Randomized, Phase II Trial of Intravenous Ascorbic Acid (Vitamin C) as an Adjunct to Pazopanib in the First-Line or Post-Immunotherapy Setting for Metastatic or Unresectable Clear Cell Renal Cell Carcinoma (ccRCC)
Phase: PHASE2
Conditions: Clear Cell Renal Cell Carcinoma, Metastatic Clear Cell Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v7, Unresectable Renal Cell Carcinoma
Sponsor: Academic and Community Cancer Research United



 
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Amendment 2 
Index 
 Schema 
 1.0 
Background 
 2.0 
Goals 
 3.0 
Patient Eligibility 
 4.0 
Test Schedule 
 5.0  
Stratification Factors  
 6.0 
Registration/Randomization Procedures 
 7.0 
Protocol Treatment 
 8.0 
Dosage Modification Based on Adverse Events  
 9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
 
  
 
 
 
 
 
  
 
 
 
 
 

 
 
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                                                                      SCHEMA 
                                             
                
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
** 
** 
* 
Metastatic or 
unresectable clear 
renal-cell carcinoma 
Randomization 
(1:1) 
Arm B 
Pazopanib  
Arm A 
Pazopanib +IV 
ascorbic acid 
Observation every 8 
weeks or as clinically 
indicated until 
progression or 2 years 
after registration 
Event monitoring every 6 months 
until death or 3 years after 
registration 
*Off -treatment for any reason other than disease 
progression, alternative therapy, or withdraw/refusal 
**Off-treatment due to disease progression, alternative 
therapy, or withdraw/refusal  
PD at any time                  
Patient withdraw/refusal              Event Monitoring     
Alternative Therapy 

 
 
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Amendment 2 
 
1:1 Randomization 
    Arm A: Pazopanib 800mg daily plus intravenous ascorbic acid 1g/kg 3 times/ week.  
    Arm B: Pazopanib 800mg daily   
 
Cycle = 28 days.  
 
Patients receiving pazopanib, with or without IV vitamin C, will be treated for 10 cycles (unless PD, 
unacceptable AEs, alternative therapy, or patient refusal). Patients may continue pazopanib after 10 
cycles (off study) based on physician discretion and patient acceptability.  
 
Targeted patients: patients with metastatic / unresectable RCC, no prior treatment other than 
immunotherapy, who qualify for treatment with pazopanib.  
 
Patients’ disease status will be assessed by CT scan, per RECIST 1.1, every 8 weeks until disease 
progression, or until 2 years since study randomization, whichever is first. 
 
In event monitoring, patients will be followed for survival every 6 months for a maximum of 3 years 
from study randomization. Once a patient has discontinued study treatment, future therapy is at the 
discretion of the treating physician.  
 
 
 
Generic name:   Pazopanib 
Brand name(s):  Votrient® 
Availability:  Commercially available 
Generic name:   Ascorbic Acid 
Brand name(s):  Vitamin C, ASCOR® 
Availability:  Clinical Research Services, a division of Rx Crossroads by 
McKesson 

 
 
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1.0    
Background  
 
Renal cell cancer (RCC) accounts for about 4% of all the adult malignancies. In the 
United States in 2016, about 61,560 cases of kidney cancer and renal pelvis cancer are 
expected to occur and lead to more than 14,080 deaths. The treatment options for 
metastatic RCC are limited. Tyrosine Kinase inhibitors (TKI) are considered to be the 
first line agents in metastatic RCC and provide a modest overall survival benefit. 
 
Clear cell RCC accounts for about 80% of all RCC and the Von Hippel Lindau (VHL) 
tumor suppressor gene is mutated, deleted or epigenetically silenced in approximately 
85% of sporadic clear cell RCC. Loss of VHL function leads to a constitutionally active 
Hypoxia Inducible Factor (HIF) pathway. The HIF pathway is considered to be the 
driver pathway in VHL mutant clear cell RCC. 
 
Pazopanib is an orally-bioavailable, adenosine triphosphate (ATP)- competitive tyrosine 
kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) receptor (VEGFR)-
1, -2, and -3, platelet-derived growth factor receptor (PDGFR)- α and - β, and stem cell 
growth factor receptor (c-Kit). Pazopanib administered as oral doses up to 800 mg daily 
is being developed for the treatment of a variety of cancers and is currently approved by 
the Food and Drug Administration (FDA; New Drug Application #022465), European 
Medicines Agency (EMA) and other regulatory authorities as a monotherapy treatment 
for patients with advanced renal cell carcinoma (RCC) and advanced soft tissue sarcoma 
(STS).  
 
Vitamin C has been used for many years as an oral anti-cancer agent. Although there 
were some studies that suggested benefit, oral ascorbic acid failed to demonstrate benefit 
in two randomized placebo controlled trials at the Mayo Clinic, [1, 2] after which 
mainstream oncologists discarded its role in cancer therapy. However, recent data on the 
pharmacokinetics of vitamin C and new understanding of its anti-cancer mechanism of 
action has led to resurgence in interest in exploring its potential in cancer therapy. These 
studies indicate that ascorbic acid at concentrations achieved only by the intravenous 
route functions as a pro-drug for hydrogen peroxide delivery to tissues and may have 
potential use in the treatment of cancer by induction of oxidative stress. [3-7] Phase 1 
trials have demonstrated that intravenous ascorbate doses of up to 1-1.25g/kg are well 
tolerated with chemotherapy as well as targeted therapy, and there may be some anti-
tumor activity.[8-10] It has also been shown to reduce the toxicity of chemotherapy. [11] 
 
Clear cell RCC is an ideal model to test this hypothesis due to its characteristic high 
intratumoral iron content[12] and constitutionally active HIF pathway. We hypothesize 
that iron is an important component of the microenvironment to help ascorbate generate 
hydrogen peroxide; and it has already been shown that the constitutionally active HIF 
pathway renders ccRCC cells more susceptible to Vitamin C induced toxicity.[13] There 
have been case reports of excellent response of metastatic RCC with intravenous 
ascorbate.[14, 15]  We propose testing the hypothesis in a randomized trial where 
patients will receive standard pazopanib either alone or with IV ascorbate.  
 
Considering the impact of Mayo Clinic’s studies on the use of vitamin C in cancer, we 
want to re-investigate the potential role of this agent in cancer therapy in the intravenous 
form, based on the accumulating evidence.  
 

 
 
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1.1 
Mechanism 1 
 
There has been a lot of debate whether ascorbic acid, which is traditionally 
considered a metal ion, ascorbic acid can readily undergo auto-oxidation to 
H2O2. Cancers have shown to increase ferritin levels. While we know that 
ferritin is an acute phase reactant, studies have demonstrated increased ferritin 
in the stroma of cancers. It is therefore believed that Fe3+ derived from the 
ferritin can act as a catalytic agent for the auto-oxidation of vitamin C, 
especially in high levels. Ascorbic acid therefore is believed to function as a 
prodrug of H2O2 in its anti-cancer activity. The large amounts of H2O2 
produced can overwhelm the antioxidant defense mechanisms in the cancer cell. 
Cancer cells have been shown to usually have lower catalase, glutathione 
peroxidase and peroxiredoxin activity than normal cells, providing a rationale 
for the selective toxicity against cancer cells.[16-18] Even in the absence of 
catalytic metal ions, the H2O2 produced by oxidation of ascorbic acid is quite 
significant. There is also data suggesting that pharmacologic level of ascorbate 
can preferentially produce ascorbyl radical and H2O2 in the extracellular fluid  
[19, 20]  Clinical proof of potent auto-oxidation of ascorbic acid and resulting 
pro-oxidant properties when given in large quantities, is the well documented 
case reports of intravascular hemolysis in patients with G6PD deficiency 
receiving large doses of intravenous vitamin C.[21, 22].  
 
The following reactions are involved in the production of H2O2 with ascorbate: 
 
1. Ascorbate reduces ferric ions (sequestered from ferritin) to ferrous ions  
 
AscH- (ascorbate) +    Fe3+        Asc*-   (ascorbate radical) + 
Fe2+… (1) 
 
2. The ferrous ions react with oxygen to form superoxide radical 
 
Fe2+ + O2      Fe3+ + O2*- … (2) 
 
3. Superoxide radical then dismutes to H2O2 and O2 
 
O2*-  +  O2*-  +   2H+    H2O2  +  O2  … (3)  
 
The H2O2 formed can diffuse into cancers cells or, if the Fenton reaction takes 
place, more potent oxidants such as the hydroxyl radical (OH*) can be formed 
from H2O2 causing further oxidative stress in cancer cells, given have lower 
antioxidant machinery.  
 
(Fenton reaction-  Fe2+ + H2O2   Fe3+ + HO*  and the Fe3+ generated is 
reduced back to Fe2+ by ascorbate as in reaction 1 ).  
Therefore, even though the eventual effect is that of a pro-oxidant with the 
generation of H2O2 and other oxidants, the first reaction involves anti-oxidant 
effect of ascorbate.   
 

 
 
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H2O2, which can diffuse into cells, depletes ATP in sensitive cells, and thereby 
cause cell death. ATP may be depleted by three mechanisms. (i) DNA damage 
induced by H2O2 activates PARP. Activated PARP catabolizes NAD+, thereby 
depleting substrate for NADH formation and consequent ATP synthesis. (ii) 
H2O2 is catabolized by concurrent oxidation of GSH to GSSG. To reduce GSSG 
back to GSH, GSH reductase utilizes NADPH, which is provided by the pentose 
pathway shunt from glucose. Glucose used to reduce NADP+ to NADPH cannot 
be used for glycolysis or NADH production so that ATP generation is 
decreased. (iii) H2O2 may directly damage mitochondria, especially ATP 
synthase, so that ATP production falls. Some cancer cells rely primarily on 
glycolysis rather than on oxidative phosphorylation respiration for ATP 
production (the Warburg effect). Compared with oxidative phosphorylation, 
ATP generation by glycolysis is inefficient. In glycolysis-dependent cancer 
cells, decreased glycolysis may lower intracellular ATP. Cancer cells that are 
glycolysis-dependent may be particularly sensitive to pharmacologic ascorbic 
acid concentrations, compared with cells that use oxidative phosphorylation.  
 
In this mechanism, the extracellular production of H2O2 is important and not 
the intracellular concentration of Vitamin C. This mechanism however relies on 
the presence of iron or other catalytic metal agents for the anticancer activity 
and may explain, in part, the variability of the effect of intravenous vitamin C. 
Some cancer cells that have overexpression of catalase have been shown to be 
protected against vitamin C induced toxicity, further supporting this mechanism. 
[23]  
 
In a fascinating study, RCC was shown to have abundant iron staining,[24] 
providing one rationale for using high dose ascorbic acid in RCC.    
 
             
 
 
Fig1. Mechanism of formation of ascorbate radical and H2O2 in 
extracellular fluid compared with blood. After parenteral 

 
 
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Amendment 2 
 
administration, ascorbic acid achieves equivalent pharmacological 
concentrations in blood (left side of the diagram) and extracellular 
fluid (right side). In extracellular fluid, a molecule of ascorbic acid 
loses 1 electron and forms ascorbate radical. This electron 
subsequently reduces a protein-centered metal, shown as the 
reduction of Fe3+ to Fe2+. This complex donates an electron to 
molecular oxygen, forming superoxide anion (O2·−) with ensuing 
dismutation to H2O2. In blood (left side), these reactions are damped 
or inhibited (dashed lines). The appearance of ascorbate radical is 
inhibited by RBC membrane-bound reducing proteins and/or by 
large plasma proteins that do not distribute to the extracellular 
space. RBC enzymes glutathione peroxidase and catalase destroy 
whatever little H2O2  is produced in blood so that none is detectable 
in blood. The extracellular fluid H2O2 has been detected using a 
synthesized probe peroxyxanthone only after parenteral 
administration of ascorbate and when Asc (*-) concentrations in 
extracellular fluid exceeded 100 nM. (from ref 14 ). The ECF H2O2  
formed then diffuses into cancer cells and causes ATP depletion and 
cell death (mechanism explained in text). The identities of the 
protein-centered metals are unknown- our hypothesis is that this 
could be the variable ferritin deposits in the tumor micro-
environment. Tumor associated Macrophages are known to have 
high ferritin content and extracellular secretion of ferritin in the 
microenvironment is thought to play an oncogenic role.[25] We 
propose using the Prussian Blue reaction to detect loosely bound 
ferric ion in the tumor microenvironment, and correlating that with 
the response to IV ascorbic acid + TKI.     
 
1.2 
Mechanism 2:  
To add to the above mechanism, it was recently shown that HIF increases the 
sensitivity of cancer cells to vitamin C induced toxicity. HIF increases the 
intracellular uptake of oxidized vitamin C ( dehydroascorbic acid/ DHA ) 
through its transcriptional target Glut 1 (which also transports glucose inside the 
cell).  The resulting high levels of vitamin C induces oxidative stress, DNA 
damage and depletes ATP reserves leading to cell death.[26]. This study used 
VHL deficient RCC cell lines as well as VHL competent non RCC lines with 
high HIF activity. Inhibition of HIF activity with shRNA resulted in reduced Vit 
C induced toxicity and inhibiton of Glut 1 also had the same effect, further 
supporting this mechanism. This mechanism is particularly exciting given that 
the HIF is activated in many cancers especially in hypoxic areas and many 
cancers overexpress Glut1 as they rely on anaerobic glycolysis for their energy 
production. It is well known that Ascorbate (AscH-) is transported into the cell 
via sodium dependent Vitamin C transporters (SCVTs) but the expression of 
SCVTs in cells is tightly regulated by intracellular vitamin C concentration. 
Hence, beyond a certain point, transporting ascorbate into the cell is limited. 
However, Ascorbate, being a water soluble antioxidant, can undergo two 
consecutive, one-electron oxidations resulting in the formation of ascorbate 
radical (Asc*−) and dehydroascorbic acid (DHA) and the DHA (i.e oxidized 
Vitamin C ) is taken up without regulation via the Glut 1 receptors, resulting in 
oxidative damage and depletion of ATP stores (as all the NAD+ is used to 

 
 
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resolve the oxidative DNA damage, resulting in lesser availability for 
glycolysis, the main energy producing mechanism of cancer cells)   
 
Fig 2. With loss of VHL activity in clear cell RCC, HIF-α avoids 
proteasomal degradation and is stabilized. HIF-α increases the 
expression of GLUT-1 (Glucose transporter-1) in an unregulated 
manner to increase uptake of glucose into the cell to meet increased 
metabolic demands via anaerobic glycolysis. Ascorbate (AscH-), 
being a water soluble antioxidant, can undergo two consecutive, one-
electron oxidations resulting in the formation of ascorbate radical 
(Asc*−) and dehydroascorbic acid (DHA); and the DHA (i.e oxidized 
Vitamin C ) is taken up without regulation via the Glut 1 receptors, 
resulting in oxidative damage and depletion of ATP stores. The anti-
oxidant form AscH-, is unable to enter the cell due to 
downregulation of Sodium dependent Vitamin C transporter (SVCT) 
with increasing intracellular vitamin C concentration. In the study 
Tian et al (ref 26), inhibition of HIF activity with shRNA resulted in 
reduced Vit C induced toxicity and inhibiton of Glut 1 also had the 
same effect, further supporting this mechanism.       
 
