your sample and/or 
data for use in approved research studies that may or may not be related to in the purpose of this study.   
The tests we might want to use to study your blood samples may not even exist at this time.  Therefore, 
we are asking for your permission to store your blood samples so that we can study them in the future.  
These future studies may provide additional information that will be helpful in understanding sarcoma, 
but it is unlikely that what we learn from these studies will have a direct benefit to you.  It is possible 
that your blood samples might be used to develop products tests, or discoveries that could be patented 
and licensed.  In some instances, these may have potential commercial value and may be developed by 
the Investigators, University of Iowa, commercial companies, and organizations funding this research, or 
others that may not be working directly with this research team.  However, donors of blood samples do 
not retain any property rights to the materials.  Therefore, there are no plans to provide financial 
compensation to you should this occur.   
Your blood samples will not be used for research involving whole genome sequencing.   
Your blood samples will be stored with a code which may be linked to your name and medical record 
number.  If you agree now to future use of your blood samples but decide in the future that you would 
like to have it removed from future research, you should contact Dr. Varun Monga at 319-384-9497.  
However, if some research with your blood samples has already been completed, the information from 
that research may still be used.  
A part of the fresh sarcoma tissue removed at the time of surgery will be used to conduct research tests. 
The tests may include looking for immune cells, amount of iron in sarcoma tissue and genetic tests to 
understand which cancers responded to the treatment and which did not. The cancer tissue will be stored 
in wax blocks and may be used for testing in the future. The findings of this research testing will be 
shared with the scientific community.       
Please place your initials in the blank next to Yes or No for each of the questions below: 
My blood samples may be stored/shared for future research in sarcoma. 
_____ Yes  
_____ No 
My blood samples may be stored/shared for future research for any other purpose. 
_____ Yes  
_____ No 
My sarcoma tissue may be used for research tests and stored/shared for future research in sarcoma 
_____ Yes  
_____ No 
 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 5 of 11 
If you agreed to provide us a tumor sample prior to treatment earlier in this form, it will be kept and 
stored for future research in the same manner as the samples describe above.  
 
WILL I BE NOTIFIED IF MY DATA\BIOSPECIMENS\IMAGES RESULT(S) IN AN 
UNEXPECTED FINDING?   
The results from the data, samples and images we collect in this research study are not the same quality 
as what you would receive as part of your routine health care. The data, sample and image results will 
not be reviewed by a physician who normally reads such results. Due to this, you will not be informed of 
any unexpected findings. The results of your data, samples and images will not be placed in your 
medical record with your primary care physician or otherwise. If you believe you are having symptoms 
that may require care, you should contact your primary care physician. 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to these, 
there may be other unknown risks, or risks that we did not anticipate, associated with being in this study.  
Research related risks 
Intravenous Ascorbate (Vitamin C) 
Serious 
• 
Diarrhea <10% 
• 
Nausea or vomiting <5% 
• 
Kidney stones <5% 
• 
Precipitation of cystine, oxalate or urate crystals in the kidney resulting in kidney damage or failure <1% 
Mild 
• 
Dry mouth/thirst (>35%) 
• 
Blood pressure elevation that may result in the need to be treated with medication <10% 
• 
Headache <5% 
• 
Abdominal pain <5% 
• 
Fatigue <5% 
• 
Facial flushing <5% 
• 
Sweating <5% 
• 
Weakness <5% 
• 
Injection site irritation may occur <2% 
• 
Faintness or dizziness may occur with rapid IV administration <5% 
• 
Ascorbic acid infusion may leak outside the vein, resulting in pain and irritation at the site <2% 
Radiation Therapy 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 6 of 11 
You will receive radiation treatments in the course of this study.  The radiation treatments are 
