Conditions: Glioblastoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
Dual center, single arm, two-stage, non-blinded, prospective study of combination therapy bevacizumab at 10mg/kg and TH-302 at 670mg/m2 every 2 weeks (6 week cycle) until disease progression.

Detailed description:

Arms:
arm 1: Patients will be treated with combination of bevacizumab and TH-302.

Interventions: intervention 1: Bevacizumab intervention 2: TH-302
Intervention descriptions: intervention 1: 10mg/kg intervention 2: 670mg/m2

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Official Study Title: A Phase 2, Investigator Initiated Study to Determine the 
Safety and Efficacy of TH-302 in Combination with Bevacizumab for Glioblastoma 
Following Bevacizumab Failure (CTRC# 12-0105) 
 
NCT number: NCT02342379 
 
IRB Approval Date: 04/04/17 
 
Unique Protocol ID: CTRC 12-0105 
 
 


 
 
A Phase 2, Investigator Initiated Study to Determine the Safety and Efficacy of TH-302 in 
Combination with Bevacizumab for Glioblastoma Following Bevacizumab Failure 
 
 
Study Centers: 
Cancer Therapy and Research Center at University of Texas 
Health Science Center at San Antonio (CTRC at UTHSCSA) 
Institute for Drug Development [Coordinating Site] 
7979 Wurzbach Rd., 4th Floor Zeller Building 
San Antonio, TX 78229 
 
The Center for Neuro-Oncology 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215-5450 
 
Massachusetts General Hospital 
55 Fruit St., Yawkey 9E 
Boston, MA 02114 
 
Principal Investigators: 
Andrew Brenner, MD, PhD 
CTRC at UTHSCSA 
Institute for Drug Development 
 
Eudocia Quant Lee, MD 
Dana-Farber Cancer Institute 
 
Elizabeth Gerstner, MD 
Massachusetts General Hospital 
 
Sub-Investigators: 
See FDA 1572 
 
IND# 
116977 
 
CTRC# 
12-0105 
 
 
 
 
 
Protocol Version 5.0, dated March 31, 2017 
Protocol Version 4.0, dated November 19, 2015 
Protocol Version 3.0, dated April 22, 2015 
Version 2.0, dated September 15, 2014 
Version 1.5, dated March 7, 2014 


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TABLE OF CONTENTS 
 
 
Synopsis 
3 
Introduction 
6 
Rationale 
16 
Objectives 
18 
Study Design 
18 
Population 
22 
Procedures 
24 
Materials and Supplies 
29 
Management of Intercurrent Events 
31 
Removing Subjects From Study 
35 
Conditions for Initiating, Modifying, or Terminating the Study 
37 
Investigator Responsibilities 
37 
Data Safety Monitoring Plan 
39 
References 
46 
Appendix A, Schedule 
48 
Appendix B, ECOG Performance Scale 
50 
Appendix C, RANO Response Criteria 
51 
Appendix D, Skin and Mucosal Toxicity Management 
Appendix E, MDASI-BT (M.D. Anderson Symptom Inventory - 
Brain Tumor) 
Appendix F, PET Imaging Tracers 
Appendix G, References 
52 
58 
60 
61 


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SYNOPSIS 
Study Title: 
A  Phase  2,  Investigator  Initiated  Study  to  Determine  the  Safety  and 
Efficacy of TH-302 in Combination with Bevacizumab for Glioblastoma 
Following Bevacizumab Failure 
Investigators: 
Andrew J. Brenner MD, PhD 
Eudocia Quant Lee, MD 
See 1572 for other investigators 
Indication 
Recurrent High Grade Glioma progressing on Conventional 
Chemoradiation with Temozolomide as well as Salvage Bevacizumab 
Primary 
Objectives: 
• To assess the safety of TH-302 in combination with 
bevacizumab for patients with high grade glioma 
• To determine the progression-free survival (PFS) for patients 
treated with combination bevacizumab and TH-302 following 
recurrence on single agent bevacizumab 
Secondary 
Objectives: 
• To evaluate overall survival of patients for patients treated with 
combination bevacizumab and TH-302 following recurrence on 
single agent bevacizumab 
• To assess preservation of Quality of Life (QOL) using the MD 
Anderson Symptom Inventory for Brain Tumors (MDASI-BT). 
Exploratory 
Objectives: 
• To explore the extent of tumor hypoxia and cerebral blood flow in 
vivo via 18F-FMISO Positron Emission Tomography with 
correlation to patient response and survival 
• To explore the role of emerging biomarkers of hypoxia in 
predicting response to TH-302 and overall survival 
Study Design: 
Multi-center, single arm, two-stage, non-blinded, prospective study of 
combination therapy bevacizumab at 10mg/kg and TH-302 at 670mg/m2 
every 2 weeks (6 week cycle) until disease progression. 
TH-302 will be administered by IV infusion over 30-60 minutes on 
Days 1, 15, and 29 of a 42-day cycle. 
Duration: 
Subjects will be allowed to continue treatment until they have evidence 
of significant treatment-related toxicity or progressive disease. 
Planned Total 
Sample Size: 
33 Patients. 
Inclusion 
Criteria 
1.   At least 18 years of age 
2.   Ability to understand the purposes and risks of the study and has 
signed a written informed consent form approved by the 
investigator’s IRB/Ethics Committee 
3.   Histologically confirmed glioblastoma 
4.   Progression following both standard combined modality treatment 
with radiation and temozolomide chemotherapy, as well as 
bevacizumab 
5.   Recovered from toxicities of prior therapy to grade 0 or 1 
6.   ECOG performance status ≤ 2 


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7.   Life expectancy of at least 3 months 
8.   Acceptable liver function: 
a.   Bilirubin ≤ 1.5 times upper limit of normal 
b.   AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal 
(ULN); 
9.   Acceptable renal function: 
a. Serum creatinine ≤ULN 
10. Acceptable hematologic status (without hematologic support): 
a.   ANC ≥1500 cells/uL 
b.   Platelet count ≥100,000/uL 
c.   Hemoglobin  ≥9.0 g/dL 
11. All women of childbearing potential must have a negative serum 
pregnancy test and male and female subjects must agree to use 
effective means of contraception (surgical sterilization or the use or 
barrier contraception with either a condom or diaphragm in 
conjunction with spermicidal gel or an IUD) with their partner from 
entry into the study through 6 months after the last dose 
Exclusion 
Criteria: 
1.  The subject is receiving warfarin (or other coumarin derivatives) and 
is unable to switch to low molecular weight heparin (LMWH) before 
the first dose of study drug. 
2.  The subject has evidence of acute intracranial or intratumoral 
hemorrhage either by MRI or computerized tomography (CT) scan. 
Subjects with resolving hemorrhage, punctate hemorrhage, or 
hemosiderin are eligible. 
3.  The subject is unable to undergo MRI scan (eg, has pacemaker). 
4.  The subject has received enzyme-inducing anti-epileptic agents 
within 14 days of study drug (eg, carbamazepine, phenytoin, 
phenobarbital, primidone). 
5.  The subject has not recovered to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
Grade ≤ 1 from AEs (except alopecia, anemia and lymphopenia) due 
to surgery, antineoplastic agents, investigational drugs, or other 
medications that were administered prior to study drug. 
6.  The subject has evidence of wound dehiscence 
7.  Severe chronic obstructive or other pulmonary disease with 
hypoxemia (requires supplementary oxygen, symptoms due to 
hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 
minute walk) or in the opinion of the investigator any physiological 
state likely to cause normal tissue hypoxia 
8.  The subject is pregnant or breast-feeding. 
9.  The subject has serious intercurrent illness, such as: 
a.   hypertension (two or more blood pressure [BP] readings 
performed at screening of > 150 mmHg systolic or > 100 
mmHg diastolic) despite optimal treatment 
b.   non-healing wound, ulcer, or bone fracture 
c.   significant cardiac arrhythmias 


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d.   untreated hypothyroidism 
e.   uncontrolled active infection 
f. symptomatic congestive heart failure or unstable angina 
pectoris within 3 months prior study drug 
g.   myocardial infarction, stroke, transient ischemic attack within 
6 months 
h.   gastrointestinal perforation, abdominal fistula, intra- 
abdominal abscess within 1 year 
i. history or clinical evidence of pancreatitis within 2 years 
10. The subject has inherited bleeding diathesis or coagulopathy with the 
risk of bleeding. 
11. The subject has received any of the following prior anticancer 
therapy: 
a.   Non-standard radiation therapy such as brachytherapy, 
systemic radioisotope therapy, or intra-operative radiotherapy 
(IORT). Note: stereotactic radiosurgery (SRS) is allowed 
b.   Non-bevacizumab systemic therapy (including investigational 
agents and small-molecule kinase inhibitors) or non-cytotoxic 
hormonal therapy (eg, tamoxifen) within 7 days or 5 half- 
lives, whichever is shorter, prior first dose of study drug 
c.   Biologic agents (antibodies, immune modulators, vaccines, 
cytokines) within 21 days prior to first dose of study drug, 
with the exception of bevacizumab which can be 14 days or 
maintain the subjects current bevacizumab dosing schedule 
d.   Nitrosoureas or mitomycin C within 42 days, or 
metronomic/protracted low-dose chemotherapy within 14 
days, or other cytotoxic chemotherapy within 28 days, prior to 
first dose of study drug 
e.   Prior treatment with carmustine wafers 
f. Prior treatment with TH-302 
Assessments of: 
• Efficacy 
• Safety 
Progression-free survival at 4 months 
Safety endpoints 
• 
Incidence and severity of adverse events 
• 
Changes in lab parameters, vital signs and weight 
Procedures 
(Summary) 
Subjects will receive study drug TH-302 and bevacizumab and will be 
assessed for adverse events at all visits. Adverse events will be reported 
for all TH-302 related events occurring after the start of treatment until 
30 days after study drug is discontinued or subsequent cancer therapy is 
initiated. 
Tumor assessments will be performed after every cycle during treatment. 


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1.     INTRODUCTION 
 
1.1   SCIENTIFIC BACKGROUND 
 
1.1.1 Glioblastoma 
 
Primary CNS tumors account for 1.4% of all cancers and 2.4% of all cancer-related deaths. 
In 2010, an estimated 22,020 new cases of primary malignant brain tumors will be 
diagnosed and 13,140 patients will die from these tumors. Approximately 50% of all 
primary brain tumors originate from astrocytes, one of the subtypes of the nonneuronal 
supportive glial cells of the brain. The second histological type of primary brain tumors are 
derived from oligodendrocytes and called oligodendrogliomas. Primary brain tumors that 
develop from astrocytes are called astrocytomas. The World Health Organization (WHO) 
classifies astrocytomas into four distinct grades referred to as Grades I, II, III and IV on the 
basis of how quickly the cells grow and spread and how the cells appear under a microscope. 
Essentially all grade II and III astrocytomas will progress to grade IV during the disease 
course. Glioblastoma (GBM, Grade IV astrocytoma) is the most common and most 
aggressive of the primary malignant brain tumors in adults. Annually there are 
approximately 13,000 cases of GBM diagnosed, with historical 1 year and 5 year survival 
rates of 29.3% and 3.3%[1]. The poor survival is attributable partly to the nature of the 
tumor. The infiltrative nature of GBM results in difficulty eliminating microscopic disease 
despite macroscopic gross-total resection, with 90% of patients having recurrence at the 
original tumor location[2]. The location of the tumor also makes drug delivery difficult with 
only small or lipophilic molecules able to cross the blood brain barrier to reach the tumor. 
Of those agents that are able to reach the tumor, GBMs have shown to be resistant to most 
cytotoxic agents and to quickly develop resistance when initially sensitive. The most 
significant advance in treatment for GBM over the last several years has come from 
concomitant chemoradiotherapy with temozolamide which can result in increased median 
survival of 14.6 months with radiotherapy plus temozolomide compared to 12.1 months 
with radiotherapy alone[3]. However, this still leaves much to be desired with an 
improvement in median survival of only 2.6 months over radiotherapy alone. In the 
recurrent and progressive setting there is no clear standard of care. Current studies have 
shown that some benefit can be seen with the topisomerase-1 inhibitor Irinotecan combined 
with the angiogenesis inhibitor Avastin. This combination can achieve median progression 
free survivals of 22- 23 weeks, and median overall survivals of 40 to 54 weeks[4, 5]. 
 