Considering that a majority of ll ccRCC are VHL mutant and as a result have 
high constitutive HIF activity, at least one of the two mechanisms elaborated 
above would be present in a large majority. In fact, there are case reports of 
remarkable benefit of high dose vitamin C therapy in renal cancer and bladder 
cancer, which are known to have dominant HIF pathway. Put together, these 
studies suggest that high dose vitamin C therapy may be more effective in 
cancers with a dominant HIF pathway.[27] Extensive clinical experiences with 

 
 
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Vitamin C in cancer have been documented mainly in the form of reports or 
series and even protocols for intravenous vitamin C in cancer have been 
suggested. [28-30] The fascinating phenomenon of intratumoral necrosis 
reported in some patients given high dose vitamin C may suggest that the 
hypoxic areas of tumors with high HIF activity may be particularly susceptible 
to high dose vit C. In VHL deficient ccRCC however, there is constitutive 
activation of HIF pathway and potentially high intracellular concentrations 
could be achieved throughout the tumor. TKIs ( pazopanib/ sunitinib ) that are 
the approved first line therapies in metastatic ccRCC, inhibit VEGF, thereby 
inhibiting neovascularization and theoretically causing more hypoxic area 
within the tumor with higher HIF activity, which could enhance the anticancer 
effect of Vitamin C.  
 
 
1.3 
Mechanism 3- Epigenetics 
Clear cell RCC is known to have genome wide hypermethylation, and the 
degree of hypermethylation has been correlated with survival [31]. TET is an 
enzyme that converts methylcytosine to hydroxymethylcytosine, which then 
leads to demethylation. Preliminary data from our lab reveals loss of 
hydroxymethylation in high grade ccRCC patient samples, likely due to 
deficient TET activity (since TET is the only known enzyme responsible for 
conversion of methylcytosine to hydroxymethylcytosine). Vitamin C was shown 
to increase TET activity in embryonal stem cells in a Nature paper in 2013 [32] 
and we have shown that TET activity is increased with ascorbic acid in RCC 
cell lines 769P and 786-O. We further confirmed this by studying genome wide 
methylation and hydroxymethylation using mass spectrometry (LC/ESI-
MS/MS) which revealed a decrease in total methylcytosine and increase in the 
fraction of hydroxymethylated DNA, correlating with the increase in TET 
activity. QPCR of Smad 7, a tumor suppressor gene of the TGF beta pathway 
known to be silenced by methylation was found to be upregulated with vit C. 
Proliferation assay data (MTT) revealed that the combination of pazopanib and 
vit C is better than either alone; and either alone is better than control. Xenograft 
data revealed a significant proliferation inhibition of ccRCC with single agent 
IV AA.  
 
Ascorbic acid in vivo leads to inhibition of RCC tumor growth 
(unpublished):  
        
 

 
 
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A: RCC cells (786O) were xenografted into immunodeficient NSG mice. After 
tumors were established, treatment was initiated with IV AA (1mg/kg/d) or 
vehicle and tumor measurements were conducted (A). AA treatment led to 
significantly delayed tumor growth (B,C) (TTest, P<0.05, Means +/- S.E.M; 
N=10 in each cohort). 
This background provides the rationale for exploring the effect of high dose 
ascorbic acid in VHL mutant clear cell RCC, exploiting the mechanisms of 
ascorbate induced toxicity i.e extracellular production of H2O2 within the tumor 
(potentially enhanced by the high iron content in the tumor micro-environment 
that has been demonstrated in ccRCC ), intracellular accumulation of oxidized 
vitamin C (secondary to high HIF activity seen in ccRCC) and TET dependent 
demethylation of the hypermethylated genome causing re-expression of tumor 
suppressors.  
High dose vitamin C is known to be well tolerated and to have negligible side 
effects in patients with preserved renal function [33, 34] and has been shown in 
many studies to improve the quality of life in advanced cancers.[35-37]  
Multiple phase I clinical trials of intravenous ascorbate in patients with 
advanced cancer measured plasma concentrations of ascorbate and evaluated 
clinical consequences. [33, 38, 39] In the study by Riordan and colleagues, 
patients were given continuous infusion of 0.15 to 0.7 g kg−1 day−1 for up to 
eight weeks; in the Hoffer study, ascorbate was administrated three times per 
week at fixed doses of 0.4, 0.6, 0.9 and 1.5 g kg−1; and in the most recent study 
by Monti et al., patients received 50, 75 and 100 g per infusion (three infusions 
per week) for 8 weeks with concomitant IV gemcitabine and oral erlotinib. In 
the Riordan study, ascorbate concentrations in serum during therapy ranged 
from 0.28 to 3.8 mM. In the Hoffer study, peak plasma ascorbate concentrations 
ranged from 2.4 to 26 mM. When 1.5 g kg−1 was administered, plasma ascorbate 
concentrations exceeded 10 mM for ≈4.5 h, levels that have been shown to 
induce cell killing in a variety of cancer cells [40, 41]. Finally in the Monti 
study, patients that received 100 g of ascorbate achieved peak plasma 
concentrations between 25 and 32 mM. All three trials demonstrated that high-
dose intravenous ascorbate was well tolerated in cancer patients with normal 
renal function; the combination of ascorbate infusion with standard of care 
chemotherapies did not increase toxicity. 
Since high dose intravenous vitamin C has been studied in combination with 
TKI sorafenib in hepatocellular carcinoma [42] and shown to be safe, we think 
it would be reasonable to conduct a phase 2 study with the therapeutic dose 
established in the phase 1 studies. 
 
1.4 
Proposal Hypotheses: 
 
1. 
Combining high dose IV ascorbic acid with pazopanib for the first 
line treatment of clear cell metastatic ccRCC will result in 
improved treatment failure-free rate at 9 months, median 
progression-free survival, objective response rate, tolerance and 
duration on therapy compared to pazopanib alone. 
 

 
 
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Exploratory Hypotheses:  
 
2. 
Patients with ccRCC having higher iron content in the tumor micro-
environment, as determined by iron staining using Prussian blue 
reaction, will have a better response to the combination of IV ascorbic 
acid and pazopanib than those with lower iron content. 
 
3. 
Patients with ccRCC having higher Hypoxia Inducible Factor (HIF-1 
and HIF-2) expression, as determined by immunohistochemistry (IHC) 
detection, will have a better response to the combination of ascorbic 
acid and pazopanib than those with lower expression.  
 
4. 
Patients with ccRCC having higher 5-methylcytosine (5-mC) and 
lower 5-hydroxymethylcytosine (5-hmC) expression, as determined 
by IHC detection, will have a better response to the combination of 
ascorbic acid and pazopanib than those with lower expression.  
 
 
1.5 
Rationale for Study Design 
 
Patients with advanced ccRCC on standard first-line therapy with pazopanib 
was chosen as the optimal setting in which to estimate the effects of IV 
Vitamin C.  As summarized in the preceding sections, ccRCC has a 
hypermethylated epigenome and high iron content in the tumor 
microenvironment.  These are the conditions under which pharmacologic 
doses of Vitamin C are hypothesized to have an anti-tumor effect.  Pazopanib 
is well tolerated and results in clinically significant objective responses and 
prolonged time to progression.  However, most patients suffer from some side 
effects that can be quantified and are occasionally dose limiting.  More than 
half of all patients with ccRCC treated with pazopanib do not have an 
objective response, and complete responses are rare.  Responding tumors 
eventually develop resistance, with median time to progression of 9 months.  
Improvements in these outcomes would be of great clinical significance for 
patients with ccRCC and would be an important proof of principle for the 
study of IV ascorbic acid in other tumor types. 
 
Pazopanib was widely used in the first line setting when enrollment to this 
trial began.  Data from subsequent randomized trials have demonstrated an 
overall survival advantage compared to first-line sunitinib for ipilimumab 
plus nivolumab in intermediate or poor-risk patients, and for pembrolizumab 
plus axitinib in all prognostic groups. The newer regimens have not been 
compared head-to-head with pazopanib, and pazopanib continues to be 
appropriate for selected patients.  To meet our targeted enrollment, however, 
we have amended the study design to allow prior immunotherapy such as 
ipilimumab plus nivolumab, since its mechanism of antitumor effect is not 
known to overlap with pazopanib or ascorbic acid.  
 
 
A randomized controlled trial design was chosen as the optimal way to detect 
improvement in clinical outcomes with IV Vitamin C.  While a placebo-
controlled trial would be ideal, we could not justify the cost and logistics of 

 
 
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giving iv placebo three times per week.  For an open-label design, we 
considered pazopanib alone or pazopanib plus oral ascorbic acid.  A three-
arm trial would be ideal, but costly and would take a long time to complete.  
Since oral ascorbic acid has been extensively studied and is considered 
ineffective, we chose instead a randomized phase II trial design with two 
treatment arms: Pazopanib plus IV ascorbate or pazopanib alone.   
 
We also considered giving IV Vitamin C 2 times/ week instead of 3, but 
chose a 3 times/ week regimen since it is considered to be the most optimal 
regimen and has been used more frequently in phase 1 studies, we decided to 
pursue that. If a twice a week regimen showed minimal benefit, the question 
would arise if giving it 3 times/ week would have been more efficacious.   
 
2.0  
Goals  
 
2.1 
Primary Objective:  
 
 
To estimate and compare treatment failure-free rate at 40 weeks from 
randomization of patients with unresectable/metastatic clear cell Renal Cell 
Carcinoma (ccRCC) receiving one of the following regimens: 
 
• 
Arm A: Pazopanib 800mg daily plus intravenous (IV) ascorbic acid  
1g/kg 3 times/week.  
 
• 
Arm B: Pazopanib 800mg daily  
 
2.2 
Secondary Objective:  
 
2.21 
To estimate and compare the overall survival (OS) in patients receiving 
pazopanib with or without IV ascorbic acid  
 
2.22      To estimate and compare the progression-free survival (PFS) in patients 
receiving pazopanib with or without IV ascorbic acid 
 
2.23 
To estimate and compare the overall response rate (ORR) in patients 
receiving pazopanib with or without IV ascorbic acid 
 
2.24 
To estimate and compare the duration on pazopanib treatment in 
patients receiving pazopanib with or without IV ascorbic acid 
 
2.25 
To assess the adverse events (AE) profile and safety of each treatment 
arm using the CTCAE   
 
2.3 
Correlative Research 
 
2.31       
 
Correlation between 5mC, 5hmC and H3K27me3 expression (as 
determined by IHC), as well as MeDIP/hMeDIP seq, and response to 
combination of IV ascorbic acid and pazopanib. 
 
 
 
2.32      Correlation between iron content in tumor microenvironment (as 
determined by Prussian blue staining) and response to combination of 
IV ascorbic acid and pazopanib. 

 
 
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2.33 
Correlation between HIF-1α and HIF-2α expression (as determined by 
IHC) and response to combination of IV ascorbic acid and pazopanib. 
 
2.34      Correlation between GLUT1 expression (as determined by IHC) and 
response to combination of IV ascorbic acid and pazopanib. 
 
2.35      Correlation between PDL1 expression (as determined by IHC) and 
response to combination of IV ascorbic acid and pazopanib. 
 
3.0  
Patient Eligibility  
 
3.1 
Inclusion Criteria   
 
3.11  
Age ≥ 18 years 
 
3.12  
Histological confirmation of clear cell renal cancer. 
 
3.13 
Documented metastatic or unresectable disease and at least one 
measurable lesion by RECIST criteria. NOTE: Nephrectomy or ablation 
of the primary tumor is allowed prior to enrollment. 
 
3.14  
No prior systemic therapy for clear cell renal cancer; or have progressed 
after immunotherapy such as ipilimumab plus nivolumab in the first 
line.  Other immunotherapies (e.g. interleukin-2) or additional lines of 
immunotherapy may be allowed after discussion with the Principal 
Investigator.   
 
 
3.15  
ECOG Performance Status (PS) 0, 1 or 2.  
 
3.16  
The following laboratory values obtained ≤21 days prior to 
randomization: 
• ANC ≥1500/mm3 
• PLT ≥100,000/mm3 
• Hgb ≥9.0 g/dL  NOTE: Subjects may not have had a transfusion ≤7 
days of randomization 
• Total Bilirubin ≤1.5 x ULN. 
 NOTE: For bilirubin elevation 1 to 1.5x ULN, ALT above 1.5 x 
ULN (upper limit of normal) is not permitted. 
 NOTE: For bilirubin elevation 1 to 1.5x ULN, AST above 1.5 x 
ULN (upper limit of normal) is not permitted. 
• Alanine amino transferase (ALT) <2.5 X ULN, with normal bilirubin. 
NOTE: Concomitant elevations in bilirubin and ALT above 1.5 x 
ULN (upper limit of normal) is not permitted. 
• Aspartate aminotransferase (AST) <2.5 X ULN, with normal 
bilirubin. NOTE: Concomitant elevations in bilirubin and AST above 
1.5 x ULN (upper limit of normal) is not permitted. 

 
 
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• Creatinine ≤ 1.5 mg/dl  OR creatinine > 1.5 mg/dl, estimated  
creatinine clearance must be >= 55 mL/minute by CockcroftGault 
formula: 
 
 
• INR and aPTT ≤ 1.5 × ULN. NOTE: This applies only to patients 
who are not receiving therapeutic anticoagulation; patients receiving 
therapeutic anticoagulation should be on a stable dose. 
 