considered standard care for your condition.  You will receive experimental drug therapy in addition to 
radiation, because it is thought that the combination may increase the effectiveness of the treatment.  
This experimental addition of ascorbate may also intensify radiation effects on some normal tissues, and 
increase the risk of radiation-related side effects.  Short-term risks include skin changes such as redness, 
hair loss, or delayed wound healing; and long-term risks include causing a new tumor.  The extent to 
which the risks of radiation therapy will be boosted by the addition of ascorbate is not known.   
Medical Imaging 
There is a risk that ascorbate could interact with contrast used for medical imaging (CT, PET/CT, or 
MRI, for example), causing an increase in liver function tests. For this reason, you should let us know if 
you have any medical imaging scheduled during your chemotherapy / ascorbate treatments. We will not 
schedule ascorbate treatments on days you are scheduled to have medical imaging. 
Blood Glucose Readings 
High-dose ascorbate has been shown to interfere with finger-stick blood glucose tests (the finger-stick 
blood sugar tests diabetics use). We do not know how long after an infusion the ascorbate interferes with 
these tests.  
High-dose ascorbate does not interfere with serum or plasma glucose tests done by medical laboratories 
(when blood is taken from your vein). 
If you need to have your blood sugar checked by a finger-stick test, or a doctor has told you to start 
checking your blood sugar with a finger-stick test, you must tell us immediately. Call 319-356-1616 
and ask for the hematology-oncology fellow on call. When the operator connects you, tell the doctor you 
are participating in Dr. Monga’s Ascorbate for Sarcoma study. 
Risks from drawing blood 
Drawing blood may cause pain, bruising, bleeding or infection at the site of the needle stick.  Care will 
be taken to avoid these complications.   
Tumor Biopsy 
The risks of the tumor biopsy include pain, infection, and bleeding. These risks are similar to the risks of 
the tumor biopsy you had at diagnosis. 
Women Capable of Becoming Pregnant 
If you are a woman who is capable of becoming pregnant, we will ask you to have a pregnancy test 
before beginning this study.  You must use effective birth control methods and try not to become 
pregnant while participating in this study.  If you become pregnant, there may be unknown risks to your 
fetus, or risks to your fetus that we did not anticipate, associated with being in the study. There may be 
long-term effects of the treatment being studied that could increase the risk of harm to an unborn child.  
If you believe or know you have become pregnant while participating in this research study, please 
contact Dr. Varun Monga at 319-384-9497 as soon as possible. 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 7 of 11 
Testing for Reportable Diseases 
If you decide to participate in this study, we may test you for Hepatitis B, Hepatitis C or HIV. The 
results of the test could indicate that you have Hepatitis B, Hepatitis C or HIV.  If that happens, we will 
refer you to a doctor who specializes in treating Hepatitis B, Hepatitis C or HIV.  We will make every 
effort to keep your personal information confidential.  However, we are required by law to report 
positive tests to the Iowa Department of Public Health.  Becoming aware of a diagnosis of Hepatitis B, 
Hepatitis C or HIV could have serious personal and/or social consequences, including difficulty 
obtaining health insurance or employment.  For more information about the risks of Hepatitis B, 
Hepatitis C or HIV testing, please talk to your study doctor. 
WHAT ARE THE BENEFITS OF THIS STUDY? 
We don’t know if you will benefit from being in this study. However, we hope that, in the future, other 
people might benefit from this study because of knowledge gained toward finding a better way to treat 
sarcoma.  
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  Instead of being in this study, you could receive the standard treatment for your 
disease or opt to be in a different clinical trial.  
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You will have additional costs for being in this research study. 
You will not be charged for: 
• 
The study drug (ascorbate). This is provided to you by the study. 
• 
The blood tests done for research purposes only.  These are not clinical tests and are provided by the 
study. 
• 
The optional MRIs. 
• 
The optional biopsies. 
 