It is well accepted that brain tumors rely on vascularization for survival and continued 
growth. While normal brain vasculature is a highly organized structure of endothelial cells, 
pericytes, and astrocytes forming a tight barrier which restricts access to the intracerebral 
system, GBMs display markedly disorganized vascular structures with conspicuous 
endothelial cell proliferation, pericyte and basement membrane abnormalities resulting in 
permeability with heterogenous leakiness and abnormal blood flow[6]. This aberrant 
process of endothelial proliferation and loss of the blood brain barrier is related to the 
expression of vascular endothelial growth factor (VEGF) by the tumor cells as well as the 
cells in the surrounding microenvironment in response to hypoxia and acidosis. This 
leakiness results in an increased interstitial pressure and an impediment to drug delivery. 
By blocking VEGF signaling either through monoclonal antibodies to VEGF-A or 
inhibition of the VEGF receptors, it has been shown that prompt reduction in interstitial 


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pressures can be achieved with presumed better drug delivery to the tumor cells. While the 
role of VEGF signaling in angiogenesis has been extensively described, another role for 
VEGF has been proposed with carcinoma progression selecting for cells that depend on 
VEGF as a survival and migration factor[7]. This would explain the high frequency of 
VEGF receptor expression in GBMs as well as other malignancies [8]. Targeting of VEGF 
has proven to be clinically relevant in recurrent glioblastoma as further discussed below. 
Current studies are addressing the impact of angiogenic inhibition upfront in newly 
diagnosed glioblastoma. 
 
1.1.2 TH-302 
 
TH-302 is a nitroimidazole prodrug of the cytotoxin, bromo-isophosphoramide mustard 
(Br-IPM). When    exposed    to    hypoxic    conditions,    TH-302    is   reduced    at the 
nitroimadazole site of the prodrug by intracellular reductases leading to the release of the 
alkylating agent Br-IPM.  Br-IPM can then act as a DNA crosslinking agent.  It may also 
diffuse to adjacent cells in normoxic regions and thus act as a cytotoxic agent outside of 
the hypoxic activation zone.  In vitro cytotoxicity and clonogenic assays indicate that 
TH-302  has little  activity under  normoxic conditions  but  is  highly cytotoxic  under 
hypoxic conditions. 
 
TH-302 does not serve as a substrate  for the clinically relevant efflux  pumps  tested. 
These include MDR1 (ABCB1), MRP1 (ABCC1) and BCRP (ABCG2). 
 
Few normal cells ever reach severe hypoxia.  In contrast, tumors often consist of large 
areas of highly hypoxic cells that are known to be resistant to chemotherapy and radiation 
treatment [9, 10].   In areas of normoxia, TH-302 remains intact as a prodrug and toxicity 
is minimized. Thus, TH-302 has been designed to be selectively activated in these highly 
hypoxic tumor regions and this makes it an attractive candidate for clinical development. 
In addition, preclinical data suggest that after activation, the active moiety may diffuse 
to areas outside the hypoxic region, demonstrating a “bystander” effect and possibly 
exhibiting additional antitumor activity. 
 
1.1.3 Nonclinical Studies with TH-302 
 
1.1.3.1 Mechanism of Action 
 
TH-302 has been tested under various levels of oxygen in proliferation and clonogenic 
assays using a number of human cancer cell lines.   Initial studies were conducted on 
H460 lung cancer and HT-29 colon cancer cell lines.  Cells were exposed to varying 
oxygen  conditions  and  TH-302  for  two  hours  and  then  followed  for  3  days.    The 
cytotoxic effect of TH-302 in a 3 day proliferation assay with H460 cells was both dose 
and oxygen dependent with a greater than 10-fold increase in cell kill (based on IC50) 
under 0.6% oxygen levels and a 500-fold increase in the absence of oxygen as compared 
with air (20% oxygen).    In normoxic conditions the drug levels  necessary to achieve 
cytotoxic effects were well above those expected to be achieved in vivo.    A similar 
oxygen dependent shift of the effect of TH-302 on proliferation was observed with HT-29 
cells.   Clonogenic assays also provided similar results.  We then tested the hypoxia- 
selective cytotoxicity profile of TH-302 across a wide range of different human cancer cell 
lines (>30).  Every line examined exhibited a greatly enhanced cytotoxicity when the TH- 


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302 exposure under hypoxic conditions (2h) is compared to the potency observed with a 2h 
exposure under normoxia.  Of particular note was the finding of a wide range of potencies 
that spanned more than two orders of magnitude among the different individual cell lines 
examined (0.1 µM – 88µM). 
 
 
1.1.3.2 Human Tumor Xenograft Studies 
 
TH-302 antitumor activity as monotherapy was dose-dependent and correlated with total 
drug exposure.  Correlation was found between antitumor activity and tumor hypoxic 
fraction across the twelve xenograft models profiled. Tumor-bearing animals breathing 
95% O2 during dosing periods exhibited attenuated TH-302 efficacy, with while those 
breathing 10% O2 exhibited enhanced TH-302 efficacy, both compared to normoxia (21% 
O2) breathing.  TH-302 treatment results in a reduction in the volume of the hypoxic 
fraction 48 hr after dosing and a corresponding increase in the necrotic fraction. TH-302 
induced DNA damage as measured by γH2AX was initially only present in the hypoxic 
regions and then radiated to the entire tumor in a time-dependent manner. 
 
To identify the optimal dosing regimen for in vivo anti-tumor efficacy of TH-302 in the 
H460 model, we performed a study employing different dosing regimens of TH-302 in 
combination with docetaxel.  Tumor-bearing mice were treated ip with TH-302 according 
to three different regimens: 50mg/kg QDx5/wk x2wk; 100mg/kg Q3Dx5; and 150mg/kg 
Q7Dx2. TH-302 monotherapy, tumor growth was inhibited 89%, 89% and 94% and the 
TGD500 compared to vehicle control were 18, 16 and 16 days, with these three regimens 
respectively.  TH-302 monotherapy did not show significant body weight loss. 
 
The antitumor activity of TH-302 was investigated in combination with seven commonly 
used chemotherapeutics (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, 
gemcitabine and temozolomide) in nine human tumor xenograft models, including H460 
and Calu6 non-small cell lung cancer (NSCLC), HT29 colon cancer, PC3 prostate cancer, 
HT1080 fibrosarcoma, A375 and Stew2 melanoma, and Hs766t, MiaPaCa-2, BxPC-3, and 
SU.86.86 pancreatic cancer. Different TH-302 dosing sequences and regimens in 
combination with the conventional chemotherapeutics were explored. The antitumor 
activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine and 
temozolomide was increased when combined with TH-302 in seven out of nine models 
tested. The two models that did not yield a statistically significant antitumor effect from the 
combination therapy were both tumor models exhibiting very high vascularity in their 
tumors, and correspondingly very low hypoxic fractions. 
 
TH-302  has  been tested  in  two  orthotopic  models  of  cancer.   Each  of these  models 
provided evidence of the superior activity of TH-302 in combination with standard 
chemotherapeutics.  In the first orthotopic model, TH-302 was studied in nude mice with 
red-fluorescent protein  (RFP)  expressing  MIA PaCa-2  tumors  that  were  surgically 
implanted on  the surface of the pancreas under anesthesia[11].    After three days the 
mice were randomized into groups of 8 and were treated with vehicle; TH-302 at 30 mg/kg, 
IP (intraperitoneal), once a day for 5 days repeated for a total of 11 doses over 15 days; 
gemcitabine IV at 200 mg/kg once a week for three doses over 15 days; or the combination 
of the two drugs.  Monotherapy with TH-302 provided minor reductions in tumor growth 


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whereas gemcitabine alone significantly inhibited tumor growth and increased survival 
significantly.   The combination of TH-302 and gemcitabine provided greatly enhanced 
reduction in tumor volume.   In addition, this combination provided greater survival than 
gemcitabine alone.    In the second orthotopic model, TH-302 was studied in nude mice 
with   green-fluorescent   protein  (GFP)   expressing   PC-3   prostate tumors that were 
surgically implanted on the surface of the prostate under anesthesia [12]. Three days after 
the  orthotopic  transplantation,  the  mice  were  randomized  into groups of 8 and were 
treated with vehicle; TH-302 at 30 or 50 mg/kg, IP, once a day for 5 days, repeated for two 
weeks; paclitaxel IV at 12 mg/kg every three days for 4 weeks; or the combination of the 
two  drugs  at  both  doses  of  TH-302.     Paclitaxel  significantly reduced mean  tumor 
volume and significantly improved survival. There was a delay in tumor growth in the 
group treated only with TH-302 at either 30 or 50 mg/kg.  However, all tumors did begin 
to grow later in the study, particularly after the end of treatment. The greatest reductions 
in  tumor  volume  occurred  in  groups  treated  with  both  agents regardless of TH-302 
dose. In these groups 5/8 mice (30 mg/kg) and 3/8 mice (50 mg/kg) had complete 
responses in the prostate tumor. Open body images collected at the end of the study 
confirmed  the absence of  fluorescent signal for four  of these mice in the 30 mg/kg 
group and all three mice in the 50 mg/kg group. 
 
TH-302 has been tested in two metastatic mouse models. Each of these models provided 
evidence  of  the  superior   activity of  TH-302  in  combination  with  standard 
chemotherapeutics.  A PC-3/luc intracardiac injection model was performed to evaluate 
the efficacy of TH-302 and TH-302 in combination with docetaxel in a model of 
metastases in the bone and soft tissue.  Treatments consisted of vehicle, docetaxel alone 
(20 mg/kg once a week for 3 weeks, IV), TH-302 alone (50 mg/kg daily IP, 5 days a 
week for 3 weeks) or the combination of the two drugs.  In addition to metastases in the 
mandible, fore or hind limbs, most mice also developed soft tissue metastases primarily 
in the liver and lungs.   Mice treated with TH-302 alone had a 95% reduction in bone 
metastases and a 96% reduction in soft tissue metastases at Day 42.  Mice treated with 
docetaxel alone had a significant reduction in both bone and soft tissue metastases with 3 
of 10 (30%) mice showing a complete response initiating on Day 21 or Day 28 and 
continuing through study termination on Day 56.  Mice treated with the combination of 
TH-302 and docetaxel demonstrated the greatest decrease in both bone and soft tissue 
metastases.  Eight of ten (80%) of mice had a complete response (bone and soft tissue 
metastases).  Toxicities of the combination regimen were similar to that of the docetaxel 
alone group with one animal in each group having a treatment related death.  All eight 
mice in the TH-302 and docetaxel combination group who survived to the end of the 
study had complete responses of the bone metastases and soft tissue metastases.  A Nd- 
H460  pleural  space  implantation  model  was  performed  to  evaluate  the efficacy  of 
TH-302 alone and in combination with docetaxel[13].  Treatments started seven days after 
implantation and consisted of vehicle, docetaxel alone (10 mg/kg once a week for 2 weeks, 
IV), TH-302 alone (50 mg/kg IP daily, 5 days a week for 2 weeks) or the combination of 
the two drugs. Median survival was 24 days for vehicle compared to 42.5 days with TH- 
302, 35 days for docetaxel alone and 56 days with TH-302 in combination with docetaxel. 
 