3.17  
Individuals of non-childbearing potential, or individual of childbearing 
potential with negative serum pregnancy test ≤7 days prior to 
randomization and willing to practice total abstinence or use a highly 
effective method of contraception, as outlined in item “c” below:  
 
a.  Non-childbearing potential (i.e., physiologically incapable of 
becoming pregnant), including any female individual who has 
had the following: 
- A hysterectomy 
- A bilateral oophorectomy (ovariectomy) 
- A bilateral tubal ligation 
- Is post-menopausal 
 
NOTE: Subjects not using hormone replacement therapy (HRT) must 
have experienced total cessation of menses for ≥ 1 year and be greater 
than 45 years in age, OR, in questionable cases, have a follicle 
stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 
40pg/mL (<140 pmol/L). 
Subjects using HRT must have experienced total cessation of menses 
for >= 1 year and be greater than 45 years of age OR have had 
documented evidence of menopause based on FSH and estradiol 
concentrations prior to initiation of HRT 
 
b. Childbearing potential, including any individual who has had a 
negative serum pregnancy test, ≤7 days prior to randomization. 
 
c. Agrees to use adequate contraception. Acceptable contraceptive 
methods, when used consistently and in accordance with both 
the product label and the instructions of the physician, are as 
follows: 
• Complete abstinence from sexual intercourse for 14 days 
before exposure to investigational product, through the 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
  
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 

 
 
16 
ACCRU-GU-1703 
 
 
Amendment 2 
 
dosing period, and for at least 21 days after the last dose of 
investigational product; 
• Oral contraceptive, either combined or progestogen alone 
• Intrauterine device (IUD) or intrauterine system (IUS) with 
a documented failure rate of less than 1% per year; 
• Male partner sterilization (vasectomy with documentation 
of azoospermia) prior to the female subject's entry into the 
study, and this male is the sole partner for that subject; 
• Double barrier method: condom and an occlusive cap 
(diaphragm or cervical/vault caps) with a vaginal 
spermicidal agent (foam/gel/film/cream/suppository). 
 
3.18      Provide informed written consent.  
 
3.19 
Willing to provide archive tissue samples for correlative research 
purposes (See Sections 4.0, 6.0 and 17.0.) 
 
3.2 
Exclusion Criteria 
 
3.21  
Any of the following because this study involves an agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus 
and newborn are unknown: 
• Individuals/or persons who are nursing ; 
• Individual/or persons who are pregnant;  
• Individuals/or persons of childbearing potential who are unwilling 
to employ adequate contraception. 
 
3.22  
Co-morbid systemic illnesses or other severe concurrent disease which, 
in the judgment of the investigator, would make the patient 
inappropriate for entry into this study or interfere significantly with the 
proper assessment of safety and toxicity of the prescribed regimens. 
 
3.23 
Immunocompromised patients (other than that related to the use of 
corticosteroids) including patients known to be HIV positive. 
 
3.24 
Prior history of receiving pazopanib or any other tyrosine kinase 
inhibitor treatments for malignancy. 
 
3.25  
Uncontrolled intercurrent illness including, but not limited to: 
• Chronic ongoing or active infection, 
• Symptomatic anemia, 
• Uncontrolled hypertension [defined as systolic blood pressure 
(SBP) of ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 
100mmHg], 
• Symptomatic congestive heart failure as defined by the New York 
Heart Association (NYHA) (see Appendix III; does not exclude 
Class III CHF), 
• unstable angina pectoris, 
• cardiac arrhythmia, 

 
 
17 
ACCRU-GU-1703 
 
 
Amendment 2 
 
• evidence of active bleeding or bleeding diathesis, 
• psychiatric illness/social situations that would limit compliance 
with study requirements, 
• any other serious uncontrolled medical disorders in the opinion of 
the investigator. 
 
3.26  
History of a major thromboembolic event ≤ 6 months prior to 
randomization, including cerebrovascular accident,  transient ischemic 
attack (TIA), myocardial infarction, symptomatic pulmonary embolism 
(PE) or untreated deep venous thrombosis (DVT), or coronary artery 
bypass graft surgery.  NOTE: Subjects with recent DVT or 
asymptomatic PE who have been treated with therapeutic 
anticoagulating agents for at least 6 weeks are eligible. 
 
3.27  
Receiving any other investigational agent which would be considered as 
a treatment for the primary neoplasm. 
 
3.28  
Other active malignancy ≤5 years prior to randomization. 
EXCEPTIONS: Nonmelanoma skin cancer or carcinoma-in-situ of the 
cervix, or cancers with low metastatic potential (e.g. Gleason score 6 
prostate cancer) treated with curative therapy. NOTE: If there is a 
history or prior malignancy, they must not be receiving other specific 
treatment for their cancer. 
 
3.29a  History or clinical evidence of central nervous system (CNS) metastases 
or leptomeningeal carcinomatosis, except for individuals who have 
previously treated CNS metastases, are asymptomatic, and have had no 
requirement for steroids or anti-seizure medication for ≤ 6 months prior 
to randomization.. Note: Screening with CNS imaging studies 
(computed tomography [CT] or magnetic resonance imaging [MRI]) is 
required only if clinically indicated or if the subject has a history of 
CNS metastases. 
 
3.29b  Clinically significant gastrointestinal abnormalities that may increase 
the risk for gastrointestinal bleeding including, but not limited to: 
• Active peptic ulcer disease, 
• Known intraluminal metastatic lesion/s with risk of bleeding, 
• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s 
disease), or other gastrointestinal conditions with increased risk of 
perforation, 
• History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess ≤28 days prior to randomization, 
• Clinically significant gastrointestinal abnormalities that may affect 
absorption of investigational product including, but not limited to: 
 Malabsorption syndrome 
 Any prior major resection of the stomach or small bowel. 
 
3.29c  Corrected QT interval (QTc) > 480 msecs using Bazett’s formula. 
 

 
 
18 
ACCRU-GU-1703 
 
 
Amendment 2 
 
3.29d  Receiving any medications or substances with risk of Torsades de 
Pointes (see Appendix IV). Note: Medications or substances on the list 
“Drugs with Risk of Torsades de Pointes” are prohibited. Medications 
or substances on the list “Drugs with Possible or Conditional Risk of 
Torsades de Pointes” may be used while on study with extreme caution 
and careful monitoring. 
 
3.29e  Treatment with any of the following anti-cancer therapies ≤ 14 days 
prior to randomization:  
• radiation therapy 
• surgery or tumor embolization 
• chemotherapy, immunotherapy 
• biologic therapy 
• investigational therapy 
• hormonal therapy  
 
3.29f 
Prior autologous or allogeneic organ or tissue transplantation. 
 
3.29g  Elective or planned major surgery to be performed during the course of 
the trial. 
 
3.29h  Receiving any medications or substances that are strong or moderate 
inhibitors of CYP3A4 (for a listing of medications or substances see 
Appendix V) Use of strong or moderate inhibitors are prohibited ≤ 7 
days prior to randomization. 
 
3.29i  Receiving any medications or substances that are inducers of CYP3A4 
(for a listing of medications or substances see Appendix V). Use of 
inducers are prohibited ≤ 7 days prior to randomization. 
 
3.29j  Glucose-6-phosphate dehydrogenase (G6PD) deficiency (i.e. below 
normal limits). 
 
3.29k   End-stage renal disease (estimated GFR <55 ml/min/BSA), unless the 
estimated creatinine clearance by Cockcroft Gault is ≥55 ml/min prior 
to randomization. 
 
3.29l  History of calcium oxalate stones. 
 
3.29m  History of iron overload. 
 
3.29n    Unable to swallow oral medications. 
 
3.29o    History of myocardial infarction ≤6 months, current symptomatic CHF 
or LVEF <40% or > grade 2 diastolic dysfunction, with no symptoms or 
signs of heart failure. 

19 
ACCRU-GU-1703 
Amendment 2 
 
4.0 
Test Schedule 
  
Cycle length = 28 days. 
 
 
 
 
 
 
 
 
Tests and procedures 
 
Active Monitoring 
 
Cycle length = 28 days 
 
+/- 7 day window for study visits and tests.5 
 
 
≤21 days 
prior to 
randomization 
 
Prior to 
each 
new 
cycle 
(≤7 
days) 
 
Prior to 3rd 
and 
subsequent 
odd cycles 
(5, 7, 9, etc.) 
 
At PD, 
withdrawal,  
removal, or 
end of 
protocol 
treatment 
 
 
Observation 
(Clinical 
follow-up) 
Informed Consent 
X 
 
 
 
 
History and exam, wt., ECOG 
PS  
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
Adverse event assessment 
X 
X6 
 
X 
X 
Echocardiogram (2D M-Mode)  
X8 
 
 
 
 
Hematology: 
CBC/ differential 
X 
X5 
 
 
X 
X 
Chemistry: SGOT (AST), alk 
phos, T. bili, creatinine, 
calcium, phos, glucose, Na, K,  
ALT, GFR, LDH11 
X 
X4,5 
 
 
X 
X 
G6PD test  
X R, 9 
 
 
 
 
Urinalysis  
X 
 
 
X 
 
Thyroid function test (TSH) 
X 
 
X 
 
 
Coagulation test: INR, APTT 
X 
 
 
 
 
Tumor measurement 
X1 
 
X1 
 
X1, 10 
CT/MRI brain, if needed (See 
Section 3.29a) 
X 
 
X 
 
 
Bone scan12  
X 
 
X 
 
 
ECG 
X 
 
X 
 
 
Pregnancy test (serum) 
X2 
 
 
 
 
Mandatory archival tissue 
collection (see Section 17.2) 
X R, 7 
 
 
 
 
Patient Medication Diary 
(Appendix II) 
 
X3 
 
X3 
 
 
1 CT chest, abdomen, and pelvis with IV contrast.  If unable to receive IV contrast, MRI 
abdomen/pelvis with contrast and CT chest without contrast are acceptable. Use same imaging 
method throughout the study. 
 

 
20  
 
ACCRU-GU-1703 
Amendment 2 
 
2 For individuals of childbearing potential only. Must be done ≤ 7 days prior to randomization. 
 
3 The diary must begin the day the patient starts taking the medication and must be completed per 
protocol and returned to the treating institution every 4 weeks.  
 
4 For ARM- A (ascorbic acid group) only: Draw at baseline then weekly for Cycle 1, then for 
subsequent cycles on Day 14 and Day 28. For ARM B only: draw at baseline then once every 
cycle. 
 
5 Labs do not have to be repeated prior to Cycle 1 if they were done ≤ 5 days prior to cycle.  
 
6 Starting with Cycle 2, AE’s for Cycle 1 are assessed prior to the beginning of Cycle 2 and are 
recorded under Cycle 1 AE, following this format for all subsequent cycles. 
 
7 Receipt of archival tumor tissue (if available) is not required for study randomization and initiation 
of therapy. . However, it is mandatory to receive the required tissue ≤ 30 days from registration. 
 
8  Echocardiogram done ≤ 6 months prior to randomization is acceptable.  
 
9 G6PD = Glucose-6-phosphate dehydrogenase. If G6PD is found to be below normal limits, patient 
will be ineligible for the trial. If below normal limits, the test can be repeated up to two additional 
times. One normal result is sufficient for eligibility if done within 6 months prior to randomization 
(does not need to be repeated within the 21-day window). 
 
10 Imaging frequency is every 8 weeks or as clinically indicated, until progression or 2 years since 
study randomization, whichever is first, or per treating physician discretion.  
 
11 LDH = Lactate dehydrogenase. Include with chemistries at baseline and during treatment.  
 
12 For patients with a history of bone metastases or for whom there is clinical suspicion of bone 
metastases at study entry. 
 
13 If the urinalysis prior to randomization indicates proteinuria, urine protein/ Cr or 24hr urine 
protein would need to be monitored as clinically indicated throughout the study period. Pazopanib 
dose modification based on significant proteinuria to be followed, as stated in section 8.12. 
 
R   Research funded (see Section 19.0). 

 
21  
 
ACCRU-GU-1703 
Amendment 2 
 
 
5.0 
Stratification Factors:  
 
• 
MSKCC risk category (Favorable risk vs. Intermediate risk vs. Poor risk. See Appendix VI for 
MSKCC risk score.) 
 
• 
Sarcomatoid differentiation (Yes vs. No) 
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Registration  Procedures 
 
6.11 
To register a patient, access the ACCRU web page at 
go to Application 
section and click on “Registration” and enter the registration/randomization application.  The 
registration/randomization application is available 24 hours a day, 7 days a week.  Back up 
and/or system support contact information is available on the Web site.  If unable to access the 
Web site, call the Academic and Community Cancer Research United (ACCRU) Registration 
Office at 
 the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
 
The instructions for the registration/randomization application are available on the above web 
page under Study Resources section, “Application Training”.  
 
Prior to initiation of protocol study intervention, this process must be completed in its entirety 
and an ACCRU subject ID number must be available as noted in the instructions.  It is the 
responsibility of the individual and institution registering the patient to confirm the process has 
been successfully completed prior to release of the study agent.  Patient registration via the 
registration/randomization application can be confirmed in any of the following ways: 
 
• 
Contact the ACCRU Registration Office 
  If the patient was fully 
registered, the ACCRU Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Application Training” at 
. Click on “Registration, 
Installation & Entry Instructions”. 
 
6.12 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19 and 17.2). 
 
6.13 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. Approvals should be uploaded using the 
online ACCRU Regulatory Management System (ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with ACCRU. Approvals should be 
uploaded using online ACCRU Regulatory Management Systems (ARMS)  If the 
necessary documentation is not submitted in advance of attempting patient registration, the 
registration will not be accepted and the patient may not be enrolled in the protocol until 
the situation is resolved. 
 
Submission of annual IRB approvals is required until the study has been closed through 
your IRB. 
 
 

 
22  
 
ACCRU-GU-1703 
Amendment 2 
 
6.14 
Prior to accepting the registration/randomization, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
 
 
6.15 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) for future 
research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) for future 
research to learn, prevent, or treat other health problems (for example:  diabetes, 
Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her tissue sample(s) to 
outside researchers. 
 
6.16 
Treatment cannot begin prior to randomization and must begin ≤ 14 days after 
randomization. 
 
6.17 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.18 
All required baseline symptoms (see Section 10.52) must be documented and graded. 
 
6.19a 
Treatment on this protocol must commence at an ACCRU institution under the supervision 
of a medical oncologist. 
 
6.19b Study drug is available on site. 
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will be used 
as stratification factors. 
 
6.22  
After the patient has been registered into the study, the values of the stratification factors 
will be recorded, and the patient will be assigned to one of the treatment groups using the 
Pocock and Simon dynamic allocation procedure which balances the marginal distributions 
of the stratification factors between the treatment groups (Pocock-Simon ref – see below). 
The goal of the algorithm is to maintain arm balance with respect to the stratification 
factors (see Section 5.0). 
 