You (and your insurance company) will be charged for: 
• 
Infusion of the study drug (ascorbate). You should check with your insurance carrier about these 
costs before agreeing to participate. 
• 
Radiation therapy 
• 
Any imaging, including standard MRI or CT scans. This is standard for your cancer. 
• 
Your doctors’ visits and any ordered blood tests. You would have those normally for your cancer care. 
You and/or your medical/hospital insurance carrier will remain responsible for your regular medical care 
expense. 
WILL I BE PAID FOR PARTICIPATING? 
You will not be paid for being in this research study.   


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 8 of 11 
WHO IS FUNDING THIS STUDY? 
The Holden Comprehensive Cancer Center is funding this research study.  The University and the 
research team are receiving no payments from other agencies, organizations, or companies to conduct 
this research study.   
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
• 
If you are injured or become ill from taking part in this study, medical treatment is available at the 
University of Iowa Hospitals and Clinics. 
• 
The University of Iowa does not plan to provide free medical care or payment for treatment of any 
illness or injury resulting from this study unless it is the direct result of proven negligence by a 
University employee.  
• 
If you experience a research-related illness or injury, you and/or your medical or hospital insurance 
carrier will be responsible for the cost of treatment. 
WHAT ABOUT CONFIDENTIALITY? 
We will keep your participation in this research study confidential to the extent permitted by law.  
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
•    federal government regulatory agencies,  
• 
the U.S. Food and Drug Administration (FDA) 
• 
the Holden Comprehensive Cancer Center  
• 
auditing departments of the University of Iowa, and  
• 
the University of Iowa Institutional Review Board (a committee that reviews and approves research 
studies)  
To help protect your confidentiality, we will keep study documents and binders in locked offices. 
Electronic information will be stored on password protected computers. Where feasible, we will use a 
research ID to minimize using your name. All printed documents are stored in a locked office at the 
hospital. Any blood samples that we take for research testing are dated and named using your Research ID. 
They are also stored at the University in a locked room.  If we write a report or article about this study or 
share the study data set with others, we will do so in such a way that you cannot be directly identified. 
The University of Iowa Hospitals and Clinics generally requires that we document in your medical 
record chart that you are participating in this study. The information included in the chart will provide 
contact information for the research team as well as information about the risks associated with this 
study. We will keep this Informed Consent Document in our research files; it will not be placed in your 
medical record chart. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will include 
a summary of the results.  You can search this website at any time. 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 9 of 11 
WILL MY HEALTH INFORMATION BE USED DURING THIS STUDY? 
The Federal Health Insurance Portability and Accountability Act (HIPAA) requires your healthcare 
provider to obtain your permission for the research team to access or create “protected health 
information” about you for purposes of this research study.  Protected health information is information 
that personally identifies you and relates to your past, present, or future physical or mental health 
condition or care.  We will access or create health information about you, as described in this document, 
for purposes of this research study and for your treatment. Once your healthcare provider has disclosed 
your protected health information to us, it may no longer be protected by the Federal HIPAA privacy 
regulations, but we will continue to protect your confidentiality as described under “Confidentiality.” 
We may share your health information related to this study with other parties including federal 
government regulatory agencies, the University of Iowa Institutional Review Boards and support staff, 
the U.S. Food and Drug Administration, and the Data and Safety Monitoring Board of the Holden 
Comprehensive Cancer Center.  
You cannot participate in this study unless you permit us to use your protected health information.   
If you choose not to allow us to use your protected health information, we will discuss any non-research 
alternatives available to you.  Your decision will not affect your right to medical care that is not 
research-related.  Your signature on this Consent Document authorizes your healthcare provider to give 
us permission to use or create health information about you. 
Although you may not be allowed to see study information until after this study is over, you may be 
given access to your health care records by contacting your health care provider. Your permission for us 
to access or create protected health information about you for purposes of this study has no expiration 
date. You may withdraw your permission for us to use your health information for this research study by 
sending a written notice to: 
Varun Monga, MBBS 
University of Iowa Hospitals & Clinics 
200 Hawkins Drive, C21 GH 
Iowa City IA 52242 
However, we may still use your health information that was collected before withdrawing your 
permission.  Also, if we have sent your health information to a third party, such as the study sponsor, or 
we have removed your identifying information, it may not be possible to prevent its future use.  You will 
receive a copy of this signed document. 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time.  If you decide not to be in this 
study, or if you stop participating at any time, you won’t be penalized or lose any benefits for which you 
otherwise qualify. 
What if I Decide to Drop Out of the Study? 
If you decide to leave the study early, we will ask you to discuss your cancer treatment plans with your 
doctors so that you continue to receive clinical treatment for your cancer. We will also: 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 10 of 11 
• 
need to take blood samples to make sure your kidneys, liver, and bone marrow are functioning 
• 
meet with you to discuss the side effects, if any, you had from ascorbate 
Will I Receive New Information About the Study while Participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
Can Someone Else End my Participation in this Study? 
Under certain circumstances, the researchers or study sponsor might decide to end your participation in 
this research study earlier than planned. This might happen because you have a bad reaction to the study 
drug or because in our judgment it would not be safe for you to continue. . Under certain circumstances, 
the University of Iowa or the Governor of Iowa may determine that all human subjects research must be 
halted due to COVID-19. If this happens, we will tell you as soon as we are notified. We will work with 
you and your doctors to ensure your standard cancer care continues. 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact:  Varun Monga, MBBS at 319-384-9497.  If you experience a research-related injury, please 
contact:  Varun Monga, MBBS at 319-384-9497.  If you are calling after hours or on a weekend, please 
call 319-356-1616 and ask the operator for the Hematology / Oncology fellow on call.  Tell the operator 
that you are a participant in Dr. Monga’s Ascorbate + Radiation study for Sarcoma.     
If you have questions, concerns, or complaints about  your rights as a research subject or about research 
related injury, please contact the Human Subjects Office, 105 Hardin Library for the Health Sciences, 
600 Newton Rd, The University of Iowa, Iowa City, IA  52242-1098, (319) 335-6564, or e-mail 
irb@uiowa.edu.  General information about being a research subject can be found by clicking “Info for 
Public” on the Human Subjects Office web site, http://hso.research.uiowa.edu/. To offer input about 
your experiences as a research subject or to speak to someone other than the research staff, call the 
Human Subjects Office at the number above. 
Optional MRIs  
The optional MRIs were described earlier in the consent document.  Please indicate your preference by 
initialing in the appropriate place below: 
I agree to have the three optional MRIs at screening, during week 3 of treatment and at the end of the 
study: 
_____ Yes  
_____ No 
 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201901810 
APPROVAL DATE: 02/24/22 
EXPIRATION DATE: 02/24/23 
 
 
 
Page 11 of 11 
This Informed Consent Document is not a contract. It is a written explanation of what will happen 
during the study if you decide to participate. You are not waiving any legal rights by signing this 
Informed Consent Document. Your signature indicates that this research study has been explained to 
you, that your questions have been answered, and that you agree to take part in this study.  You will 
receive a copy of this form. 
 
 
Subject's Name (printed):  __________________________________________________________ 
 
 
Do not sign this form if today’s date is on or after EXPIRATION DATE: 02/24/23. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Subject)  
 
 
 
 
(Date) 
 
Statement of Person Who Obtained Consent 
I have discussed the above points with the subject or, where appropriate, with the subject’s legally 
authorized representative.  It is my opinion that the subject understands the risks, benefits, and 
procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date)