TH-302 has also been tested in ectopic tumor xenograft models in combination with 
clinically approved VEGFR kinase antiangiogenesis agents (sunitinib and sorafenib). 
Several  published  studies  have  demonstrated  an  increase  in  tumor  hypoxia  after 


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administration of anti-angiogenesis agents that target VEGF signaling (e.g. sunitinib, 
sorafenib, bevacizumab). To characterize sunitinib-induced effects on tumor vasculature 
and tumor hypoxia, 786-O (RCC) and H460 (NSCLC) human ectopic tumor xenografts 
were treated with sunitinib (20 or 40 mg/kg) daily for 5 days and then 72 hours later animals 
were injected with pimonidazole to label hypoxic cells and Hoechst 33342 to label vascular 
perfusion. The NSCLC model (H460) exhibits a baseline hypoxic fraction of 7%. Sunitinib 
induced a dose-dependent increase in tumor hypoxia volume (24 ± 3.2% with 40 mg/kg vs. 
7.3 ± 3.8% with Vehicle, p<0.05) and a corresponding decrease in tumor microvasculature. 
The 786-O RCC model is a well-vascularized tumor as characterized by CD31 and Hoechst 
staining with a relatively small baseline hypoxic compartment (<5% volume) in the 
xenograft tumors. Sunitinib also induced a dose-dependent increase in tumor hypoxia 
volume (17.2 ± 7.1% with 40 mg/kg vs. 1.4 ± 0.9% with Vehicle, p<0.05) and a 
corresponding decrease in functional vasculature in the RCC model. To test the 
combination of TH-302 with sunitinib, H460 NSCLC tumor-bearing animals (~150mm3 at 
start of dosing) were randomized into groups of 10 and treated with sunitinib at 20, 40, or 
80 mg/kg p.o. daily for 3 weeks (QDx21). After one week of sunitinib monotherapy animals 
began combination therapy with the addition of TH-302 at 50 mg/kg i.p. daily for 5 days 
on and 2 days off (QDx5) for 2 weeks. Sunitinib was administered 4 hours before TH-302 
on days when both agents were given. Control arms included all 3 doses of sunitinib 
monotherapy, TH-302 monotherapy, and vehicles-only groups. Sunitinib exhibited dose- 
dependent antitumor efficacy (by TGI, TGD, and conditional survival), as did TH-302 
monotherapy. All three combination therapy treatment groups exhibited superior efficacy 
compared to the corresponding monotherapy groups. A similarly designed experiment was 
performed in the RCC (786-O) model with sunitinib and the H460 NSCLC and A375 
melanoma models with sorafenib, and similar results were obtained of TH-302 addition 
potentiating the antiangiogenic antitumor effects. The results support the hypothesis that 
the hypoxia-activated prodrug TH-302 may be an effective addition to antiangiogenic- 
containing chemotherapy regimens. 
 
1.1.3.2.1 Preclinical Pharmacokinetic Studies 
 
The intravenous pharmacokinetics of TH-302 have been studied in mice, rats, dogs, and 
monkeys. In all species, the drug was cleared rapidly from the circulation with mean 
effective half-lives of 10-50 minutes.  TH-302 was stable when incubated with hepatic 
microsomes from mice, rats, dogs, monkeys and humans. TH-302 was relatively stable in 
rat, dog  and  human hepatocytes  but  less  stable  in  mouse and  monkey hepatocytes. 
TH-302 caused no apparent inhibition of CYP1A2, CYP2C19, CYP2D6 and CYP3A4, 
but exhibited weak drug-drug interaction potential towards CYP2C9. TH-302 is 
extensively metabolized following IV administration and is renally and fecally excreted 
in rat and dog.    A  tissue  distribution  study  in  rats  showed  that  TH-302  is  rapidly 
distributed to tissues following IV administration with the highest concentrations of TH- 
302-related radioactivity present in the kidney and small intestinal content; however, low 
but quantifiable  levels  of  radioactivity  were  observed  in  the  brain  and  spinal  cord. 
Protein binding was low (<55%) in mouse, rat, dog, monkey and human plasma and 
independent of plasma concentration. 
Following IV administration of [14C]-TH-302 to male rats, radioactive material was 
distributed rapidly into the tissues evaluated and then eliminated rapidly over the 24 hours 
after dosing.  The highest concentrations of radioactive material within the 24 hours after 


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dosing were found in the kidney and the GI tract.  The presence of substantial amounts of 
radioactive material in the GI tract suggests the presence of either significant biliary 
excretion and/or secretion into the gut of TH-302–derived radioactivity.   The high 
concentrations of radioactive material in the urinary bladder contents and the kidney 
indicate that the kidney also contributes to the elimination of TH-302-derived radioactivity. 
Low concentrations of radioactive material were found in the brain and spinal cord, 
indicating low passage of radioactive material across the blood-brain barrier and 
subsequent protracted elimination from CNS tissues. 
 
1.1.3.2.2 Acute and Subacute Toxicity Studies 
 
Initial single-dose toxicity studies of TH-302 were conducted in rats and dogs.    The 
infusion period was limited to 30 minutes in order to achieve a rapid increase to relatively 
high drug levels. At the highest dose levels of 100 and 200 mg/kg in rats and 32 mg/kg in 
dogs, TH-302 was lethal.   Organs affected in both species were bone marrow, kidney, 
thymus and intestine. Species specific toxicity at the highest dose was seen in rat adipose 
tissue and spleen.  Minimal reversible toxicity was observed in rats at 50 mg/kg and in 
dogs at 8 mg/kg. Based on these results, doses of 12.5, 25 and 50 mg/kg of TH-302 were 
administered in a GLP multiple-dose toxicity study in rats. Each rat received a 30 minute 
infusion once a week for three weeks. The primary toxicities were hematologic in nature 
and were reversible.  These effects were pronounced only at the highest dose (50 mg/kg) 
at which histopathology revealed effects on the bone marrow and the tongue with minor 
effects on the kidney and the uterus.  The minimally toxic multiple-dose in rats was 25 
mg/kg. In the repeat dose GLP study with dogs receiving 4, 8, or 16 mg/kg of TH-302, 
leukopenia and neutropenia were evident, particularly at the high dose level where 
hypocellularity was also reported in the bone marrow.  These changes were reversible. 
There was no sign of vein irritation in either species tested and exposure of human blood 
to high levels of TH-302 did not reveal signs of hemolysis. The minimally toxic multiple- 
dose level in dogs was 8 mg/kg. 
 
1.1.4 Clinical Studies with TH-302 
 
Study TH-CR 401 is a Phase 1 dose escalation and dose expansion study investigating TH- 
302 monotherapy in subjects with solid tumors.   TH-302 monotherapy administered 
weekly for 3 weeks of an every 4 week cycle (Arm A) was initiated at a weekly dose of 
7.5 mg/m2 and the maximum tolerated dose (MTD) was established at 575 mg/m2.  Based 
on the toxicology studies, hematologic toxicity was expected to be the major dose-limiting 
adverse reaction of TH-302; however, hematologic toxicity has rarely been significant and 
dose-limiting toxicities were mucosal and skin toxicity.  Dose-limiting toxicities (DLTs) 
of perianal and rectal ulcers and oral mucositis with associated dehydration were observed 
at 670 mg/m2.  Common adverse events include nausea, fatigue, vomiting, constipation 
and diarrhea.   Skin toxicities including intertriginous erythema, desquamation and 
hyperpigmentation and mucosal toxicities including stomatitis and mucosal inflammation 
are also common.  At TH-302 doses above 240 mg/m2, prophylaxis against nausea and 
vomiting should be implemented using a regimen intended for moderately emetogenic 
chemotherapy.  During the dose escalation, anti-tumor activity was observed in subjects 
with malignant melanoma, small cell lung cancer (SCLC) and non-small cell lung cancer 
(NSCLC). Based on these data, a dose expansion cohort was opened at 575 mg/m2 to enroll 


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subjects in these indications.  Subsequently, to help determine the recommended Phase 2 
dose, a dose expansion cohort was opened at 480 mg/m2 to obtain safety and tolerability 
data and to obtain efficacy data in subjects with malignant melanoma, SCLC, 
hepatocellular cancer (HCC) and tumors with squamous or transitional cell histologies 
based on anti-tumor activity observed in TH-302 monotherapy and/or combination therapy 
in these indications. A separate treatment arm (Arm B) was opened to determine the MTD, 
DLTs, safety and preliminary anti-tumor activity utilizing a once every 3 week dosing 
regimen of TH-302.  The Arm B dose was escalated from 670 mg/m2 to 940 mg/m2 and 
the MTD was established at 670 mg/m2. 
 
TH-CR-402 is a Phase 1/2 three-arm, multicenter, dose-escalation study to determine the 
MTD, DLT, safety and pharmacokinetics and to make a preliminary assessment of efficacy 
of TH-302 when used in combination with standard doses of gemcitabine, docetaxel, or 
pemetrexed. Subjects with advanced solid tumors who are candidates for therapy with one 
of the three cytotoxic chemotherapies were enrolled in the dose escalation portion of the 
study.  The dose expansion portion of the study enrolled subjects with pancreatic cancer 
(gemcitabine arm), castrate-resistant prostate cancer (docetaxel) or NSCLC (docetaxel and 
pemetrexed).  The starting dose of TH-302 in each of the treatment arms was 240 mg/m2. 
The MTD of TH-302 in combination with weekly gemcitabine (1000 mg/m2) was 340 
mg/m2.  DLTs at higher TH-302 doses were Grade 3 esophagitis, Grade 3 pain due to 
perianal rash, Grade 4 neutropenia and Grade 4 thrombocytopenia.   RECIST tumor 
response assessments have been reported for 34 subjects.   One subject with locally 
advanced unresectable disease had a confirmed complete response.  Eight subjects had a 
best response of partial response (four confirmed, three unconfirmed, one unconfirmed 
continuing on-study).  An additional 22 subjects had stable disease.  The stable disease or 
better rate was 91%.  The MTD of TH-302 in combination with 75 mg/m2 docetaxel was 
340 mg/m2.  DLTs at higher TH-302 doses were Grade 4 neutropenia, Grade 3 infection 
with neutropenia and Grade 3 febrile neutropenia/Grade 3 diarrhea.  The MTD of TH-302 
in combination with 500 mg/m2 pemetrexed was 480 mg/m2. DLTs at higher TH-302 doses 
were Grade 3 stomatitis and Grade 4 thrombocytopenia. 
 