In order to ensure that treatment assignment is not deterministic, a level of randomness has 
been added to the algorithm such that patients will be assigned to the arm that leads to less 
imbalance 90% of the time. 
 
 

 
23  
 
ACCRU-GU-1703 
Amendment 2 
 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention per institutional 
guidelines. 
 
Arm 
Agent 
Dose Level 
Route 
Frequency 
ReRx1 
A 
Pazopanib 
 
800mg 
 
PO 
 
Once Daily 
 
 
 
Every 28 days 
Ascorbic acid 
 
1g/kg, titrate first 3 
doses: 0.25, 0.5, and 
0.75g/kg) in 1000ml 
sterile water** 
The maximum 
allowed dose is 100g. 
IV (0.75-
1g/min 
IV*) 
 
 
3 times/ week  
(Mon/Wed/Fri) or 
(Tue/Thu/Sat) or 
 
B 
Pazopanib 
800mg  
PO 
Once Daily  
1. Cycles = 28 days 
* Start infusion rate at 0.75g/minute. If no dizziness after 15 minutes the rate can be increased 
to 1 g/min. Infusion times are approximate (+/- 15 minutes) and may need to be adjusted based on 
patient tolerability. 
**Exceptions during titration: First dose in 250 ml sterile water. Second dose in 500ml sterile water. If 
the maximum dose (based on the patient’s weight) is less than 75 grams, then dose schedule is 25g, 
50g, and then maximum calculated dose.  
 
NOTE: Patients should be observed for 30 minutes after administration of ascorbic acid for at least the 
first 5 doses. Ascorbic acid infusions may not be given less than 24 hours apart. If patients miss one 
day of ascorbic acid IV, they can continue the following day. If a patient misses more than 4 doses of 
ascorbic acid IV in any cycle, the local study doctor must consult with the Principal Investigator 
before the patient will be allowed to continue on study.  
 
 
7.2 
Protocol treatment for Arm A consists of four 200mg tablets (800 mg) of pazopanib by mouth once 
each day plus IV ascorbic acid at 1g/kg given 3 times/week.  
 
 
 
Protocol treatment for Arm B consists of four 200mg tablets (800 mg) of pazopanib by mouth once 
each day. 
 
 
 
7.21 
Dosage and Administration of Pazopanib 
 
Administration of pazopanib with a high-fat or low-fat meal results in an  approximately 2-
fold increase in area under the plasma drug concentration curve (AUC) and maximum 
observed plasma drug concentration (Cmax). 
 
If a dose is missed, the subject should take the dose as soon as possible, but only if there 
are 12 or more hours remaining before the next dose is due.  If the next dose is due in less 
than 12 hours, the subject should skip the missed dose and take the next dose as scheduled. 
 
If vomiting occurs after taking pazopanib, the subject should not take a replacement dose 
on that day.  The subject should resume taking pazopanib at the next scheduled dose on the 
following day.  If vomiting persists, the subject should be instructed to notify the 
investigator. 
 

 
24  
 
ACCRU-GU-1703 
Amendment 2 
 
 
As a general rule, if dose reduction of pazopanib is necessary, the dose should be reduced 
stepwise by 200 mg at each step, and the subject should be monitored for approximately 10 
to 14 days at each dose level.  If toxicity does not abate during this monitoring time, the 
medication may need to be interrupted and/or the dose further decreased with continued 
monitoring for an additional 10-14 days at each dose level, and so on.  
 
If the toxicity has abated with reduction of the dose and dose re-escalation is considered 
safe by the investigator, the dose can then be increased step-wise back to the pre-event 
dose (in 200 mg increments, after monitoring for 10-14 days at each dose level to ensure 
that toxicity did not recur or worsen).  
 
If a subject’s treatment with pazopanib has been interrupted for more than 21 consecutive 
days, the local medicals doctor must contact the Study Principal Investigator to review the 
subject’s condition in order to resume the treatment.   
 
7.3 
For this protocol, the patient must return to the consenting ACCRU institution for evaluation at 
least every 28 days during treatment  
 
  
7.5 
Administration of IV ascorbic acid by a non-study local medical doctor (LMD) is not allowed. 
 
8.0         Dosage Modification Based on Adverse Events  
 
8.1  
Pazopanib 
  
 
 
  
8.11 Pazopanib Dose Reduction Levels 
 
Starting Dose 
800 mg once daily 
Dose Level -1 
600 mg once daily 
Dose Level -2 
400 mg once daily 
 
 
 

 
25  
 
ACCRU-GU-1703 
Amendment 2 
 
 
 
8.12 
Dose Modifications for Pazopanib at Time of Treatment 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
Investigations 
 
Platelet count decreased 
 Grade 3 or 4 
 
 
Pazopanib 
 
Omit until ≤ Grade 2 then restart at next 
lower dose level.  If no recovery to 
grade 2, discontinue 
Investigations 
 
 
 
Prolongation of QTc Interval 
(If the QTc is prolonged, the ECG 
should be manually read to ensure 
accuracy of the reading.  The values 
below refer to manually read ECGs.   
 
 
 
 
QTc  ≥ 480 < 500 msec 
 
 
 
 
 
 
 
 
QTc  ≥ 500 msec 
 
 
 
 
 
 
 
 
 
 
Pazopanib 
 
 
 
 
 
 
 
 
 
 
 
Continue pazopanib; monitor as 
clinically indicated. Consider reducing 
Pazopanib dose to dose level 1 and 
gradually increase as tolerated. 
Recommend discontinuing any other 
QT prolonging agent in the patient’s 
medication list.  
 
 
Interrupt Pazopanib and discontinue any 
other QT prolonging agent in the 
patient’s medication list. Recheck EKG 
in 1 week, If < 500msec, restart 
Pazopanib at dose level 2 with close 
monitoring. If recurrent/ refractory QTc 
> 500msec, discontinue pazopanib and 
continue follow-up per protocol. 
 
Renal and 
urinary 
disorders 
 
 
 
Creatinine 
≥Grade 3 
 
Pazopanib 
 
 
Omit until < Grade 3 then restart at next 
lower dose level.  If ≥ Grade 3 recurs,  
reduce one dose level again until no 
dose can be given (see Section 8.2 
regarding ascorbic acid dose reduction) 

 
26  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
 
 
Proteinuria 
 
UPC <3 
 
 
UPC ≥3 or 24-h urine protein ≥3g 
 
Pazopanib 
 
 
 
 
 
Continue pazopanib at the current dose; 
monitor as clinically indicated 
 
1. Interrupt pazopanib. 
 
2. Weekly UPC or 24-hr urine 
protein monitoring until UPC is <3 
or 24-hr urine protein is <3 grams.  
Then restart pazopanib dose-
reduced by 200 mg. 
 
3.  If UPC ≥3 or 24-h urine protein 
≥3g recurs, repeat steps 1 and 2. 
 
4.  If UPC ≥3 or 24-hr urine protein ≥3 
recurs and the pazopanib dose can no 
longer be reduced, discontinue 
pazopanib and continue follow-up per 
protocol. 

 
27  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Vascular 
disorders 
 
Thromboembolic event  
 
DVT/PE  
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
 
 
Arterial Thrombosis/Ischemia 
Any Grade 
 
Pazopanib 
 
 
 
 
Continue  pazopanib  at the current 
dose; monitor as clinically 
indicated 
 
 
Omit and initiate anticoagulant.  Restart 
at reduced dose if  
• Subject must have been treated at 
desired level of anticoagulation for 
at least 1 week 
• No Grade 3 or 4 or clinically 
significant Grade 2, hemorrhagic 
events have occurred while on 
anticoagulation treatment. 
Note: When treating with warfarin, INR 
S/B monitored within 3 to 5 days after 
any change in pazopanib dosing and 
then at least weekly until INR is stable.  
The dose of warfarin may need to be 
adjusted to maintain the desired level 
of anticoagulation. 
 
Discontinue pazopanib 
 
 
 
Discontinue pazopanib 
Thrombocytopenia: Investigate and 
document underlying cause 
 
Grade 1 or 2 
 
 
Grade 3 or 4 
 
Continue pazopanib with current dose; 
monitor as clinically indicated. 
 
Step 1. Interrupt pazopanib until 
toxicity resolves to ≤ Grade 2. 
Step 2. Restart pazopanib dose-
reduced by 200 mg and monitor as 
clinically indicated.  
If no recovery to ≤ Grade 2 or recurrent 
Grade 3 or 4 thrombocytopenia, 
discontinue Pazopanib and follow-up 
per protocol. 
 

 
28  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Vascular 
disorders 
 
 
 
 
 
 
 
 
Hypertension 
 
(Scenario A) 
 
Asymptomatic and persistentd 
SBP of ≥140 and <160 mmHg, 
or DBP ≥90 and <100 mmHg,  
 
Or 
 
Clinically significant increase 
in DBP of 20 mmHg (but still 
below 110 mmHg). 
 
 
 
 
 
 
Pazopanib 
 
• 
Continue pazopanib 
treatment at the current 
dose  
• 
Adjust current or initiate 
new antihypertensive 
medication 
• 
Titrate antihypertensive 
medication(s) during the 
next 2 weeks as indicated 
to achieve well-controlled 
BP 
• 
If BP is not well controlled 
within 2 weeks, consider 
referral to a specialist and go 
to scenario (B). 
 
(Scenario B) 
 
 
 
Asymptomatic SBP ≥160 
mmHg, or DBP ≥100 mmHg,  
 
Or 
  
Failure to achieve well-controlled 
BP within 2 weeks in Scenario A 
 
 
 
 
 
 
 
 
Pazopanib 
 
• Interrupt  pazopanib  
treatment if clinically 
indicated 
• Adjust current or initiate 
new antihypertensive 
medication(s) 
• Titrate antihypertensive 
medication(s) during the 
next 2 weeks as indicated 
to achieve well-controlled 
BP 
• Once BP is well 
controllede, restart 
pazopanib treatment 
reduced by one dose level 
 

 
29  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
 
 
Symptomaticf hypertension  
 
or  
 
Persistentg SBP ≥160 mmHg, or 
DBP ≥100 mmHg, despite 
antihypertensive medication and 
dose reduction of study treatment 
 
 
 
 
 
 
 
Pazopanib 
 
• 
Interrupt pazopanib treatment 
• 
Adjust current or initiate new 
antihypertensive medication(s) 
• 
Titrate antihypertensive 
medication during the next 2 
weeks as indicated to achieve 
well-controlled BP 
• 
Referral to a specialist for 
further evaluation and follow-
up is recommended 
Once BP is well 
controlled, restart 
pazopanib  treatment 
reduced by one dose 
level  
 
Refractory hypertension 
unresponsive to above 
interventions. 
 
Pazopanib 
 
• 
Permanently discontinue 
pazopanib treatment  
 
• Continue follow-up per 
protocol. 

 
30  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Cardiac 
Disorders 
LVEF-drop (%) or 
CTCAE grade 
 
 
 
 
 
 
 
 
 
 
 
 
Asymptomatic:  Absolute 
decrease of >10% in LVEF 
compared to baseline and 
ejection fraction below the 
institution’s LLN 
 
Or 
 
LVEF drop >15% from baseline 
regardless of whether value is 
below institution’s LLN. 
 
 
 
 
 
Pazopanib 
• 
Interrupt pazopanib study 
treatment and repeat 
ECHO within 2 
weeksb  and  monitor and 
control BP. 
• 
If the LVEF recovers 
within 4 weeks 
(defined as LVEF ≥LLN 
and absolute decrease 
≤10% compared to 
baseline)  
-Restart study 
treatmentf reduced by 
one dose level 
(Contact ACCRU if 
there are any 
questions prior to 
restarting) 
-Repeat ECHO 2 , 4 , 
8 and 12 weeks after 
re-start; monitor BP; 
continue in intervals of 
12 weeks thereafter 
• 
If repeat LVEF does not 
recover within 4 weeks 
-Consult with 
cardiologist 
-Permanently 
discontinue 
pazopanib treatment 
Repeat ECHO after 2, 
4, 8, 12, and 16 weeks 
or until resolution. 
(Contact ACCRU if 
there are any 
questions) 
Symptomaticc:  Grade 3: 
resting LVEF 39-20% or 
>20% absolute reduction from 
baseline 
 
 
 
 
Pazopanib 
 
• 
Permanently discontinue 
pazopanib treatment   
• 
Consult with cardiologist 
• 
Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution 
Symptomaticc   Grade 4: 
resting LVEF <20% 

 
31  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Gastrointestinal 
disorders 
 
GI bleed 
Grade 2 
 
 
 
 
Grade 3 or Grade 4  
 
Pazopanib  
 
Interrupt pazopanib, restart at dose level 
2 when bleeding has resolved and 
gradually titrate up as tolerated.   
 
 
Discontinue Pazopanib 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
 
Pulmonary bleed  
 
Grade 1 
 
 
Pazopanib 
 
 
 
For Grade I hemoptysis, continue 
pazopanib at the current dose; monitor 
as clinically indicated. 
 
Grade 2 
 
Interrupt pazopanib, restart at dose level 
2 when bleeding has resolved and 
gradually titrate up as tolerated.   
 
Grade 3 or 4  
or  
Recurrent ≥ Grade 2 event after 
dose interruption/reduction. 
 
 
Discontinue pazopanib and 
continue with follow-up per 
protocol.  
 
Dermatology/ 
Skin 
Dermatitis  
 
Grade 2 skin changes w/pain, 
limiting ADL’s 
 
 
 
Grade3 severe skin changes w/pain 
Limiting self-care ADL’s 
 
Pazopanib  
 
 
Omit until ≤ Grade 1, then restart at 
next lower dose level. If recurrent, 
reduce by another dose level or 
discontinue 
 
Discontinue pazopanib   

 
32  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Skin and 
subcutaneous 
tissue disorders 
Palmar-plantar Erythrodysesthesia 
Syndrome 
 
Grade 1 
Minimal skin changes or 
dermatitis without pain 
(erythema, oedema, hyperkeratosis) 
 
 
Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily 
living (ADLs) (peeling, blisters, 
oedema, bleed, hyperkeratosis) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3 
Severe skin changes with pain and 
limiting self-care 
 
Pazopanib 
 
 
 
Continue  pazopanib  at present dose 
 
 
 
 
 
1. Hold  pazopanib   
 
2. Treat as clinically appropriate 
 
3. Upon resolution to Level 1 or 
better restart   pazopanib with a 
dose reduction to dose level -1 
(if it was a full dose [800mg]) 
or one dose lower than the 
patient was receiving prior to 
developing the skin changes. 
 