TH-CR-403 is a Phase 1/2, multi center, dose escalation study to determine the safety, 
efficacy and PK of TH-302 in combination with full-dose doxorubicin in subjects with soft 
tissue sarcoma.  In this study, the MTD of 300 mg/m2 was established for the combination 
of TH-302 and 75 mg/m2 doxorubicin with prophylactic growth factor support. DLTs at a 
TH-302 dose of 340 mg/m2 were Grade 4 thrombocytopenia and Grade 3 infection with 
Grade 4 neutropenia.  Enrollment was expanded at the MTD for subjects with advanced 
soft tissue sarcoma previously untreated with chemotherapy (neoadjuvant and adjuvant 
chemotherapy permitted).  Tumor response data were available for 54 of the first 57 
subjects and the best response rates were: partial response (18 of 54, 33%), stable disease 
(28 of 54, 52%) and progressive disease (8 of 54, 15%).  The median progression-free 
survival was 6.4 months (95% CI: 5.6 months to 6.9 months).  The 6-month progression- 
free rate was 56% and the 3-month progression-free 
 
rate was 83%. The median overall survival had not been reached. The tumor response and 
stable disease rates and progression-free survival were all higher than those reported with 
single-agent doxorubicin.  The combination regimen was well tolerated with acceptable 


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hematologic toxicity and manageable safety events. 
 
Study TH-CR-404 is an open-label multi-center randomized controlled crossover Phase 2 
study of two dose levels of TH-302 (240 and 340 mg/m2) in combination with gemcitabine 
versus gemcitabine alone in patients with locally advanced unresectable or metastatic 
pancreatic adenocarcinoma. A total of 165 subjects are planned to be enrolled at a ratio of 
1:1:1. Subjects on the gemcitabine arm who discontinue for disease progression and meet 
laboratory, tumor and performance status eligibility criteria may crossover to TH-302 plus 
gemcitabine at a randomized TH-302 dose of 240 mg/m2 or 340 mg/m2.  TH-302 doses of 
240 mg/m2 or 340 mg/m2 are administered IV over 30 minutes on Days 1, 8 and 15 of every 
28-day cycle.  The dose of gemcitabine is 1,000 mg/m2 administered IV over 30 minutes 
on Days 1, 8 and 15 of a 28-day cycle. Gemcitabine administration will start 2 hours after 
completion of the TH-302 infusion when used in combination with TH-302.  The primary 
efficacy endpoint is progression-free survival.  Enrollment in the study was initiated in 
June of 2010. 
 
Study TH-CR-407 is a Phase 1 open-label dose-escalation study with expansion at the 
MTD in subjects with advanced leukemias.  TH-302 is administered as a 30-minute 
intravenous infusion daily for 5 days every 21 days.   The starting dose is 120 mg/m2. 
Subjects who successfully complete a 3-week treatment cycle without evidence of 
significant treatment-related toxicity or clinically significant progressive disease continue 
to receive treatment for up to six cycles.  Enrollment in the study was initiated in June of 
2010. 
 
Study CTRC 11-24 (IND 112417) is a phase 1 dose escalation study in glioblastoma, with 
patients who were administered TH302 at a single preoperative dose of 575 mg/m2. Once 
recovery from surgery was observed, patients received bevacizumab at the standard dose 
of 10mg/kg and TH302 at 240, 340, 480, or 670mg/m2 given together in a Q2week 
schedule. In the final cohort of 670 mg/m2, the surgical requirement was eliminated and 
patients were allowed to go directly to combination therapy with bevacizumab. No patients 
experienced a dose limiting toxicity within the first cycle at any dose level. The most 
common toxicity of any grade observed was anal mucositis, which was observed in 2 of 4 
(50%) patients in the 480mg/m2 cohort and 4 of 4 (100%) patients at 670 mg/m2. The anal 
mucositis can be controlled with supportive care (see Appendix D). As 670 mg/m2 has 
already been documented as  the MTD when given every three weeks in single agent 
studies, no further dose escalation is planned.  The phase 2 dose in combination with 
bevacizumab every 2 weeks is therefore 670 mg/m2. While efficacy was not a primary 
endpoint of this study, two partial responses have been observed and 5 patients 
demonstrating stable disease, for a combined clinical benefit rate of 58% (n=12; with 2 not 
yet evaluable). Further, one patient has reached cycle 24 (day 640) and continues with 
stable disease. These observations suggest potential clinical activity of TH-302 in 
bevacizumab resistant glioblastoma. 
 
 
 
1.1.5 Standard Treatment for Glioblastoma 
 
Glioblastoma are highly aggressive tumors and invariably recur after standard of care first- 
line therapy. Currently, front-line treatment consists of a multi-modality approach that 


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includes maximal surgical resection, adjuvant radiation therapy with concurrent 
temozolomide at 75 mg/m2 followed by 6 months of single-agent temozolomide at up to 
200 mg/m2. Temozolomide (a prodrug) is a rapidly and non-enzymatically converted to the 
active alkylating metabolite MTIC [(methyl-triazene-1-yl) – imidazole-4-carboxamide]. 
The cytotoxic effects of MTIC are manifested through alkylation of DNA at the O6, N7 
guanine positions. 
 
This multimodal approach has been the standard of care ever since the publication of the 
landmark EORTC phase III trial published by Roger Stupp et al in 2005 that demonstrated 
an improved primary end-point of median overall survival of this regimen when compared 
to adjuvant radiation alone. A median survival of 14.6 months was reported in the 
temozolomide group versus 12.1 months in the radiation alone group. At that time, 
radiation alone was considered standard of care in most countries. In the US, common 
practice was to add adjuvant nitrosurea-based chemotherapy regimen with a small survival 
benefit with significant adverse effects. 
 
However, once a patient fails standard front-line therapy, prognosis is very poor and new 
therapies are needed. In the era of targeted therapies, anti-angiogenic drugs have come into 
the limelight. Bevacizumab, a recombinant humanized monoclonal antibody against 
VEGF, has been studied extensively over the past several years and has demonstrated 
rather impressive radiographic and clinical response rates when compared to historical data 
but the responses are not very long-lasting. The largest study to date was a phase II, 
multicenter, open-label, noncomparative trial conducted by Friedman et al in 2009 which 
evaluated the efficacy of bevacizumab (10 mg/kg every 2 weeks), alone and in combination 
with irinotecan (125 mg/m2 in those non receiving enzyme-inducing anti-epileptic agents 
and 340 mg/m2 in those who were taking these drugs), in patients with recurrent 
glioblastoma. In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, 
estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; 
objective response rates were 28.2% and 37.8%, respectively; and median overall survival 
times were 9.2 months and 8.7 months, respectively. Nonetheless, these are all improved 
outcomes when compared to historical data in the recurrent setting. 
 
Dose limiting toxicities of bevacizumab are hypertension, proteinuria, thromboembolic 
events, spontaneous bleeding and wound healing complications. In the phase II study 
conducted by Friedman, bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 
65.8%, respectively, experienced grade >or = 3 adverse events, the most common of which 
were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and 
convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus- 
irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the 
bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the 
bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). Bevacizumab 
obtained accelerated FDA-approval in 2009 for patients with recurrent glioblastoma 
multiforme. 
 
1.1.6  Hypoxia Biomarkers 


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Hypoxia promotes more aggressive tumor phenotypes and has been associated with 
resistance to radiation and chemotherapies in GBM, as well as tumor invasion and poor 
patient survival. In particular, cells at pO2 <10 mm Hg resist the ionizing effect of 
radiotherapy and cytotoxic effect of chemotherapy. Hypoxic necrotic foci with 
pseudopalisading tumor cells are one of the features that define GBM. A variety of methods 
have been devised to assess degree of hypoxia in xenografts and patient tumors. 
 
Traditionally, the gold standard to measure hypoxia has been the use of a polarographic 
oxygen-sensitive probe, which provides direct measurement of tissue oxygen tension. 
However, this method has limitations, such as its inability to differentiate between viable 
and necrotic foci and is not practical in larger scale studies or in inaccessible tumors. 
 
Other hypoxic markers that have been identified in pre-clinical studies include GLUT-1, 
HIF-1a, LDH-A and VEGF. Studies have also attempted to examine the spatial relationship 
between tumor hypoxia assessed by immunohistochemistry and 18F-FDG and 18F-FMISO 
auto-radiography but these have yet to receive regulatory approval. 
 
The hypoxia-induced modulation of GLUT-1 and LDH-A also entails changes in cell 
metabolism, in particular glucose metabolism and lactate production. These metabolic 
changes, and in particular the modulation of lactate levels, provide valuable metabolic 
biomarkers that have the potential to be non-invasively imaged using magnetic resonance 
spectroscopic imaging (MRSI). Additional metabolic biomarkers of hypoxia have been 
investigated in various tumor types. Jiang and colleagues reported increased levels of 
choline-containing metabolites and lipid CH3  colocalizing with the hypoxic areas of the 
tumor in a breast cancer model[14]. High resolution methods based on either MR 
spectroscopy or mass spectrometry platforms are also of value to obtain a detailed metabolic 
signature due to hypoxia in biopsy tissue or patient biofluids [15, 16]. 
 
1.1.7  Risks and Benefits 
 
Phase I dose-escalation clinical studies involving TH-302 in combination with other 
cytotoxic agents (gemcitabine, docetaxel) have demonstrated dose limiting toxicities to be 
mostly hematological and dermatological. The MTD was 340 mg/m2  when administered 
with gemcitabine and docetaxel. However, TH-302 increases the hematological toxicity of 
the chemotherapy. The TH-CR-401 phase I dose escalation study of TH-302 as a 
monotherapy in subjects with advanced solid tumors evaluated TH-302 given IV every 
week for 3 weeks of a 4 week cycle as well as TH-302 administered once every 3 weeks. 
The first dose-limiting toxicities were reported at weekly doses of 670 mg/m2  and these 
were related to mucosal toxicities and not hematological. 
 
It is important to note that TH-302 should not be administered to pregnant or lactating 
women since there is not enough data to determine teratogenicity or risks of breast feeding 
after receiving this drug. Animal studies suggest that TH-302 may have embryotoxic or 
teratogenic effects. Contraceptive measures should be applied during, and for at least six 
months after completion of therapy. Other potential sites of organ injury, include kidney, 
liver and GI function. The active metabolite of TH-302, Br-IPM, is an alkylating agent 
similar to the active metabolite of ifosphamide, IPM, therefore, renal tubular toxicity may 


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occur, especially if used concomitantly with other nephrotoxic drugs. There is no known 
antidote against TH-302. 
 
Phase II clinical studies involving patients with recurrent glioblastoma treated with the anti- 
VEGF receptor monoclonal antibody, bevacizumab, have demonstrated improved 
radiographic response rates, based on traditional criteria, when compared to historical data. 
Most studies have administered this anti-angiogenic agent at a dose of 10 mg/kg IV every 
two weeks. Overall, this drug has been well tolerated. However, dose limiting toxicities that 
have been consistently reported include hypertension, proteinuria, thromboembolic events, 
spontaneous bleeding and wound healing complications. 
 
The risk-to-benefit ratio is considered acceptable for both drugs to be used in this phase II 
clinical study based upon the patient population, the limited number of active agents for this 
aggressive cancer and the pre-clinical as well as clinical evidence of tumor activity and drug 
tolerability. 
 
1.2 Rationale for the study 
 
Clinical studies have demonstrated anti-tumor activity in patients treated with anti- 
angiogenic agents such as with bevacizumab, a recombinant human monoclonal antibody 
against VEGF receptor. VEGF has been found to be a critical regulator of angiogenesis. 
Response rates using bevacizumab have been reported to be between 20-50% in recurrent 
glioblastoma with a direct effect on vessel permeability. This direct vessel effect makes it 
difficult to interpret changes in contrast enhancement seen on brain MRI and assess whether 
these changes correlate with tumor burden after receiving bevacizumab. In many patients 
who recur after bevacizumab therapy, progression is manifest as a diffuse infiltrative pattern 
without worsening enhancement, resembling gliomatosis cerebri. Using a human GBM 
model in rats via xenografted tumors, Keunen et al, reported that anti-angiogenic treatment 
leads to loss of large-sized vessels resulting in reduced perfusion, blood volume and increase 
in hypoxia in the tumor microenvironment[16]. This increase in hypoxia leads to an increase 
in lactate production, stabilization of HIF-1 alpha and is accompanied by a dramatic increase 
in cell invasion into the normal brain. 
 
Hypoxia is a powerful trigger for altered gene expression and has a multitude of tumorigenic 
properties, including, activation of specific pathways and transcription factors that control 
tumor stem cells. Hypoxia causes a shift to glycolytic metabolism, upregulates survival and 
growth factors, inhibits apoptosis, and stimulates the production of enzymes mediating 
invasiveness. This imbalance between oxygen delivery and oxygen consumption renders 
tumor cells with greater resistance to anticancer therapy such as radiation. Therefore, factors 
that regulate the hypoxic state represent potential targets for treatment of high grade glioma. 
 
TH-302 is a pro-drug that when it is exposed to hypoxic conditions, it is reduced at the 
nitroimidazole site of the prodrug by intracellular reductases leading to the release of the 
alkylating agent Br-IPM. This active metabolite acts as a DNA crosslinking agent and is 
highly cytotoxic under hypoxic condition. The prodrug also diffuses to adjacent cells in 
normoxic regions, acting as a cytotoxic agent outside of the hypoxic activation zone. Pre- 
clinical studies have demonstrated that this drug is highly active in in vitro proliferation 


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assays in multiple human cancer cell lines. This tumor-selective hypoxia-activated pro-drug 
TH-302 has been shown to potentiate, in vivo, the anti-tumor efficacy of other anti- 
angiogenic agents such as sunitinib and sorafenib by targeting tumor hypoxia. These 
observations provide a translational rationale for the study of the combination of TH-302 
with the anti-angiogenic anti-VEGF monoclonal antibody, bevacizumab. 
 
This phase II study will enroll subjects with recurrent glioblastoma following disease 
progression while on bevacizumab. Since TH-302 remains intact as a prodrug in areas of 
normoxia toxicity is minimized. 
 
1.3 Rationale for dose selection 
 
TH-302 
Phase I clinical studies have established the MTD of TH-302 given in a Q3week schedule 
at    670    mg/m2      and    when    given    in    a    Q1week    schedule    at    575    mg/m2. 
In our Phase 1 investigator-initiated, dose-escalation study in glioblastoma, patients were 
administered TH302 at a single preoperative dose of 575 mg/m2.  Once recovery from 
surgery was observed, they received bevacizumab at the standard dose of 10mg/kg and 
TH302 at 240, 340, 480, and 670 mg/m2 given together in a Q2week schedule. In the final 
cohort of 670 mg/m2, the surgical requirement was eliminated and patients were allowed to 
go directly to combination therapy with bevacizumab. 
 
No patients experienced a dose limiting toxicity within the first cycle at any dose level. 
Further, 670 mg/m2 has already been documented as the MTD when given every three weeks 
in single agent studies. Therefore, based upon the lack of DLT in our Phase 1, the Phase 2 
dose in combination with bevacizumab every 2 weeks is 670 mg/m2. 
 
Bevacizumab (Avastin) 
Phase II clinical studies as well as the FDA have established the standard bevacizumab dose 
of 10 mg/kg IV every 2 weeks when treating patients with recurrent glioblastoma. 
 
1.4 Rationale for selection of the subject population 
 
There are no effective established treatments available after progression while on 
bevacizumab for patients with high-grade glioma. These patients invariably recur and have 
a poor prognosis. In this phase II study, patients with recurrent glioblastoma after 
bevacizumab and with no standard treatment options will be eligible for enrollment. 
 
1.5 Rationale for in vivo Positron Emission Tomography Studies of Tumor Hypoxia 
In order to generate in vivo measurements of hypoxia, subjects will be asked to participate 
in 18F-Fluoromisonidazole (FMISO) PET scans, which have been used safely numerous 
times in humans since the 1980’s [17]. FMISO is a nitromidazole family derivative, 
analogous to TH-302, which diffuses into cells and undergoes reduction in a hypoxic 
environment. This compound has also been used before to successfully image hypoxia in 
Grade IV astrocytomas [18,19]. Images will be corrected to background attenuation. The 
estimated average dose of 18F-FMISO subjects will receive per scan is 250-300 MBq (range 
from 120-450 MBq). The scan will be initiated approximately 110-120 minutes post 18F- 


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FMISO administration, and plasma pharmacokinetic samples (1mL) will be collected to 
assess decay of 18F-FMISO. 
 
1.6 Study Compliance 
 
This study will be conducted in compliance with this protocol, the principles of Good 
Clinical Practices, and applicable regulations. 
 
 
2.  OBJECTIVES OF THE STUDY 
 
2.1 Primary Objectives 
 
1.   To assess the safety of TH-302 in combination with bevacizumab for 
patients with high grade glioma 
2.   To determine the proportional progression-free survival (PFS) at 4 months 
for patients treated with combination bevacizumab and TH-302 following 
recurrence on single agent bevacizumab 
 
2.2 Secondary Objectives 
 
1.   To evaluate overall survival of patients for patients treated with combination 
bevacizumab and TH-302 following recurrence on single agent 
bevacizumab 
2.   To assess preservation of Quality of Life (QOL) using the MD Anderson 
Symptom Inventory for Brain Tumors (MDASI-BT). 
 
2.3 Exploratory Objectives 
 
1.   To explore the extent of tumor hypoxia and cerebral blood flow in vivo via 
18F-FMISO Positron Emission Tomography with correlation to patient 
response and survival 
2.   To explore the role of emerging biomarkers of hypoxia in predicting 
response to TH-302 and overall survival 
 
 
3.  STUDY DESIGN AND METHODS 
3.1 Design 
1.   Multi-center, single-arm, two-stage prospective study, non-blinded 
2.   Combination therapy with bevacizumab at 10 mg/kg intravenously (IV) every 
2 weeks and TH-302 at 670 mg/m2 IV every 2 weeks, in 6 week cycles, until 
disease progression. 
3.   33 patients will be enrolled 
4.   TH-302 will be administered by IV infusion over 30-60 minutes on day 1, day 
15, and day 29 of each 42 day cycle. 
5.   Bevacizumab will be administered by IV infusion on day 1, day 15, and day 29 
of each 42-day cycle. The initial bevacizumab dose will be infused over 60 


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minutes. Infusion may be shortened to 30 minutes if the 60-minute infusion is 
tolerated well. 
 
3.1.1 Investigational Sites 
This study is a multi-center, single arm, two stage, open label trial. The only participating 
sites will be the CTRC @ UTHSCSA and Dana Farber Cancer Center. CTRC@UTHSCSA 
will implement ongoing monitoring activities to ensure that Participating Institutions are 
complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring will occur before the clinical phase of the protocol begins, continue during 
protocol performance and through study completion. Additional monitoring practices may 
include but are not limited to; source verification of case report forms, review and analysis 
of the following: eligibility requirements of all participants , informed consent procedures, 
adverse events and all associated documentation, study drug administration/treatment, 
regulatory files, protocol deviations, pharmacy records, response assessments, and data 
management. Participating institutions will be required to participate in monthly 
teleconferences. 
 
3.1.2 Statistics 
3.1.2.1 Sample size justification 
Subjects will be assessed on Day 1 of each 6 week cycle by MRI until disease progression 
according to RANO criteria[18] and as described below. This study will include up to 33 
experimental subjects (plus an undetermined number of subjects rolling over from Protocol 
CTRC# 11-24) with an accrual interval of 12 months. There will be an additional follow 
up period of 12 months. Based on historical data, the median progression free survival of 
54 patients on control salvage therapy was 37.5 days (Quant et al 2008). If the true median 
progression-free survival in the historical control group and the experimental treatment 
group treated at the MTD are 37.5 days and 67 days, then assuming a one-parameter 
exponential model, the corresponding mean times to progression are 54.1 [=37.5/log(2)] 
and 96.7 [=67/log(2)] days, and the proportion progression-free at 4 months is estimated 
to be 0.289 in the experimental group and 0.109 in the historical control group. With one- 
sample 2-stage testing and alpha=0.05 and 80% power, the optimal 2-stage design will 
enroll 11 subjects in the first stage. If 1 or fewer subjects are progression-free at 4 months 
then the trial will be terminated.  If the trial goes to the second stage, then a total of 33 
subjects will be studied.  If the total number progression-free at 4 months is less than or 
equal to 6 then the test drug is rejected [PASS Version 11, NCSS, Kaysville, Utah]. 
 
 
 
 
3.1.2.2 Methods 
The numbers of patients screened, screen failures by reason, the number enrolled and 
completing the study at each stage and the number and proportion progression-free at 4 
months at each stage will be tabulated. The distribution of time to progression and death 
will be summarized with Kaplan-Meier curves. If the trial goes to the second stage, the 


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hypothesis Ho:θ=θC  versus Ho:θ≠θC, where θ and θC are the mean times to disease 
progression of the experimental and historical control groups, will be contrasted with a 
one-sample two-sided log rank statistic.  Analyses of the relation between hypoxia and 
cerebral blood flow in vivo, between hypoxia and selected biomarkers and between 
hypoxia and quality of life will be exploratory and descriptive.  Adverse events will be 
tabulated. All statistical testing will be two sided with a significance level of 5%.  SAS 
Version 9.3 for Windows (SAS Institute, Cary, North Carolina) will be used throughout. 
Statistical analyses will be performed by Joel E. Michalek, PhD, Department of 
Epidemiology and Biostatistics University of Texas Health Science Center at San Antonio. 
 
 
3.1.3 Treatment Regimens 
3.1.3.1 TH-302 
 
TH-302 will be administered intravenously over 30-60 minutes at 670 mg/m2 on Days 1, 
15 and 29 of each 42-Day (6 week) cycle. 
 
Dose of TH-302 is to be re-calculated only if a subject’s body weight changes by >10% 
from baseline. 
 
Each dose will be prepared in D5W for injection in non-DEHP containing infusion bags 
and administered intravenously via an infusion pump through a non-DEHP containing IV 
administration set (See Section 6.3 for details). The full recommended infusion volume 
should be used. When possible, TH-302 should be administered through a central line. 
Detailed instructions for dilution and administration are provided in the Pharmacy Manual. 
 
Prophylaxis against nausea and vomiting should be applied using a regimen intended for 
moderately emetogenic chemotherapy. 
 
 
3.1.3.2 Bevacizumab 
Bevacizumab will be administered intravenously at 10 mg/kg on day 1, day 15, and day 29 
of each cycle. 
 
 
3.1.3.3 Dose Modifications 
Dose modification rules should be followed for all hematologic and non-hematological 
toxicity regardless of causality and for any other toxicity that is not clearly related to disease 
progression, intercurrent illness, concomitant medications or other non-drug intervention. 
 