4.  If recurrent consider a further 
dose reduction by 1 dose level 
until dose level -2.  If patient 
has a Grade 2 toxicity on dose 
level -2, then consider stopping 
the drug. 
 
 
Discontinue  pazopanib 
Blood and 
lymphatic 
system disorders 
Anemia 
Pazopanib 
No specific dose reduction rules are 
indicated for anemia unless due to 
hemorrhage or bleeding as noted above. 
All Other 
 
Grade 1 
 
 
Grade 2 or 3, if clinically 
significant 
 
 
 
Grade 4 
Pazopanib  
 
Continue pazopanib; monitor as 
clinically indicated. 
 
Omit until ≤ Grade 1 
Restart pazopanib dose-reduced by 200 
mg (1 dose level) and monitor as 
clinically indicated. 
 
Discontinue Pazopanib and continue 
follow-up per protocol.    
 
 
* 
Located at 
 

 
33  
 
ACCRU-GU-1703 
Amendment 2 
 
 
**  Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
a. AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 
(NCI CTCAE v4) 
b. If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
c. Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary 
congestion and edema. 
d. Hypertension detected in two separate readings during up to three consecutive visits 
e. Well-controlled blood pressure defined as SBP <140 mm Hg and DBP <90 mm Hg in two 
separate readings during up to three consecutive visits. 
f. Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, 
light-headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is 
controlled within the normal range. 
g. Persistent hypertension is defined as asymptomatic hypertension after initially successful anti-
hypertensive intervention. 
 
8.13 
Dose Modifications for Pazopanib at Time of Retreatment 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
Investigations 
 
Platelet count decreased 
 Grade 3 or 4 
 
 
Pazopanib 
 
Hold until ≤ Grade 2 then restart at 
next lower dose level.  If no 
recovery to grade 2, discontinue 
Investigations 
 
Electrocardiogram QT corrected 
interval prolonged ≥ 500msec 
Grade 3 
 
Pazopanib 
 
Discontinue pazopanib 
Renal and 
urinary 
disorders 
Creatinine 
> Grade 3 
 
Pazopanib 
 
 
Hold until < Grade 3 then restart at 
next lower dose level.  If ≥ Grade 
3 recurs, dose reduce again until 
no dose can be given 

 
34  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Vascular 
disorders 
 
Thromboembolic event  
 
DVT/PE  
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
 
Arterial Thrombosis/Ischemia 
Any Grade 
 
Pazopanib 
 
 
Hold and initiate anticoagulant.  
Decrease 1 dose level if  
• 
Subject must have been 
treated at desired level of 
anticoagulation for at least 
1 week 
• 
No Grade 3 or 4 or 
clinically significant 
Grade 2, hemorrhagic 
events have occurred 
while on anticoagulation 
treatment. 
Note: When treating with 
warfarin, INR S/B monitored 
within 3 to 5 days after any 
change in pazopanib dosing and 
then at least weekly until INR is 
stable.  The dose of warfarin may 
need to be adjusted to maintain 
the desired level of 
anticoagulation. 
 
Discontinue pazopanib 
 
 
Discontinue pazopanib 
Vascular 
disorders 
Hypertension 
 
Pazopanib 
 
See table 8.3  
Gastrointestinal 
disorders 
 
GI bleed 
Grade 2 
 
 
 
 
Grade 3 or 4 
 
Pazopanib  
 
Interrupt pazopanib, restart at dose 
level 2 when bleeding has resolved 
and gradually titrate up as 
tolerated.   
 
Discontinue Pazopanib 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
Pulmonary bleed 
Grade 2 
 
 
 
 
Grade 3 or 4 
 
Pazopanib  
 
Interrupt pazopanib, restart at dose 
level 2 when bleeding has resolved 
and gradually titrate up as 
tolerated.   
 
Discontinue Pazopanib 

 
35  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Dermatology/ 
Skin 
 
 
 
 
 
 
 
Dermatitis  
 
Grade 2 skin changes w/pain, limiting 
ADL’s 
 
 
 
Grade3 severe skin changes w/pain 
Limiting self-care ADL’s 
 
Pazopanib  
 
Hold until ≤ 1, then restart at next 
lower dose level.  
 
If recurrent, reduce by another 
dose level or discontinue. 
 
Discontinue pazopanib 
All others 
 
Grade 2 or 3, if clinically significant 
 
 
Grade 4 
 
 
Hold until ≤ Grade 1 
 
 
Discontinue pazopanib 
 
 
* 
Located at 
 
**  Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
 
 
 

 
36  
 
ACCRU-GU-1703 
Amendment 2 
 
 
8.14 
Guidelines for Management of Treatment Emergent Hepatotoxicity 
 
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x ULN 
Continue pazopanib at current dose with full panel LFTsc monitored as 
per protocol. 
(B). ALT >3.0 x ULN to 
≤8.0 x ULN without 
bilirubin elevation (defined 
as total bilirubin0 <2.0 x 
ULN or direct bilirubin 
≤35%) and without 
hypersensitivity symptoms 
(e.g., fever, rash)  
Liver Event Monitoring Criteria: 
(1) Continue pazopanib at current dose levels.  
 (2) Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTsa weekly or more frequently if clinically indicated until 
ALT/AST is reduced to Grade 1. 
(C). ALT >8.0 x ULN 
without bilirubin elevation 
(defined as total bilirubinb 
<2.0 x ULN or direct 
bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, rash) 
1st occurrence – Liver Event Interruption Criteriac: 
(1) Interrupt pazopanib until toxicity resolves to ≤Grade 1 or baseline.   
(2)  Liver imaging and other laboratory investigations should be 
considered as clinically appropriate. 
(3) Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTsa weekly or more frequently if clinically indicated until 
ALT/AST is reduced to Grade 1.   
(4) Re-treatment may be considered if ALL following criteria are met:  
- ALT/AST reduced to Grade 1 
- Total bilirubin <1.5 x ULN or direct bilirubin ≤35% 
- No hypersensitivity signs or symptoms 
- Subject is benefiting from therapy.  
 
Recurrence – Liver Event Stopping Criteriac: 
Discontinue pazopanib permanently and monitor subject closely for 
clinical signs and symptoms; perform full panel LFTs a weekly or more 
frequently if clinically indicated until ALT/AST is reduced to Grade 1.   
 (D). ALT >3.0 x ULN with 
concomitant elevation in 
bilirubin0 (defined as total 
bilirubin ≥2.0 x ULN; with 
direct bilirubin >35%) or 
with hypersensitivity 
symptoms (e.g., fever, rash).  
Liver Event Stopping Criteriac: 
(1) Discontinue pazopanib immediately. 
(2) Perform the following assessments to identify potential co-factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, cytomegalovirus, Epstein-
Barr virus (IgM antibody, heterophile antibody, or monospot testing)  
- Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies. 
- Serum creatinine phosphokinase for possible muscle injury caused LFT 
elevation 
- Liver imaging 
-Consider toxicological blood screen for possible contributing 
chemical/medical entities  
(3) Monitor subject closely for clinical signs and symptoms; record the 
appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever rash or eosinophilia as relevant on the AE report 
form.  Perform full panel LFTsa weekly or more frequently if clinically 
indicated until LFTs are reduced to Grade 1.   

 
37  
 
ACCRU-GU-1703 
Amendment 2 
 
Event 
Dose Modification Algorithms 
For isolated total bilirubin0 
elevation without concurrent 
ALT increases (defined as 
ALT <3 X ULN). 
 
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or 
other signs/symptoms of liver injury) does not require dose 
modification.  Pazopanib inhibits UGT1A1 and OATP1B1, which 
can cause elevation of indirect (unconjugated) bilirubin in the 
absence of liver injury. 
(2)  If bilirubin is >1.5 x ULN in the absence of ALT elevation, 
fractionation of bilirubin elevation should be performed.  If bilirubin 
is >35% direct (conjugated), further evaluation for underlying cause 
of cholestasis should be performed. 
 
a.   Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.  Coagulation tests 
should be performed as clinically indicated. 
b.   Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a 
subject meets the criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported as an 
SAE. 
 
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; LFT liver function tests;; SAE 
serious adverse event; ULN upper limit of normal 
 
 
 
 

 
38  
 
ACCRU-GU-1703 
Amendment 2 
 
8.2   Dose Modifications for IV Ascorbic Acid at Time of Treatment 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise specified  
 
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
DAY OF TREATMENT ADVERSE EVENT 
Renal and Urinary 
disorders 
Renal Function 
Ascorbic Acid 
SEE TABLE IMMEDIATELY 
BELOW(section 8.21) 
General Disorders and 
Administration Site 
Conditions 
Dizziness during Infusion 
Grade 1 (mild) -3 (severe) 
Grade 1 = mild unsteadiness or 
sensation of movement 
Grade 2 = Moderate unsteadiness or 
sensation of movement limiting 
instrumental ADL 
Grade 3 Severe 
 
Ascorbic Acid 
Stop infusion until dizziness resolves 
(about 10-15 min), restart at half 
the infusion rate when dizziness has 
resolved, and gradually increase as 
tolerated. If dizziness re-occurs then 
repeat above instructions.  
 
Respiratory, Thoracic and 
Mediastinal Disorders 
Bronchopulmonary 
hemorrhage 
 
Grade 1  
 
Grade 2-4 
Ascorbic Acid 
 
 
 
No dose adjustment required  
 
Hold until resolution to grade 1 
 
Vascular  
Disorders  
Hypotension  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
 
Hemorrhage (any organ)  
 
Grade 1  
 
Grade 2-4 
 
 
Ascorbic Acid 
 
 
No dosage adjustment required  
 
Cut dose by 50%  
 
Hold until improvement to Grade 3 
 
 
 
 
No dose adjustment required  
 
Hold until resolution to grade 1 
 
  
Gastrointestinal 
Disorders 
Gastrointestinal symptoms 
(Nausea, vomiting, or diarrhea) 
 
Grade 2-3  
 
 
 
 
 
 
Grade 4  
Ascorbic Acid 
Antiemetics and antidiarrheals can be 
used and should be used prior to 
reducing dose. If they are ineffective 
then reduce dose by 50%.   
 
Provision to gradually increase (at next 
infusion day) back to target dose as 
tolerated at treating physician judgment 
 
Hold until resolution to grade 3 or 
below 

 
39  
 
ACCRU-GU-1703 
Amendment 2 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise specified  
 
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Hepatobiliary Disorders  
Hepatobiliary disorders 
Other, specify  
 
Grade 2-3  
 
Grade 4 
 
Ascorbic acid  
 
 
 
No dose adjustment necessary  
 
Cut dose by 50% 
 
* 
Located at 
 
**  Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
 
8.21      Dose modifications for IV Ascorbic Acid based on Renal function  
 
 
Increase from baseline 
serum creatinine 
Creatinine < 2.0 mg/dL 
Creatinine ≥ 2.0 mg/dL 
< 50% 
• 
Continue treatment. 
• 
No dose reduction.  
• 
Hold dose. 
• 
Ensure adequate hydration. 
• 
Resume when creatinine < 2.0 
mg/dL. 
50% (1.5 times) 
• 
Ensure adequate hydration. 
• 
For first occurrence only:  
o Administer 50% of the 
previous dose. 
o Increase the next scheduled 
dose to 75%, then to 100% 
as long as creatinine 
remains < 2 times baseline.   
o Continue at the highest dose 
tolerated. 
60% (1.6 times) 
70% (1.7 times) 
80% (1.8 times) 
90% (1.9 times) 
≥ 100% (≥2 times) 
• 
Hold dose. 
• 
Ensure adequate hydration. 
• 
Resume when creatinine < 2 
times baseline. 
• 
Hold dose. 
• 
Ensure adequate hydration. 
• 
Resume when creatinine < 2.0 
mg/dL and < 2 times baseline. 
 
 
9.0  
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetic’s may be used at the discretion of the attending physician.  
 
9.2 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, 
and/or antiemetics received from the first day of study treatment administration until 30 days 
after the final dose will be recorded in the medical records. 
 

 
40  
 
ACCRU-GU-1703 
Amendment 2 
 
9.3 
Diarrhea: This could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free (maximum 
16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: hydration, 
octreotide, and antidiarrheals.  
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients with severe 
diarrhea or any diarrhea associated with severe nausea or vomiting should be hospitalized for 
intravenous hydration and correction of electrolyte imbalances. 
 
 9.4        Dizziness during infusion: Stop infusion until dizziness resolves (about 10-15 min), restart at half 
the infusion rate when dizziness has resolved, and gradually increase as tolerated. If dizziness re-
occurs then repeat above instructions.  
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware of the 
event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but that 
for a specific protocol are being reported via expedited means in order to facilitate the review of 
safety data (may be requested by the FDA or the sponsor).  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site: 
     
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.   
b. Identify the grade and severity of the event using the CTCAE version 4.0 
c. Determine whether the event is expected or unexpected (see Section 10.2).  

 
41  
 
ACCRU-GU-1703 
Amendment 2 
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
e. Determine whether the event must be reported as an expedited report. If yes, determine the 
timeframe/mechanism (see Section 10.4).  
f. Determine if other reporting is required (see Section 10.5). 
g. Note: All AEs reported via expedited mechanisms must also be reported via the routine 
data reporting mechanisms defined by the protocol (see Sections 10.5 and 18.0). 
 
Each CTCAE term in the current version is a unique representation of a specific event used for 
medical documentation and scientific analysis and is a single MedDRA Lowest Level Term (LLT). 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as serious AE which 
is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study specific 
consent form, package insert (if applicable), and/or the investigator brochure, (if an investigator 
brochure is not required, otherwise described in the general investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 15.0 of the 
protocol, the study specific consent form, package insert (if applicable), or in the investigator 
brochure (or are not listed at the specificity or severity that has been observed); if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs but have not been observed with the drug 
under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical treatment 
suggest there is evidence to indicate a causal relationship between the drug/device and the 
adverse event.  
 
 

 
43  
 
ACCRU-GU-1703 
Amendment 2 
 
3.  Submit MedWatch form 3500A 
 or found on the 
ACCRU web site) along with the MedWatch Fax Cover Sheet (found on the ACCRU web site) to the ACCRU 
SAE Coordinator via fax 
   
 
    4.   The ACCRU SAE Coordinator will forward to 
as appropriate.  The   
ACCRU IND Coordinator will assist the sponsor-investigator in notifying the FDA if required. 
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in general, 
include any incident, experience, or outcome that meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
Some unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with adverse events.  In other cases, unanticipated problems 
place subjects or others at increased risk of harm, but no harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not considered an 
adverse experience for this trial, and if the consent form does not indicate that subjects 
should not get pregnant/impregnate others, then any pregnancy in a subject/patient or a 
male patient’s partner (spontaneously reported) which occurs during the study or within 
120 days of completing the study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required by your 
institutional policies.   
 