 
 
Please   follow   the   package   insert   for   all   bevacizumab   dose   modifications   and 
discontinuations. 
• If a subject requires more than 2 dose level reductions for non-hematological toxicity, 
he/she should discontinue from the study. 
• Any subject who misses one complete cycle or treatment-related toxicity should 
discontinue from the study. 


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3.1.4.1 TH-302 Dose Modifications 
 
• If Day 1 of a cycle for either drug must be withheld, the whole cycle should be delayed. 
 
• At Day 15 or Day 29, if both drugs must be withheld, the dose should be skipped. 
 
• At Day 15 or Day 29,  if only one drug must be withheld, that drug’s dose should be 
skipped rather than delayed and the other drug may be given alone. 
 
• Dose modifications for hematologic toxicity should be independently assessed at each 
visit as described on Table 3.1-1. 
 
• Prophylactic G-CSF may be implemented in subsequent cycles if neutropenia results 
in dose reduction or dose delay at prior doses.  Therapeutic use of hematopoietic 
colony-stimulating factors is permitted following ASCO guidelines. 
 
• G-CSF  may  be  implemented  in  the  management  of  neutropenia  to  avoid  dose 
reductions or holding a dose if neutropenia recovers within 48 hours 
 
Hemoglobin must be ≥9 g/dL at Cycle 1/Day 1 and must be ≥8 g/dL for all subsequent doses. 
 
 
Table 3.1-1 TH-302 dose modifications for hematologic toxicity 
 
% of Full Dose for any Cycle 
ANC (/µL) 
Platelets (/µL) 
Day 1 
Days 15 or 29 
≥1500 
AND ≥100,000 
100 
100 
1000-1499 
AND ≥75,000-99,999 
75 
100 
500 – 999 
OR 
50,000-74,999 
Hold 
75 
<500 
OR 
<50,000 
Hold 
Hold 
 
Follow Table 3.1-2 for TH-302 dose modifications for non-hematologic toxicity. 
 
• For bevacizumab dose modifications should follow the manufacturer’s labeling. 
• All treatment related toxicities will be documented and graded based on NCI CTCAE 
v4.03. 
• Management of toxicity is as directed under section 7 and per algorithms for management 
of hand-foot skin reactions, anal mucositis, oral mucositis, injection site reaction,  and 
hyperpigmentation listed in Appendix D. 
 
 
 
 
Table 3.1-2  TH-302 Dose Modifications for Non-Hematologic Toxicity 
 
TH-302 
Toxicity 
Details 
Hold Dose 
% of Dose 
after Recovery 


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Grade 2 or 3 
Bilirubin 
Regardless of causality 
Hold dose until resolution to 
Grade 0 or 1 
100 
Grade 2 
except for elevated 
ALT/AST, nausea, 
vomiting, diarrhea, 
alopecia and fatigue 
Hold dose until resolution to 
Grade 0 or 1 
100 
Intolerable skin toxicity1 
Hold dose until resolution to 
Grade 0 or 1 
75 
Grade 3 
Except for elevated 
ALT/AST, nausea and 
vomiting 
Hold dose until resolution to 
Grade 0 or 1 
75 
Grade 3 
Nausea 
Hold dose until resolution to 
≤ Grade 2 
100 
Grade 3 
Vomiting and AST/ALT 
elevation 
Hold dose until resolution to 
≤ Grade 1 
100 
Grade 4 
Life-threatening conditions 
(study drug-related) 
Treatment should be 
discontinued 
NA 
1Please see Appendix D for algorithms for management of hand-foot skin reactions, anal 
mucositis, oral mucositis, injection site reaction,  and hyperpigmentation. 
 
Any subject who misses more than one cycle for treatment-related toxicity should 
discontinue from the study. All treatment related toxicities will be documented and graded 
based on NCI CTCAE v4.03. 
 
 
4. PATIENT POPULATION 
 
4.1 Inclusion Criteria 
 
1.   At least 18 years of age 
2.   Ability to understand the purposes and risks of the study and has signed a 
written informed consent form approved by the investigator’s IRB/Ethics 
Committee 
 
3.   Histologically confirmed glioblastoma 
4.   Progression following both standard combined modality treatment with radiation 
and temozolomide chemotherapy, as well as bevacizumab 
5.   Recovered from toxicities of prior therapy to grade 0 or 1 
6.   ECOG performance status ≤ 2 
7.   Life expectancy of at least 3 months 
8.   Acceptable liver function: 


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a.   Bilirubin ≤ 1.5 times upper limit of normal 
b.   AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal (ULN); 
9.   Acceptable renal function: 
a. Serum creatinine ≤ULN 
10. Acceptable hematologic status (without hematologic support): 
a.   ANC ≥1500 cells/uL 
b.   Platelet count ≥100,000/uL 
c.   Hemoglobin  ≥9.0 g/dL 
11. All women of childbearing potential must have a negative serum pregnancy test and 
male and female subjects must agree to use effective means of contraception 
(surgical sterilization or the use or barrier contraception with either a condom or 
diaphragm in conjunction with spermicidal gel or an IUD) with their partner from 
entry into the study through 6 months after the last dose 
 
4.2 Exclusion Criteria 
 
1.   The subject is receiving warfarin (or other coumarin derivatives) and is unable to 
switch to low molecular weight heparin (LMWH) before the first dose of study 
drug. 
2.   The subject has evidence of acute intracranial or intratumoral hemorrhage either 
by MRI or computerized tomography (CT) scan. Subjects with resolving 
hemorrhage, punctate hemorrhage, or hemosiderin are eligible. 
3.   The subject is unable to undergo MRI scan (eg, has pacemaker). 
4.   The subject has received enzyme-inducing anti-epileptic agents within 14 days of 
study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone). 
5.   The subject has not recovered to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≤ 1 from AEs 
(except alopecia, anemia and lymphopenia) due to surgery, antineoplastic agents, 
investigational drugs, or other medications that were administered prior to study 
drug. 
6.   The subject has evidence of wound dehiscence 
7.   Severe chronic obstructive or other pulmonary disease with hypoxemia (requires 
supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% 
by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any 
physiological state likely to cause normal tissue hypoxia 
8.   The subject is pregnant or breast-feeding. 
9.   The subject has serious intercurrent illness, such as: 
a.   hypertension (two or more blood pressure [BP] readings performed at 
screening of > 150 mmHg systolic or > 100 mmHg diastolic) despite optimal 
treatment 
b.   non-healing wound, ulcer, or bone fracture 
c.   significant cardiac arrhythmias 
d.   untreated hypothyroidism 
e.   uncontrolled active infection 
f. symptomatic congestive heart failure or unstable angina pectoris within 3 
months prior study drug 
g.   myocardial infarction, stroke, transient ischemic attack within 6 months 
h.   gastrointestinal perforation, abdominal fistula, intra- abdominal abscess within 


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1 year 
i. history or clinical evidence of pancreatitis within 2 years 
10. The subject has inherited bleeding diathesis or coagulopathy with the risk of 
bleeding. 
11. The subject has received any of the following prior anticancer therapy: 
a.   Non-standard radiation therapy such as brachytherapy, systemic radioisotope 
therapy, or intra-operative radiotherapy (IORT). Note: stereotactic 
radiosurgery (SRS) is allowed 
b.   Non-bevacizumab systemic therapy (including investigational agents and 
small-molecule kinase inhibitors) or non-cytotoxic hormonal therapy (eg, 
tamoxifen) within 7 days or 5 half-lives, whichever is shorter, prior first dose 
of study drug 
c.   Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 
21 days prior to first dose of study drug, with the exception of bevacizumab 
which can be 14 days or maintain the subjects current bevacizumab dosing 
schedule 
d.   Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low- 
dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 
days, prior to first dose of study drug 
e.   Prior treatment with carmustine wafers 
f. Prior treatment with TH-302 
 
 
5.        PROCEDURES 
 
5.1      SUMMARY OF PROCEDURES 
 
Subjects are expected to participate with continued follow up for survival until one year 
after the last dose of study drug. Please refer to Appendix A, Schedule of Assessments, for 
an overview of the study assessments. Subjects who withdraw from the study before all 
follow-up  procedures  have  been performed  will  be  managed  and  documented  as 
described  in Section  8,  Removing Subjects from  the Study. 
 
A summary of visits and clinical procedures is found in Appendix A, Schedule of 
Assessments. The total duration of the active part of the study for each subject will be 
approximately 30 weeks, divided as follows: 
 
• Up to 3 weeks predose (screening period) 
• Up to four 6-week treatment periods of combined TH-302 and bevacizumab. 
• Study termination visit 1-2 weeks after last dose of study medication 
 
 
 
When a subject has completed the study termination or early termination visit, he/she and/or 
a family member will be contacted for survival information every 3 months until one year 
from last dose. 
 
 
5.2 SCREENING PROCEDURES 
All subjects will be screened within 21 days prior to Cycle 1 Day 1. Vital signs, clinical 


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laboratory test results, weight and AEs will be used to assess safety. Efficacy  will   be 
 
 
assessed based on tumor assessments (objective response rate, progression-free survival 
and duration of response) conducted at intervals during the study. Subjects who have not 
progressed after 4 cycles will be permitted to continue therapy.. 
 
During screening, candidates for the study will be fully informed about the nature of the 
study and possible risks, and will receive a copy of the informed consent for review. 
Candidates must read the consent form and sign the document after the investigator has 
answered all questions to the candidate's satisfaction. Further procedures can begin only 
after the consent form has been signed. The original signed consent form will be retained 
by the investigator and a copy will be given to the candidate. Candidates will be evaluated 
for entry into the study according to the stated inclusion and exclusion criteria (Section 4, 
Study Population). The investigator will evaluate the results of all examinations, including 
clinical  laboratory tests,  and  will  determine each candidate's  suitability for the study. 
The investigator must know the baseline results before enrollment. The pregnancy test for 
females  of  reproductive  potential  must  be negative  for those  subjects to proceed to 
enrollment. All screening procedures must be done within 21 days of Cycle 1 Day 1, unless 
otherwise specified.  The following procedures   will   be   performed   to   establish   each 
candidate's   general   health   and qualifications for possible enrollment into the study: 
 
• Obtain signed, written informed consent and permission to use protected health 
information, (in accordance with the Health Insurance Portability and 
Accountability Act or HIPAA). Refusal to sign informed consent and permission 
excludes an individual from the study. 
• Record medical  history,  including  cancer  history:  histology  of  primary  tumor 
(including degree of differentiation), date  of  cancer diagnosis, types and dates of 
prior anti-tumor therapy (including surgery, radiation therapy, systemic therapy), 
and  date of most  recent  disease progression. 
• Record recent medication history, including vitamins, herbal preparations, blood 
products, and other over the counter (OTC) drugs. 
• Record    blood    pressure    (BP), heart    rate    (HR), respiratory rate    (RR) and 
temperature measurements. In subjects with known significant pulmonary disease, 
measure oxygen saturation using pulse oximeter after a 2 minute walk 
 
 
• Perform a complete physical examination, including height and weight. 
• Perform tumor assessment with MRI of the brain per RANO criteria (refer to 
Appendix C) 
• Assess Eastern Cooperative Oncology Group (ECOG) Performance Status score 
(see Appendix B, Eastern Cooperative Oncology Group Performance Status Scale). 
• Draw  blood  samples  for  hematology,  chemistry  and  coagulation  (if  clinically 
indicated) 
• Obtain a blood sample for serum HCG pregnancy test in female subjects of child- 


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bearing potential (all female subjects unless surgically sterilized or at least 1 year 
post-menopausal). 
• Obtain a urine sample for urinalysis with micro. 
• Obtain a baseline ECG to assess for cardiac arrhythmias or evidence of recent 
cardiac events. 
• Review inclusion and exclusion criteria (see Section 4, Study Population). 
 