10.52 Pregnancy  
 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn infant’s parent 
or legal guardian before any data collection can occur.  A consent form will need to be 
submitted to the IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. In cases where 
the child/fetus experiences a serious adverse event other than fetal death, the child/fetus is 
the patient. 
 
NOTE: When submitting ACCRU Adverse Event Report reports for “Pregnancy”, 
“Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure of the fetus to the 

 
44  
 
ACCRU-GU-1703 
Amendment 2 
 
investigational agent(s) or chemotherapy agent(s) should be documented in the 
“Description of Event” section. Include any available medical documentation.  
 
10.53 Baseline and Adverse Events Evaluations 
 
 
The following pre-treatment symptoms/conditions are to be graded at baseline and adverse 
events are to be graded at each evaluation using CTCAE v4.0 grading. If CTCAE v4.0 
grading is not used, note the grading scale used in the table below 
 
 
System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
General 
Disorders 
Fatigue 
X 
X 
Gastrointestinal 
Disorders 
 
Nausea 
X 
X 
Diarrhea 
# of stools 
X 
Mucositis oral 
X 
X 
Injury, poisoning 
and procedural 
complications 
Vascular access complication 
 
X 
 Infections and 
infestations 
Catheter related infection 
 
X 
Investigations 
 
Blood bilirubin increased 
X 
X 
Aspartate aminotransferase 
increased 
X 
X 
Alanine aminotransferase 
increased 
X 
X 
Creatinine increased 
X 
X 
 
10.54 Case Report Forms - Academic and Community Cancer Research United (ACCRU) 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as applicable)  
 
10.541 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.542 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.543 Grade 5 AEs (Deaths) 
 
10.5431 Any death within 30 days of the patient’s last study treatment or    
procedure regardless of attribution to the study treatment or procedure. 
 
10.5432 Any death more than 30 days after the patient’s last study treatment or 
procedure that is felt to be at least possibly treatment related must also be 
submitted as a Grade 5 AE, with a CTCAE type and attribution assigned. 
 
 

 
45  
 
ACCRU-GU-1703 
Amendment 2 
 
 
10.55   Refer to the instructions in the Case Report Forms (CRF) Packet (or electronic data entry 
screens, as applicable) regarding the submission of late occurring AEs following 
completion of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the table 
regarding measureable disease in Section 11.44, as it pertains to data collection and analysis. 
 
Response and progression will be evaluated in this study using the most recent criteria proposed by the 
revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). [43] Changes in 
the largest diameter (unidimensional measurement) of the tumor lesions and the short axis measurements in 
the case of lymph nodes are used in the RECIST guideline. 
 
 
11.1 
Schedule of Evaluations: For the purposes of this study, patients should be reevaluated every 8 
weeks. In addition to a baseline scan, confirmatory scans should also be obtained 4 weeks 
following initial documentation of objective response. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21  Measurable Disease 
 
11.211 A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT 
component of a PET/CT, or MRI.  
 
11.212 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging. In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
 
11.213 A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm).  
                                                     
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable as well. Tumor lesions in a 
previously irradiated area are not considered measurable disease. 
 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. In addition, lymph nodes that have a short axis <1.0 
cm are considered non- pathological (i.e., normal) and should not be recorded or 
followed. 
 
 

 
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11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:  
 
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
 
• 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients having 
only lesions measuring at least 1 cm to less than 2 cm must use CT imaging for both 
pre- and post-treatment tumor assessments.  
 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation to assess the antitumor effect of a 
treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:  
 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  
 
• 
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. 
The lesions should be measured on the same pulse sequence. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
 
11.33 Measurement at Follow-up Evaluation:  
 
• 
In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks (see Section 
11.44). 
 
• 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain.) 
 
 

 
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11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline. These lesions can be non-nodal or nodal (as defined 
in 11.21), where no more than 2 lesions are from the same organ and no more than 2 
malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.  
 
• 
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion (or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected.  
 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target lesions 
plus the sum of the short axis of all the target lymph nodes will be calculated and 
reported as the baseline sum of dimensions (BSD). The BSD will be used as reference 
to further characterize any objective tumor response in the measurable dimension of the 
disease.  
 
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD). If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm. If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned. If it is the opinion of the radiologist that the 
target lesion or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target lesions or non-
target lymph nodes and should also be recorded at baseline. These lesions and lymph nodes 
should be followed in accord with 11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/PET-CT must be measured on re-evaluation at evaluation times specified 
in Section 11.1. Specifically, a change in objective status to either a PR or CR 
cannot be done without re-measuring target lesions and target lymph nodes.  
 

 
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Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In 
selected circumstances, certain non-target organs may be evaluated less frequently. 
For example, bone scans may need to be repeated only when complete response is 
identified in target disease or when progression in bone is suspected. 
 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have reduction in 
short axis to <1.0 cm. 
 
• Partial Response (PR): 
At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum 
of the short axis of all the target lymph nodes at 
current evaluation) taking as reference the BSD (see 
Section 11.41). 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, which also 
includes any lymph node that was normal at 
baseline (< 1.0 cm short axis) and increased to ≥ 
1.0 cm short axis during follow-up.  
 
b. At least a 20% increase in PBSD (sum of the 
longest diameter for all target lesions plus the 
sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference 
the MSD (Section 11.41). In addition, the PBSD 
must also demonstrate an absolute increase of at 
least 0.5 cm from the MSD.  
 
 
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as 
reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target lesions.  
 
b. Each non-target lymph node must have a 
reduction in short axis to <1.0 cm. 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target lesions or 
non-target lymph nodes. 
 
• Progression (PD): 
At least one of the following must be true: 

 
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12.0 
Descriptive Factors  
 
• 
Nephrectomy (Yes vs. No) 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol up to a maximum of 10 cycles 
or until PD whichever is first.  After 10 cycles of treatment, treatment may be continued off study 
per physician discretion.  Patients who are CR, PR, or SD after 10 cycles will move to Observation 
Phase of the trial (see section 13.2). 
 
13.2      Observation:  
 
 
Patients who complete protocol treatment, or discontinue protocol treatment due to unacceptable 
toxicity or other complicating disease, will be followed every 8 weeks (+/- 7 days) for a maximum 
of 2 years from the registration in the Observation Phase per Section 4.0 of the protocol. 
 
13.3 
Event Monitoring: 
 
 
 
Patients who develop PD, choose alternative therapy, refuse treatment or refuse to be followed in 
observation at any time will go to the Event Monitoring phase and be followed every 6 months (+/-
30 days) for a maximum of 3 years from registration per Section 18.0 of the protocol.  
             Treatment options for these patients are at the discretion of the treating physician. 
                           
13.4 
Patients who develop PD in the CNS only should receive whole brain radiotherapy (WBRT) and 
continue treatment on study after completion of WBRT.  
 
 13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of registration, 
the patient did not satisfy each and every eligibility criteria for study entry. The patient may 
continue treatment off-protocol at the discretion of the physician as long as there are no safety 
concerns, and the patient was properly registered. The patient will go directly to the event-
monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of ineligibility must 
be submitted. Event monitoring will be required per Section 18.0 of the protocol.  
 
• 
If the patient never received treatment, on-study material must be submitted.  On-study 
material and the Off Treatment Form must be submitted. No further data submission is 
necessary.  
13.6 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are severely violated that evaluability for primary end point is questionable. All 
data up until the point of confirmation of a major violation must be submitted. The patient will go 
directly to the event-monitoring phase of the study. The patient may continue treatment off-
protocol at the discretion of the physician as long as there are no safety concerns, and the patient 
was properly registered. Event monitoring will be required per Section 18.0 of the protocol. 
 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given. On-study material and the Off Treatment Form must be submitted. No further 
data submission is necessary. 
 
 

 
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14.0 
Body Fluid Biospecimens: None  
 
 
15.0 
Drug Information 
 
The study drug is IND exempt because:  
 
• The drug product is lawfully marketed in the United States.  
• The investigation is not intended to be reported to FDA as a well-controlled study in support of a 
new indication and there is no intent to use it to support any other significant change in the labeling 
of the drug.  
• In the case of a prescription drug, the investigation is not intended to support a significant change 
in the advertising for the drug.  
• The investigation does not involve a route of administration, dose, patient population, or other 
factor that significantly increases the risk (or decreases the acceptability of the risk) associated with 
the use of the drug product (21 CFR 312.2(b)(1)(iii)).  
• The investigation is conducted in compliance with the requirements of §312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product).  
 
 
15.1  
Pazopanib (Votrient®) 
 
15.11  Background: Tyrosine kinase (multikinase) inhibitor; limits tumor growth via inhibition 
of angiogenesis by inhibiting cell surface vascular endothelial growth factor receptors 
(VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-
alpha and -beta), fibroblast growth factor receptor (FGFR-1 and -3), cytokine receptor 
(cKIT), interleukin-2 receptor inducible T-cell kinase, lymphocyte-specific protein tyrosine 
kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms) 
 
15.12 Formulation:  Commercially available for oral administration as 200 mg tablets.  
 
15.13 Preparation and storage:  Refer to package insert for complete dispensing instructions. 
Store tablets at room temperature between 20ºC and 25ºC (68ºF and 77ºF); excursions 
permitted between 15ºC and 30ºC (59ºF and 86ºF). 
 
15.14 Administration:  Refer to the treatment section for specific administration instructions. 
The manufacturer recommends pazopanib be administered on an empty stomach, 1 hour 
before or 2 hours after a meal. Do not crush tablet (rate of absorption may be increased; 
may affect systemic exposure). 
 
 
15.15 Pharmacokinetic information: 
Absorption and Bioavailability: Pazopanib is absorbed orally with median time to 
achieve peak concentration of 2 to 4 hours after the dose. Median absolute bioavailability 
is 21%.  Systemic exposure to pazopanib is increased when administered with food.  
Administration with a high-fat or low-fat meal results in an approximately 2-fold increase 
in AUC and Cmax.  Pazopanib should be administered at least one hour before or 2 hours 
after a meal.  
Plasma protein binding: 99% 
Half-life elimination: 30.9 hours after administration of a single 800 mg dose 
Time to peak, plasma: 2-4 hours  
Excretion: Primarily via feces with renal elimination accounting for < 4% of the 
administered dose 
Metabolism: In vitro studies demonstrate pazopanib is metabolized by CYP3A4 with a 
minor contribution from CYP1A2 and CYP2C8. 
 

 
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15.16 Potential Drug Interactions:   
Cytochrome P450 Effect: Pazopanib is metabolized principally by CYP3A4 with minor 
contributions from CYP1A2 and CYP3A4.  Therefore, inhibitors and inducers of CYP3A4 
may alter the metabolism of pazopanib.   
 
CYP3A4 Inhibitors and Inducers:  Coadministration of pazopanib with strong inhibitors of 
CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations 
and should be avoided.  Grapefruit juice should be avoided as it inhibits CYP3A4 activity 
and may also increase plasma concentrations of pazopanib. CYP3A4 inducers such as 
rifampin may decrease plasma pazopanib concentrations. Pazopanib should not be used if 
chronic use of strong CYP3A4 inducers cannot be avoided.   
 
Transporter Inhibitors:  In vitro studies suggested that pazopanib is a substrate of P-
glycoprotein and breast cancer resistance protein (BCRP).  Therefore, absorption and 
subsequent elimination of pazopanib may be influence by products that affect P-
glycoprotein and BCRP.  Concomitant treatment with strong inhibitors of P-glycoprotein 
and BCRP should be avoided.   
 
CYP Substrates:  Results from drug-drug interaction trials conducted in cancer patients 
suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but 
had no effect on CYP1A2, CYP2C9, or CYP2C19.   Concomitant use of pazopanib with 
agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or 
CYP2C8 is not recommended.  Coadministration may result in inhibition of the 
metabolism of these products and create the potential for serious adverse events. 
 
Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations.  
If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing 
guidelines for pazopanib or consider discontinuing simvastatin.  Insufficient data are 
available to assess the risk of concomitant administration of alternative statins and 
pazopanib. 
 
Concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor, 
decreased the exposure of pazopanib by approximately 40% (AUC and Cmax).  
Concomitant use of pazopanib with drugs that raise gastric pH should be avoided.  If such 
drugs are needed, short acting antacids should be considered in place of proton pump 
inhibitors and H2 receptor antagonists.  Separate antacid and pazopanib dosing by several 
hours to avoid a reduction in pazopanib exposure.   
 
Pazopanib should be used with caution in patients with a history of QT interval 
prolongation, in patients taking antiarrhythmics or other medications that may 
prolong QT interval, and those with relevant pre-existing cardiac disease.  Baseline 
and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g. 
calcium, magnesium, potassium) within the normal range should be performed. 
 
 
15.17 Known potential toxicities: 
 
 
Consult the package insert for the most current and complete information. Important 
Safety Information including Boxed WARNING: Severe and fatal hepatotoxicity, 
manifested as increases in serum transaminases (ALT, AST) and bilirubin, has been 
observed in clinical trials.  Monitor hepatic function and interrupt, reduce or 
discontinue dosing as recommended. 
 
 
 
Common known potential toxicities, > 10%:   
Cardiovascular: Hypertension, bradycardia, peripheral edema, cardiac insufficiency  
Central nervous system: Fatigue, headache, dizziness  
Dermatologic: Hair discoloration, exfoliative dermatitis, alopecia, dermatological disease, 

 
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hypopigmentation, palmar-plantar erythrodysesthesia  
Endocrine & metabolic: Weight loss, hyperglycemia, increased thyroid-stimulating 
hormone (TSH), decreased serum albumin, hypophosphatemia, hyponatremia, 
hypomagnesemia, hypoglycemia, hyperkalemia 
Gastrointestinal:  Diarrhea, nausea, decreased appetite, anorexia, vomiting, dysgeusia, 
increased serum lipase, gastrointestinal pain, abdominal pain, mucositis, stomatitis 
Hematologic & oncologic:  Leukopenia, lymphocytopenia, thrombocytopenia, neutropenia, 
hemorrhage 
 
Hepatic:  Increased serum AST, increased serum ALT, increased serum bilirubin, 
decreased serum albumin, increased serum alkaline phosphatase 
Neuromuscular & skeletal: Musculoskeletal pain, myalgia, weakness 
Respiratory:  Dyspnea, cough 
Miscellaneous: Tumor pain 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Chest pain, left ventricular systolic dysfunction, venous thrombosis, 
ischemia, myocardial infarction, prolonged QT interval on ECG, facial edema, transient 
ischemic attacks 
Central nervous system:  Insomnia, voice disorder, chills 
Dermatologic: Skin rash, skin depigmentation, xeroderma, nail disease 
Endocrine & metabolic:  Hypothyroidism 
Gastrointestinal:  Dyspepsia, anal hemorrhage, gastrointestinal fistula, gastrointestinal 
perforation 
Hematologic & oncologic:  Oral hemorrhage, rectal hemorrhage 
Ophthalmic:  Blurred vision 
Renal: Proteinuria, hematuria 
Respiratory: Epistaxis, pneumothorax, hemoptysis 
 
Frequently not defined: 
Cardiovascular:  Decreased left ventricular ejection fraction, hypertensive crisis 
Central nervous system:  Reversible posterior leukoencephalopathy syndrome 
Hematologic & oncologic:  Hemolytic-uremic syndrome, neutropenic infection, thrombotic 
thrombocytopenic purpura 
Hepatic:  Hepatotoxicity, sever hepatotoxicity 
Infection:  Serious infection 
Neuromuscular & skeletal:  Arthralgia, muscle spasm 
 
Rare, less than 1% (limited to important or life-threatening): 
Cardiac disease, cerebral hemorrhage, cerebrovascular accident, congestive heart failure, 
interstitial pneumonitis, nephrotic syndrome, pancreatitis, retinal changes (tear), retinal 
detachment, torsade de pointes 
 
15.18 Drug procurement:  Commercial supplies.  Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler. 
 
15.19 Nursing Guidelines:  
 
15.191 Pazopanib should be taken without food (1 hour before or 2 hours after a meal). 
Should be taken whole with water and not broken or crushed. If a dose is missed, 
do not take if it is less than 12 hours until the next dose. 
 
 
 
 

 
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15.192 There are numerous drug to drug interactions between pazopanib and other agents 
metabolized through the P450 system.  Assess patient’s concomitant medications, 
including OTC and herbal products.  Refer to appendix for medications that should 
be avoided or used concomitantly with caution. 
 
15.193  Hypertension is a commonly reported side effect. Monitor blood pressure closely 
per study guidelines. Administer antihypertensives as ordered by MD. 
 
15.194 Inform patient of possible changes in hair color. 
 
15.195 Gastrointestinal side effects are common (diarrhea, nausea, vomiting, loss of 
appetite). Treat symptomatically and assess for effectiveness. 
 
15.196  Due to the similarity in nature of this agent to other VEGF inhibitors 
(bevacizumab, VEGF-trap, etc.) monitor for signs of bleeding, thrombosis and PE. 
Instruct patient to report any calf tenderness, shortness of breath, chest pain or 
bleeding immediately. 
 
15.197  Cytopenias are common. Monitor CBC w/diff and instruct patient to report any 
unusual bruising or bleeding and/or signs of infection to study team. 
 
15.198  Monitor LFT’s. Patients who have AST/ALT levels > 3x ULN and concurrent 
bilirubin >2X ULN should permanently discontinue pazopanib. Patients with 
AST/ALT levels as above and mild hyperbilirubinemia (with suspected or known 
Gibert’s syndrome) should be monitored weekly while continuing pazopanib. 
 
15.199aCardiac side effects (CHF, MI, chest pain, etc).  While rare can be serious and life 
threatening. Instruct patient to report any cardiac symptoms to study team 
immediately. 
 
15.199bRPLS, CVA, and TIA are uncommon, but are life threatening. Instruct patient to 
report any neurological symptoms to the study team immediately.  
 
15.2 
Ascorbic Acid (Vitamin C, ASCOR®)  
 
15.21  Background:  Ascorbic acid (vitamin C), a water-soluble vitamin, is an essential 
coenzyme for collagen formation, tissue repair and synthesis of lipids and proteins.  It acts 
both as a reducing agent and as an antioxidant and is necessary for many physiologic 
functions such as metabolism of iron and folic acid, resistance to infection, and 
preservation of blood vessel integrity. 
 
15.22 Formulation: ASCOR® (ascorbic acid injection) 25,000 mg/50 mL (500 mg/mL) for 
intravenous use is a colorless to pale yellow, preservative-free, hypertonic, sterile, non-
pyrogenic solution of ascorbic acid. [49] ASCOR must be diluted with an appropriate 
infusion solution (e.g. 5% Dextrose Injection, USP, Sterile Water for Injection, USP).  
Each ASCOR, 50 mL, Pharmacy Bulk Package vial contains 25,000 mg ascorbic acid, 
equivalent to 28,125 mg sodium ascorbate.  Each mL of ASCOR contains 500 mg of 
ascorbic acid (equivalent to 562.5 mg of sodium ascorbate which amounts to 65 mg 
sodium/mL of ASCOR), 0.25 mg of edetate disodium, and water for injection. Sodium 
hydroxide and sodium bicarbonate are added for pH adjustment (pH range 5.6 to 6.6). It 
contains no bacteriostatic or antimicrobial agent. 
 
 

 
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15.23 Preparation and storage:   
Penetrate each PBP vial closure only one time with a suitable sterile transfer 
device or dispensing set that allows measured dispensing of the contents. Given 
that pressure may develop within the vial during storage, exercise caution when 
withdrawing contents from the vial.  Once the closure system has been penetrated, 
complete all dispensing from the PBP vial within 4 hours. Each dose must be 
used immediately. Discard unused portion.  
 
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F).  Protect vials from light and 
product has an expiration of 24 hours at room temperature.  This product contains no 
preservative. 
 
15.24 Administration:   Do not administer ASCOR as an undiluted intravenous injection.  
             Administer 750mg – 1000 mg/minute as outlined in Section 7.1. 
Start infusion rate at 0.75g/minute. If no dizziness after 15 minutes the rate can be 
increased to 1 g/min. Infusion times are approx. (±15 minutes) and may need to be adjusted 
based on patient tolerability. The maximum allowed dose is 100 g per infusion. 
 
 
15.25 Pharmacokinetic information: 
 
Distribution:  Ascorbic acid is distributed widely in the body, with large 
concentrations found in the liver, leukocytes, platelets, glandular tissues, and lens of 
the eye. Based on data from oral exposure, ascorbic acid is known to be distributed 
into breast milk and crosses the placental barrier. 
Metabolism:  A major route of metabolism of ascorbic acid involves its conversion 
to urinary oxalate, presumably through intermediate formation of its oxidized 
product, hehydroascorbic acid. 
 
Elimination:  When the body is saturated with ascorbic acid, the plasma concentration will 
be about the same as that of the renal threshold; if further amounts are then administered, 
most of it is excreted in the urine. When body tissues are not saturated and plasma 
concentration is low, administration of ascorbic acid results in little or no renal excretion. 
The mean±SD (N=3) half-life observed in the single dose PK study as described above, 
was 7.4±1.4 h. 
 
Excretion:  
There is a renal threshold for ascorbic acid (Vitamin C); the vitamin is excreted by the 
kidney in large amounts only when the plasma concentration exceeds this threshold, which 
is approximately 1.4 mg/100 mL. 
 
 

 
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15.26 Potential Drug Interactions: 
 
 
Antibiotics:  Ascorbic acid may decrease activities of erythromycin, kanamycin, 
streptomycin, doxycycline, and lincomycin. Bleomycin is inactivated in vitro by 
ascorbic acid. If the antibiotic efficacy is suspected to be decreased by concomitant 
administration of ASCOR, discontinue ASCOR administration. 
 
 
Amphetamine & Other Drugs Affected by Urine Acidification:  Ascorbic acid 
may acidify the urine and lower serum concentrations of amphetamine by increasing 
renal excretion (as reflected by changes in amphetamine urine recovery rates). In 
case of decreased amphetamine efficacy discontinue ASCOR administration. 
Standard monitoring of therapy is warranted. 
 
In addition, acidification of urine by ascorbic acid will alter the excretion of certain 
drugs affected by the pH of the urine (e.g. fluphenazine) when administered 
concurrently. It has been reported that concurrent administration of ascorbic acid 
and fluphenazine has resulted in decreased fluphenazine plasma concentrations. 
Standard monitoring of therapy is warranted. 
 
 
 
Warfarin:  Limited case reports have suggested interference of ascorbic acid with 
the anticoagulation effects of warfarin, however, patients on warfarin therapy treated 
with ascorbic acid doses up to 1000 mg/day (5 times the largest recommended single 
dose) for 2 weeks (twice the maximum recommended duration), no effect was 
observed. Standard monitoring for anti-coagulation therapy should continue during 
ascorbic acid treatment, as per standard of care. 
 
 
Laboratory Test Interference:  Because ascorbic acid is a strong reducing agent, it 
can interfere with numerous laboratory tests based on oxidation-reduction reactions 
(e.g. glucose, nitrite and bilirubin levels, leukocyte count, etc.). Chemical detecting 
methods based on colorimetric reactions are generally those tests affected. Ascorbic 
acid may lead to inaccurate results (false negatives) obtained for checking blood or 
urinary glucose levels, nitrite, bilirubin, and leukocytes if tested during or within 24 
hours after infusion. 
 
15.27 Known potential toxicities: 
 
Most common adverse reactions are pain and swelling at the site of infusion. 
 
Patients with glucose-6-phosphate dehydrogenase deficiency are at risk of severe 
hemolysis; a reduced dose is recommended. 
 
Hot flashes, headache, fatigue, insomnia, stomach cramp, nausea and vomiting.  
Allergy to ascorbic acid is extremely rare. Four cases of respiratory and cutaneous allergies 
to ascorbic acid have been documented.  
Too rapid intravenous injection can cause temporary dizziness or faintness.  
Acidification of urine by large doses of ascorbic acid might cause precipitation of urate, 
oxalate or cystine stones or drugs in the urinary tract, especially since some ascorbate is 
metabolized to oxalate. Some patients with pre-existing renal disease have been reported to 
develop renal failure following treatment with high doses of ascorbic acid.  
High dosage of ascorbic acid may cause diarrhea.  
Deep-vein thrombosis has been reported after large doses of ascorbic acid.  
Rarely, decreased blood pH leading to sickle-cell crisis has been reported in patients with 
sickle cell disease.  
At doses of greater than 600 mg, ascorbic acid has been reported to have a diuretic action.  
High doses can increase serum cholesterol in atherosclerotic patients.  
 
 

 
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16.11 Primary Endpoint:  
 
The primary endpoint of this trial is the Treatment Failure-Free rate at 40 week 
(TFF40). Treatment failure is defined as any of the following: radiographic disease 
progression, off-protocol treatment due to adverse event, initiation of alternative 
therapy (except metastatectomy post clinical benefit (CR, PR, or SD per RECIST 1.1) 
to treatment), and death due to any cause.  Treatment failure-free rate at 40 weeks is 
defined as the proportion of evaluable patients who are not treatment failure at 40 
weeks post randomization. All patients meeting the eligibility criteria who have 
signed a consent form and have received any protocol treatment will be considered 
evaluable. All eligible patients will be followed for disease evaluation until PD or a 
maximum of 2 years post-randomization then go to event monitoring for a maximum 
of 3 years post-randomization. 
 
16.2  
Statistical Design 
 
16.21 Sample Size and Power: 
 
Based on a study conducted by Motzer et. al, the median duration of pazopanib 
treatment was 8 month which is approximately equal to a TFF40 rate of 45%. A total of 
82 eligible patients (41 in the IV ascorbic acid plus Pazopanib arm and 41 in the 
Pazopanib only arm) will provide 81% power to detect a 19% increase of TFF40 from 
45% (in Pazopanib only arm) to 64% (in the IV ascorbic acid plus Pazopanib arm) 
assuming a one-sided type I error rate of 0.19 (EAST 6.4). We anticipate accruing an 
additional 9 patients to account for ineligibility, cancellations, and major violation for a 
maximum sample size of 91 patients. 
 
 
16.22  Accrual Time and Study Duration: 
 
The anticipated accrual rate is approximately 5 patients per month.  Therefore, the 
accrual period for this randomized phase II study is expected to be 18.2. The final 
analysis can begin approximately 27.7 months after the trial is activated, i.e. as soon as 
the last patient has been observed for 40 weeks. 
 
 
16.23 Operating Characteristics: 
 
This randomized phase II design has a significance level of 0.19 when the true success 
proportion is 45%, and a power of 81% for detecting a true success proportion of 64%, 
assuming that the number of successes is binomially distributed. The probability of 
declaring that this regimen warrants further study (i.e. statistical power) under various 
success proportions can be tabulated as a function of the true success proportion as 
follows: 
 
True TFF40 rate † 
%‡ of times that 
Pazopanib+IV ascorbic acid 
is superior at the final 
analysis 
Pazopanib only 
Pazopanib+IV ascorbic 
acid 
45% 
45% 
18.34 
45% 
55% 
47.93 
45% 
64% 
79.45 
‡ Proportions are based on 10,000 replicates in the simulation study 
 

 
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16.3  
Analysis Plan 
 
Efficacy analysis will be based on evaluable patients where evaluable patients are defined as 
those who are eligible, consented, and received any protocol treatment. 
 
The primary efficacy analysis will be performed at the time at which all patients have been 
followed at least 40 weeks. The point estimate and confidence intervals of TTF40 will be 
calculated according to the approach of Duffy and Santner (1987) for each arm.  TTF40 rate will be 
compared across arm using normal approximation with un-pooled variance.  At the final analysis, 
if the p-value for comparison across arm is ≤ 0.19, we will reject the null hypothesis and conclude 
that the pazopanib+IV ascorbic acid is promising.  Otherwise, the alternative hypothesis is rejected 
in favor of concluding that IV ascorbic acid plus Pazopanib offers no benefit relative to Pazopanib 
only arm.  
A planned sub analysis will compare primary and secondary endpoints for patients with prior 
immunotherapy to those with no prior systemic therapy at the time of study entry. 
 
16.31 Over Accrual: If more than the target number of patients are accrued, the additional 
patients will be used to evaluate the stopping rule or used in any decision making 
processes and they will be included in final point estimates and confidence intervals. 
 
16.32  Definitions and Analyses of Secondary Endpoints  
16.321  Overall Survival 
 
Survival time is defined as the time from randomization to death due to any 
cause. Patients who are alive will be censored for death at the time of last 
known alive.  All patients meeting the eligibility criteria that have signed a 
consent form and begun treatment will be considered evaluable for estimation 
of the survival distribution. The distribution of survival time will be estimated 
using the method of Kaplan-Meier and be compared using log rank tests. 
 