 
5.3      TREATMENT PERIOD ALL CYCLES 
Study drug should be administered within ±2 days of the nominal time point. Lab tests used 
for determining dosing must be done within 5 days before the first dose of study drug (Cycle 
l/Day 1), within 3 days before Days 15 and 29 of Cycle 1, and Days 1, 15, and 29 of all 
subsequent cycles. All other required study assessments should be obtained within 5 days 
of the nominal time point unless otherwise specified.  Subjects must receive the first dose 
of study drug within 21 days of the start of screening. 
 
5.3.1   Pretreatment Evaluations and Procedures 
The following procedures will be done in all subjects: 
 
• If screening assessments have not been performed within 5 days of Cycle 1 Day 1, 
then screening assessments will be repeated with the exception of informed consent, 
demographics, MRI, medical/surgical history, and ECG; 
• Serum and whole blood for biomarker analysis will be collected from patients on 
screening and immediately prior to treatment on Day 1 of each cycle. 
• Baseline PET imaging will be performed within 3 days prior to Cycle 1 Day 1 
 
5.3.2 Procedures (Day 1 of each cycle) 
Before administering TH-302, the following procedures will be done in all subjects within 
5 days of Cycle 1 Day 1: 
• Record interim medical history since screening; 
• Confirm that subject continues to meet inclusion/exclusion criteria; 
• Record concomitant medications for previous 14 days; 
• Draw serum and whole blood samples for biomarker analysis 
 
 
 
The following procedures will be done predose on all subjects within a 5 day window prior 
to Cycle 1 Day 1 and within 3 days of Day 1 for All Future Cycles (unless otherwise 
specified) and before administering TH-302 in subjects: 
 
• Assess Eastern Cooperative Oncology Group (ECOG) Performance Status score; 
• Assess whether subject is adequately hydrated for administration of study drugs 
• Cycle 2 and all subsequent cycles: Record AEs since last visit; 
• Any   skin   or   mucosal   lesions   considered   due   to   TH-302   should   be 
photographed; 
• Record concomitant medications since last cycle; 


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• Record weight and vital signs; 
• Detailed physical exam including neurologic assessment; 
• Draw  blood  samples  for hematology,  chemistry,  and  coagulation  (if  clinically 
indicated); 
• Draw serum and whole blood samples for biomarker analysis; 
• Obtain (serum or urine) pregnancy test for females of childbearing potential prior to 
start of Cycle 1, and at every other cycle thereafter; 
• Urine dipstick for protein and glucose. If positive and a change from baseline or 
previous cycle, complete urinalysis including microscopic analysis should be 
performed; 
• Triplicate ECG measurements will be done within 30 minutes prior to infusion of 
TH-302 and within 30 minutes of the end of infusion of TH-302 (Cycle 1 only); 
• Administer TH-302 (see section 3.1.4.1 for details) (Plus or minus 2 days.); 
• Administer bevacizumab (see section 3.1.4.2 for details). (Plus or minus 2 days.). 
 
5.3.3 Procedures (Days 15 and 29 of each cycle) 
 
• A physical exam will be done on D15 of Cycles 1 and 2.  This may occur up to 3 
days prior to Day 15; 
• Physical exam on D15 for Cycle 3 and beyond will only be done if clinically 
indicated.  If done, this may occur up to 3 days prior to Day 15; 
• Physical exam will be done on every Day 29 visit (This may occur up to 3 days prior 
to Day 29); 
• Record concomitant medications drugs since the last visit. This may occur up to 3 
days prior to Days 15 and 29; 
• Record AEs since the last visit. This may occur up to 3 days prior to Days 15 and 
29; 
• Urine dipstick for protein and glucose. If positive and a change from baseline or 
previous cycle, complete urinalysis including microscopic analysis should be 
performed; 
• Measure and record vital signs (BP, HR, RR, temperature). This may occur up to 3 
days prior to Days 15 and 29; 
• Triplicate ECG measurements will be done within 30 minutes prior to infusion of 
TH-302 and within 30 minutes of the end of infusion of TH-302 (Cycle 1, Day 15 
only); 
• Obtain   blood   samples  for  hematology, chemistry. This may occur up to 3 days 
prior to Days 15 and 29; 
• Administer TH-302 (see section 3.1.4.1 for details). (Plus or minus 2 days.); 
• Administer bevacizumab (see section 3.1.3.2 for details). (Plus or minus 2 days.). 
 
5.3.4 F-MISO PET Imaging Procedures 
• F-MISO PET imaging will be performed within 3 days of the first dose of TH-302. 


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• Prior to Cycle 2 Day 1, F-MISO PET imaging will be performed in select individuals 
following review of initial imaging results. This imaging will be optional. 
• Plasma pharmacokinetic samples (1ml) will be collected to assess the decay of 18F- 
MISO 
 
 
5.4    STUDY TERMINATION/EARLY STUDY TERMINATION AND SURVIVAL 
FOLLOW-UP 
 
5.4.1 Study Termination / Early Study Termination 
 
This visit will occur 1-2 weeks after the last dose of TH-302 treatment for subjects who 
terminate. The following will be done at the Termination/Early Termination visit: 
 
• Record concomitant medications, including vitamins, herbal preparations, blood 
products, and other OTC drugs since the last visit; 
• Record AEs since the last visit; 
• Perform a complete physical examination, including weight; 
• Assess Eastern Cooperative Oncology Group (ECOG) Performance Status score; 
• Measure and record vital signs (BP, HR, RR, temperature); 
• Obtain   blood   samples   for  hematology, and chemistry 
• Obtain serum and whole blood samples for biomarker analysis; 
• Obtain a blood sample for serum HCG pregnancy test in female subjects of child- 
bearing potential (all female subjects unless surgically sterilized or at least  1 year 
post-menopausal); 
• Obtain  a urine sample  for urinalysis  with  micro; and 
• Perform tumor assessments, using the same imaging assessments done at baseline, 
if not done within past 6 weeks. 
 
In accordance with good medical practice, any ongoing study drug-related AE present at 
study termination, including a clinically significant laboratory test abnormality, will be 
followed until resolved or until the event stabilizes and the overall clinical outcome has been 
ascertained.  Adverse  events  starting  up  to  30  days  after  the  last  dose  of  study 
medication may be collected by telephone contacts. 
 
5.4.2 Survival Follow-up 
When a subject has completed the study termination or early termination visit, he/she 
and/or a family member will be contacted for survival information every 3 months until one 
year from the last dose.  Anti-tumor therapy (description and dates) since the last contact 
will be collected at each survival follow up. 
 
 
5.5 SAFETY PROCEDURES 
 
5.5.1.1 Physical Examination 
A complete physical examination will be performed at screening and at study termination 
or early study termination and results will be recorded by the investigator (or designee). 
Limited physical examination will be done within 5 days before Day 1 of each cycle. Body 


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weight will be measured on Day 1 of every cycle.   The  results   of   the  physical 
examinations  will  be  used  for  safety  monitoring purposes  only.  At  each  study  visit, 
according  to  good  medical  practice,  the  subject's general  health  (e.g.,  appearance, 
adequacy  of  hydration,  presence  of  illness  or  injury, temperature,  and  vital  signs 
indicative  of  a  concurrent  illness)  will  be  assessed  to determine whether continued 
dosing is appropriate. 
 
 
5.5.1.2   Vital Signs 
BP, HR, RR and temperature will be measured at the following time points: 
• Screening 
• Cycles 1-4 
• All  subjects:  Day 1, Day 15, and Day 29 of every cycle (predose and postdose 
for each study drug administered) 
• Study Termination or Early Study Termination 
 
Blood pressure and HR measurements should be obtained with the subject's arm 
unconstrained by clothing or other material. The measurements will be obtained with the 
appropriate cuff  size  from the  opposite  arm  from that  used  for blood  sampling, where 
possible,  which  is  supported  at  the  level  of  the  heart.  All BP measurements will be 
obtained from the same arm throughout the dosing period. The cuff should be placed on the 
designated arm at least 10 minutes prior to taking BP measurements. 
 
 
5.5.1.3   Disease Assessment 
Patients will be assessed at screening, within 3 days prior to the first dose, and at the end of 
every cycle, with MRI per the modified RANO criteria as detailed in Appendix C. 
 
 
 
6.       MATERIALS AND SUPPLIES 
The following instructions are for the study drug, TH-302. 
 
6.1      Supplies 
Liquid Drug Product: TH-302 injection will be supplied in a 10 mL glass vial with a rubber 
stopper and aluminum crimped seal. Each vial contains 650 mg TH-302 (100 mg/mL). Each 
vial of study medication will be labeled clearly with information as required by institutional 
policy which may include: disclosing the lot number, route of administration, Sponsor’s 
name, and appropriate, required precautionary labeling. 
 
6.2     Storage 
Liquid Drug Product: TH-302 injection must be stored in a secure area with limited access 
under controlled conditions as outlined in the TH-302 pharmacy manual. 
 
6.3     Dose Preparation and Method Of Administration 
Liquid Drug Product: Each dose will be prepared in a non-DEHP containing 5% Dextrose 
in Water (D5W) for injection for clinical use infusion bag and administered intravenously 
via an infusion pump and non-DEHP containing IV administration set. Detailed instructions 
for dilution are provided in the Pharmacy Manual. 


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The following table outlines the dilution volume and infusion time based on total dose 
administered. 
 
Total TH-302 Dose 
(mg) 
Infusion Volume 
(mL) 
Infusion Duration 
(minutes) 
< 1000 
500 
30-60 
≥ 1000 
1000 
60 
 
6.4 Drug Accountability 
The investigator is responsible for the control of drugs under investigation.   Adequate 
records of the receipt and disposition of all study drug shipped to the site must be 
maintained.  Records will include dates, quantities received, quantities dispensed, and the 
identification codes   of   the   subjects who   received   study   drug.      The   individual 
administering the study drug will write the study number, subject number, date, and 
start/stop times of administration on the study drug label, and the Drug Accountability 
Record, as appropriate. 
 
6.5      Disposition of Used and Unused Vials of Study Medication 
All used and partially used vials will be destroyed by the pharmacy per the site’s standard 
institutional procedures and in accordance with local and federal regulations as applicable. 
Periodically throughout and at the conclusion of the study, inventory   checks   and 
accountability of study  materials  will  be  conducted  by  a  representative  of  Threshold 
or its designated agent. All unused vials must be retained by the pharmacy until such time 
they receive approval from Threshold or its designated agent to ship unused vials back to 
the sponsor or the sponsor instructs the site to destroy the unused vials. At the end of the 
study, a final drug accountability will be performed in accordance with the site’s 
institutional procedures. The final Drug Accountability and Drug Destruction Record(s) will 
be retained on site which will include the date, lot number, and quantities returned to 
Threshold or its designated agent or destroyed locally. 
 
The investigator’s copy of the Drug Return Destruction Record(s) must accurately 
document the destruction of all study drug supplies.  Records will also include dates, lot 
numbers,  and  quantities  returned  to  Threshold  or  its  designated  agent  or  destroyed 
locally. 
 
7.        MANAGEMENT OF INTERCURRENT EVENTS 
Comprehensive assessments of any apparent toxicity experienced by the subject will be 
performed throughout the course of the study.  Study site personnel will report any clinical 
AE, whether observed by the investigator or reported by the subject. 
 