16.322 Progression Free Survival  
 
Progression Free Survival is defined as the time from start of study therapy to 
documentation of disease progression or death, whichever comes first. 
Patients who are still alive and have not progressed will be censored for 
progression at the time of the last tumor assessment. All patients meeting the 
eligibility criteria that have signed a consent form and begun treatment will be 
considered evaluable for estimation of the survival distribution. The 
progression free survival distribution will be estimated using the Kaplan-
Meier method. 
 
16.323 Overall Response Rate 
 
 
 
A tumor response is defined to be a CR or PR noted as the objective response 
(according to RECIST v. 1.1) All patients meeting the eligibility criteria who 
have signed a consent form and have begun treatment will be evaluable for 
response. The best objective response rates between the two arms will be 
compared using a Chi-Square test. 
 
16.324 Duration of time on pazopanib  
 
 
Duration of time on pazopanib is defined as the time from initial dose of 

 
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pazopanib until the date the patient is considered off-treatment for pazopanib 
or death, whichever comes first. Only patients received at least 1 dose of 
pazopanib will be considered evaluable for this analysis. The time on 
pazopanib will be described using descriptive statistics.   
 
16.325 Adverse events:  
 
 
As per NCI CTCAE version 4.0,the term toxicity is defined as adverse events 
that are classified as either “possibly,” “probably,” or “definitely related” to 
study treatment.  The maximum grade for each type of toxicity will be 
recorded for each patient, and frequency tables will be reviewed to determine 
toxicity patterns within patient groups. In addition, we will review all adverse 
event data that is graded as 3, 4, or 5 and classified as either “unrelated” or 
“unlikely to be related” to study treatment in the event of an actual 
relationship developing. 
 
 
 
Adverse events and toxicities will be evaluated using all patients who have 
received any study treatment as well as summarizing those who have been 
included in the efficacy analyses. The overall adverse event rates for grade 3 
or higher adverse events will be compared using Chi-Square tests between the 
2 treatment arms. 
 
16.33  Analyses of Correlative Research  
 
For each correlative research aim, the biomarker of interest (e.g. 5mC, 5hmC, etc) will 
be evaluated per section 17.42.  The biomarker values will be summarized graphically 
and descriptively.  The prognostic and predictive effect of each biomarker will be 
evaluated separately. 
 
 
5hmC specific analysis plan 
Hypothesis: The improvement of the primary endpoint due to the addition of ascorbic 
acid to pazopanib in patients with low 5hmC intensity is more than that of patients with 
high 5hmC intensity. 
 
Analysis plan: For each patient, the intensity of 5hmC will be determined by IHC and 
categorized to one of the following category: absent, mild, moderate, and marked.  For 
the purpose of this analysis, patients will be separated into 2 5hmC groups, high 
intensity (defined as moderate or marked in IHC read) vs. low intensity (defined as 
absent or mild in IHC read).  The treatment failure-free rate at 40 week (TFF40) and 
corresponding confidence interval will be estimated for Arm A and B patients with low 
intensity and high intensity separately.  Logistic regression for TFF40 will be carried 
out to determine the likelihood of TFF40 for Arm A vs. B in different 5hmC intensity 
groups by incorporating the interaction term between treatment arms and 5hmC 
intensity (low vs. high).  The interaction term will be tested by likelihood ratio test to 
determine whether the differential treatment effect is statistically significant across 
5hmC intensity groups (low vs. high).  The p-value < 0.1 will be considered as 
statically significant for the test of interaction term. 
 
 
16.4  
Data & Safety Monitoring: 
 
16.41 The study chair(s) and the study statistician will review the study at least twice a year to 
identify accrual, adverse event, and any endpoint problems that might be developing. 
The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) is 
responsible for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 

 
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16.42  Adverse Event Stopping Rules:  
 
 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in the 
event of either (1) the study re-opening to accrual or (2) at any time during the conduct 
of the trial and in consideration of newly acquired information regarding the adverse 
event profile of the treatment(s) under investigation. The study team may choose to 
suspend accrual because of unexpected adverse event profiles that have not crossed the 
specified rule below. 
 
 
Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (i.e., an adverse event with attribute 
specified as "possible", "probable", or "definite") that satisfy any of the following criteria 
for each arm separately: 
 
• If at any time, 4 of the initial 10 treated patients or 40% or more of all patients (i.e. 
when accrual is greater than 10 patients) have experienced a grade 4 adverse event  
• If at any time, 2 patients have experienced a grade 5 adverse event (not due to 
progressive disease). 
 
            16.5       Results Reporting on ClinicalTrials.gov  
 
At study activation, this study will have been registered within the “ClincialTrials.gov” 
website. The Primary and Secondary Endpoints (i.e., “Outcome Measures”) along with 
other required information for this study will be reported on ClinicalTrials.gov.  
 
• 
For purposes of timing of the Results Reporting, the initial estimated completion 
date for the Primary Endpoint of this study is 27 months after the study opens to 
accrual.  
 
• 
The definition of “Primary Endpoint Completion Date” (PECD) for this study is 
the time the last patient registered has been followed for at least 40 weeks. 
 
 

 
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17.0  
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen Submission  
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
Type of tissue 
biospecimen 
to submit 
Mandatory or 
optional* 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for 
biospecimen 
submission 
Formalin-fixed 
paraffin-
embedded 
(FFPE) tissue 
blocks with 
corresponding 
H&E (OR 10 
unstained 
slides with 1 
corresponding 
H&E) from 
primary tumor 
Mandatory 
≤ 30 days after 
registration 
Correlative studies (Section 
17.4.2) 
Section 17.2 
 
*Receipt of archival tumor tissue is not required for study registration and initiation of therapy. However, it 
is strongly recommended to receive the required tissue, if available, within 30 days from registration. 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides  
 
17.21 In patients with prior surgical resection of the primary tumor or surgical resection of a 
metastasis, submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block with 
largest amount of tumor. In the case of a biopsy specimen from a metastatic tumor or 
unresectable primary tumor, the tissue block with the largest amount of tumor should be 
submitted.   In patients with surgical resection of the primary tumor, and material from a 
metastasis, a block from each specimen should be submitted. 
 
17.22 The FFPE tissue block is preferred; however, if an institution is unable to provide a 
tissue block, cut 10 five-micron sections and mount on charged glass slides. Label the 
slides with ACCRU patient ID number, accession number, and order of sections. 
H&E stain the first cut slide (i.e. slide labeled 1). These H&E slides will be reviewed 
centrally under the research base’s protocol for assessing tissue quality. The remaining 
unstained slides will be processed as described in 17.4.2. For needle biopsy specimens, 
multiple sections should be mounted onto each slide to ensure that an adequate amount of 
tumor tissue is available. Do not bake or place covers slips on the slides. Do not place 
sticky labels on slides. 
 
17.23 The following materials below are mandatory (unless indicated otherwise) and required for 
shipment: 
 
• 
Paraffin embedded tissue blocks with corresponding H&E slide OR 10 unstained slides 
with one corresponding H&E s.  
• 
Specimen Submission: Tissue (Baseline) Form 
• 
Surgical Pathology Report 
Pathology/Operative Report (optional).  
 
Note: Please include the ACCRU patient ID number on all materials listed above. 
 

 
64  
 
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17.425 Immune mechanism:   PDL1 IHC on pre- and treatment biopsy on 10 patients in 
both arms.  
 
17.43 At the completion of the study, any unused/remaining material will be stored in the 
ACCRU Central Operations 
 for future research 
according to the patient consent permission (see Section 6.15). Potential future research 
may include IHC analyses to analyze predictive biomarkers, changes in expression pattern 
with therapy, and correlation with response and/or adverse events. When a protocol is 
developed, it will be presented for IRB review and approval. 
 
17.44 Banking of tumor tissue, according to the patient consent permission (see Section 6.15), is 
for future research.(This collection is part of a general strategy of investigation for 
ACCRU studies). 
 
 
17.45 The institutional pathologist will be notified by the Pathology Coordinator if the block may 
be depleted. 
 
17.46 Blocks requested to accommodate individual patient management will be returned 
promptly upon request. 
 
17.47 Return of Genetic Testing Research Results: No genetic specimens will be collected from 
tissue biospecimens for this study. If future genetic testing is being requested for stored 
tissue, patient reconsent is required. 
 
 

 
65  
 
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18.0 
Records and Data Collection Procedures 
 
All data must be entered by Remote Date Entry (RDE) and completed by qualified and authorized 
personnel. Access the RAVE system through the iMedidata portal at 
 All data 
on the CRF must reflect the corresponding source document. Please refer to the ACCRU website for 
instructions
.  
 
 
18.1 
Submission Timetables 
 
 
 
 Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Institutional Contacts 
 
≤ 2 weeks after registration 
On-Study Form 
Adverse Events: Baseline  
On-Study: Prior Radiation1 
RECIST Measurements: Baseline 
ACCRU Deviation Form 
Supporting Documentation: Baseline 
Laboratory Tests and Results: Baseline 
Specimen Submission: Tissue (Baseline)2 
Patient Status: Baseline 
OP and Path Reports (see Section 17.0)3 
Off Treatment 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
1. Submit only if applicable. 
2. ≤ 30 days 
3. Attach an electronic copy in RAVE on the Supporting Documentation Form. This is in addition to 
the pathology material requirements for tissue submission (Section 17.0). NOTE: All reports 
must be de-identified, and labeled with study number, ACCRU patient ID number, and 
initials. 
 
 
 
 
 

 
66  
 
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Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
 
Observation 
 
Treatment (Intervention) Form 
X1 
X 
 
Treatment (Intervention):Dose modifications, 
Omissions, and Delays2 
X2 
X2 
 
Adverse Events: Solicited 
X 
X 
 
Adverse Events: Other2 
X2 
X2 
 
RECIST Measurements 
X 
X 
X 
Supporting Documentation2 
X2 
X1 
 
Laboratory Tests and Results 
X 
X 
X 
Patient Status: Treatment (Intervention) 
X 
X 
 
Off Treatment 
 
X 
 
Patient Status: Clinical Follow-
up/Observation 
 
 
X 
Ascorbic Acid and Pazopanib in Off Study 
Setting 
 
 
X2 
Adverse Event: Late2 
 
 
X2 
Consent Withdrawal2 
X2 
X2 
X2 
Consent Withdrawal: Specimen Only2 
X2 
X2 
X2 
Consent Withdrawal: Clinical Follow-Up 
Only2 
X2 
X2 
X2 
Consent Withdrawal: All Follow-Up2 
X2 
X2 
X2 
ACCRU Deviation Form2 
X2 
X2 
X2 
 
1. Attach a copy of documentation of response or progression in RAVE on the Supporting 
Documentation form if disease is evaluated. NOTE: All reports must be de-identified, and labeled 
with study number, ACCRU patient ID number, and initials. 
2. Submit only if applicable. 
 
 
 

 
67  
 
ACCRU-GU-1703 
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Follow-up Material(s)  
CRF 
Event Monitoring Phase/Survival Follow-Up1 
q. 6 
months 
until PD2 
At 
PD2 
After 
PD q. 
6 mos. 
Death 
At Each Event 
Occurrence 
Patient Status: Survival and 
Disease Status  Follow-
up/Event Monitoring 
X 
X 
X 
X 
 
Supporting Documentation2 
 
X 
 
 
 
Non-Protocol Treatment3 
X 
 
X 
 
 
Adverse Events: Late3 
X 
 
X 
 
 
Consent Withdrawal (choose 
appropriate form)3 
• 
Consent 
Withdrawal: 
Specimen Only 
• 
Consent 
Withdrawal: Clinical 
Follow-Up Only 
• 
Consent 
Withdrawal: All 
Follow-up 
X 
 
X 
 
 
Ascorbic Acid and 
Pazopanib in Off Study 
Setting 
 
 
 
 
X 
Lost to Follow-up3 
X 
 
 X 
 
 
ACCRU Deviation Form3 
 
 
 
 
X 
Notice of New Primary3 
 
 
 
 
X 
1. 
Patients are followed in Event Monitoring for a maximum of 3 years from registration. 
2. 
Attach a copy in RAVE for documentation of progression on the Supporting 
Documentation Form. NOTE: All reports must be de-identified, and labeled with study 
number, ACCRU patient ID number, and initials. 
3. 
Submit only if applicable.  
 
19.0 
Budget 
 
19.1 
Costs charged to patient: Each site should review the test schedule (Section 4.0) taking into account 
local and regional coverage policies to determine which items are standard of care and which are 
research at their site. Refer to the payment synopsis for funding provided per accrual for covering 
study costs, as well as any additional invoiceables that may be allowed.  
 
19.2 
Tests to be research funded:  Mandatory tissue collection and analysis, and G6PD (Glucose-6-
phosphate dehydrogenase) test.  
              
19.3 
Other budget concerns: ASCOR® is provided free of charge to patients while they are participating 
on this study. 
 
 
 
 

 
68  
 
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20.0 
References 
 
1. 
Creagan, E.T., et al., Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with 
advanced cancer. A controlled trial. N Engl J Med, 1979. 301(13): p. 687-90. 
2. 
Moertel, C.G., et al., High-dose vitamin C versus placebo in the treatment of patients with advanced cancer 
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3. 
Chen, Q., et al., Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-
drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A, 2005. 102(38): p. 13604-9. 
4. 
Chen, Q., et al., Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and 
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5. 
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18. 
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Strategies. Journal of Cancer Therapy. 6: p. 511-521. 
 
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with advanced cancer: a phase I-II clinical trial. PLoS One, 2015. 10(4): p. e0120228. 
 

 
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36. 
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patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological 
cohort study in Germany. In Vivo, 2011. 25(6): p. 983-90. 
 
37. 
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38. 
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P R Health Sci J, 2005. 24(4): p. 269-76. 
 
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erlotinib in patients with metastatic pancreatic cancer. PLoS One, 2012. 7(1): p. e29794. 
 
40. 
Chen, Q., et al., Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive 
tumor xenografts in mice. Proc Natl Acad Sci U S A, 2008. 105(32): p. 11105-9. 
 
41. 
Du, J., et al., Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res, 2010. 
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47.        Pocock SJ, Simon R.  Sequential Treatment Assignment with Balancing for Prognostic Factors in  the 
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48.        CredibleMeds Flitered QTDrug List; http://www.torsades.org. Accessed 10/06/17 
 
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50.  
Motzer RJ et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.  N Engl 
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Rini BI et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.  N Engl J 
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