7.1.1 Grading of Toxicity 
Clinical  AEs  or  abnormal  laboratory  test  results  will  be  assessed  by  the  principal 
investigator or other designated other physician, in accordance with the CTCAE v4.03 
criteria (available at http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 


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7.1.2 Monitoring and Treatment of Toxicity 
A  physician  or  other  qualified  medical  professional  (e.g.  Physician  Assistant,  Nurse 
Practitioner) designated by the Principal Investigator will manage and treat any  toxicity. 
Specific algorithms for management of hand-foot skin reactions, anal mucositis, oral 
mucositis, injection site reaction, and hyperpigmentation are included in Appendix D. 
Subjects should be referred to an ophthalmologist for evaluation if  clinically significant 
ophthalmologic  abnormalities  are  noted.      The ophthalmologist should be directed to 
perform examinations as clinically indicated. 
 
7.2 Adverse Events 
A  physician  or  other  qualified  medical  professional  (e.g.  Physician  Assistant,  Nurse 
Practitioner)   designated   by   the   Principal Investigator   will assess   the   seriousness, 
severity,  and  causality of an  AE  based  on  the  following definitions. 
 
7.2.1   Defining Adverse Events 
An adverse event (AE) is any undesirable event occurring to or in a subject enrolled in a 
clinical trial, whether or not the event is considered related to the study drugs (TH-302, 
bevacizumab).  This includes the time periods beginning after the  first  administration  of 
study drug until  30  days  after the last  dose of study drug. 
Adverse events include the following types of occurrences: 
1) Suspected adverse reactions; 
2)  Other  medical  experiences, regardless  of  their  relationship to  the  study  drug, such 
as injury, causes for surgery, accidents, increased severity of pre-existing symptoms, 
apparently  unrelated  illnesses,  and  significant   abnormalities  in clinical    laboratory 
values,  physiological  testing,   or physical   examination findings; and 
3) Reactions from drug overdose, abuse, withdrawal, sensitivity, or toxicity. 
 
7.2.1.1 Serious Adverse Events 
A serious adverse event (SAE) is any adverse' experience that occurs at any dose and 
results in any of the following outcomes. 
 
1)  Death. This includes any death that occurs during the conduct of the  clinical study, 
including deaths that appear to be completely unrelated to the study drug (e.g., car accident). 
However, deaths that occur due to disease progression are not considered SAEs, but should 
be reported as a death on study.   If  a subject  dies  during the study,  and  an  autopsy is 
performed, the autopsy results should be sent to Threshold. Possible evidence of organ 
toxicity  and  the  potential  relationship  of  the  toxicity  to  the  study  drug  are  of 
particular  interest.   The autopsy   report   should   distinguish between the   relationship 
between   the underlying diseases, their side effects, and the cause of death. 
 
2)  Life-threatening adverse experience. This includes any AE during which the subject 
is, in the view of the investigator, at immediate risk of death from the event as it  occurs. 
This definition does not include any event that may have caused death if it had occurred in 
a more severe form. 
 
3) Persistent or significant disability or incapacity 
 
4)  Inpatient hospitalization or prolongation of existing hospitalization 
 
5) Congenital anomaly or birth defect 


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6) Other medically important event which, according to appropriate medical judgment, 
may  require  medical  or  surgical intervention to  prevent  one  of the outcomes listed 
above. 
 
7) Pregnancy occurring in subjects treated with TH-302 should be reported using the serious 
adverse event reporting form. 
 
 
7.2.1.2   Nonserious adverse events 
A nonserious AE includes any AE that is not defined as an SAE. 
 
 
7.2.1.3 Unexpected adverse events 
An unexpected AE is any AE that is not identified in nature, severity or frequency. 
 
 
7.2.2 Documenting All Adverse Events 
Record all AEs as descriptive findings (symptoms, or  laboratory, physical exam, or vitals 
abnormalities) or diagnoses if etiology is known.  Included are all AEs that occur after the 
start of treatment or within 30 days of administration of the last dose of study drug. Record 
AEs of any severity and AEs that are assessed as serious or not serious. 
 
Note: Unchanged, chronic conditions and cancer symptoms present at baseline are NOT 
AEs and should not be recorded unless there is an exacerbation or   worsening   in 
severity of a chronic condition or cancer symptom after the first administration of 
study  drug  until  30  days  after  the  last  dose  of  study  drug.  Chronic conditions 
and/or   cancer   symptoms   that   exacerbate   or   worsen   in   severity   should   be 
documented  as  a  "worsening"   condition.    Death  due  to  disease progression  and 
measures  of  disease  progression  collected  as  efficacy  endpoints  (eg increasing 
tumor size or new lesions) are not considered adverse events, but should be collected 
as termination reasons (if applicable) and/or noted in tumor assessment appropriate. 
Other reasons for death occurring during the AE reporting period are SAEs and should 
be reported as such. 
 
7.2.2.1 Grading of Adverse Events 
 
Severity of AEs or clinically significant laboratory test results will be assessed in 
accordance  with  the  grading  scale  presented  in  the  Common  Toxicity  Criteria  for 
Adverse  Events  (CTCAE)  version  4.03.  A  copy  of  this  document  can  be  found  at 
the following   internet   site:   http://evs.nci.nih.gov/ftp1/CTCAE/About.html.    Clinically 
significant abnormal laboratory results and lab results requiring an intervention will be 
recorded as AEs and should describe whether the lab result was increased or decreased. 
The following definitions for rating severity of AEs will be used for events not covered in 
the CTCAE. 
 
Grade 1: Mild; awareness of signs or symptoms that are easily tolerated, are of minor 
irritant type,  cause no  loss  of time  from usual  activities, do  not require medication 
or further medical evaluation, and/or are transient. 
 
Grade 2: Moderate; signs or symptoms sufficient to interfere with function but not 


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activities of daily living. 
 
Grade 3:  Severe; signs or symptoms sufficient to interfere with activities of daily 
living; signs and symptoms may be of a systemic nature, or require further medical 
evaluation and/or treatment. 
 
Grade 4:  Disabling or with life-threatening consequences. (This definition does not 
include any event that might have caused death if it had occurred in a more severe form.) 
 
Grade 5: Death 
 
 
7.2.2.2 Relationship to Study Drug 
Using  the  following  criteria,  investigators  will  assess  whether  there  is  a  reasonable 
possibility that the study drugs (TH-302, bevacizumab) caused or contributed to the AE. 
 
Yes 
The  time  sequence  between  the  onset  of  the  AE  and  study  drug  administration  is 
consistent with the event being related to study drug; and/or There is a possible biologic 
mechanism for study drug causing or contributing to the AE; and the AE may or may not 
be attributed to concurrent/underlying illness, other drugs, or procedures. 
 
No 
Another cause of the AE is most likely; and/or the  time  sequence  between  the  onset  of 
the  AE  and  study  drug  administration  is inconsistent with a causal relationship; and/or 
a causal relationship is considered biologically unlikely. 
 
 
7.2.2.3 Abnormal Laboratory Test Results as Adverse Events 
The  investigator  will  monitor  the  laboratory  test  results  and  determine  the  clinical 
significance of any result that falls outside of the reference range.  In accordance with good 
medical practice, any clinically significant abnormal laboratory test results must be followed 
until resolved or stabilized. Abnormal laboratory test results should not be reported as AEs 
unless, in the opinion of the investigator, the results constitute or are associated with a 
clinically relevant condition or require intervention. 
 
In the event of unexplained, clinically significant abnormal laboratory test results, the tests 
should be repeated immediately and followed up until the values have returned to within 
the reference range or to baseline for that subject. 
 
7.2.3 Reporting and Documenting Serious Adverse Events 
Serious adverse events (SAE) that occur at any time point after the first dose of study drug 
until 30 days after the last dose of study drug must be reported. SAEs must be reported as 
per institutional policy and as required under the Data Safety Monitoring Plan (see Section 
10.6 for DSMP).  Contact information for SAE reporting to CTRC@UTHSCSA will be 
provided to each study site. 
 
Submit all known subject information (listed below) within 24 hours of knowledge of the 


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SAE occurrence. The following information should also be entered in the database (or as 
much as possible to obtain and still report the event within 24 hours): 
 
a)  Subject's Demographic Data 
b)  Subject's weight 
c)  Description of SAE, including date of onset and duration, severity, and outcome 
 
d) All  dosing data of study drugs  administered  up  to  the date the SAE occurred 
e) Action taken regarding study drug administration 
f)  Relationship of SAE to study drugs 
 
g) Concomitant medications, including regimen and indication 
 
h)  Intervention, including concomitant medications used to treat SAE 
 
i)  Pertinent laboratory data and diagnostic tests conducted and date 
j) Pertinent medical history of subject 
k) Date of hospital admission discharge (if applicable) 
 
l)  Date of death (if applicable) 
 
2) Perform appropriate diagnostic tests and therapeutic measures, and submit all follow-up 
substantiating data, such as diagnostic test reports and autopsy report to the study PI. 
 
3) Conduct appropriate consultation and follow-up evaluations until the events are resolved, 
stabilized, or otherwise explained by the principal investigator. 
 
4)  Review  each  SAE  report  and  evaluate  the  relationship  of  the  SAE  to  study 
treatment and to the underlying disease.  The study PI will determine whether the SAE is 
unexpected in nature. 
 
 
5)  Based on a cooperative assessment of the SAE between the treating physician and the 
study PI, a decision for any further action will be made.   The primary consideration is 
subject safety.  If the discovery of a new SAE related to the study drug raises concern over 
the safety of its continued administration to subjects, the PI will consult with Threshold 
Pharmaceuticals and will take immediate steps to notify the FDA. 
6)  The investigator must report all SAEs and unexpected problems promptly to his or her 
IRB/IEC,  as appropriate  (see  ICH  Guidelines, Good  Clinical  Practice [E6]). 
Other actions regarding SAEs might include the following: 
a)  Protocol amendment 


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b)  Discontinuation or suspension of the protocol 
 
c) Modification of informed consent to include recent findings 
d)  Informing current study participants of new findings 
e)  Identification of specific AEs as drug-related 
 
 
7.2.4 Follow Up of Adverse Events 
All AEs are followed until they are resolved or determined to be irreversible or otherwise 
explained by the principal investigator. 
 
 
 
7.3     CONCOMITANT AND EXCLUDED THERAPY 
All medications and blood products (prescription and over-the-counter including herbal 
preparations) taken within 14 days of Cycle l/Week 1 will be recorded by the  investigator 
(or designee).  The reason(s) for treatment, dosage, and dates of treatment should be 
recorded in the source documents. In addition, concomitant medications used to treat 
adverse events occurring up to  30 days after the last dose of study drug will be recorded. 
 
Female subjects who have been on hormone replacement therapy (HRT) for menopausal 
symptoms for a period of at least 2 months will not be excluded from the study provided the 
HRT regimen remains unchanged during the conduct of the study. 
 
 
 
8.       REMOVING SUBJECTS FROM THE STUDY 
 
8.1     Criteria for Termination 
Subjects are  free  to  discontinue (withdraw)  at  any time  during  this  clinical  trial.  If a 
subject withdraws from participation in the study during the treatment period, he or she 
should be encouraged to return for an early termination visit for evaluation of safety (see 
Section 5.4.1, Study Termination/Early Study Termination). 
 
The investigator has the right to discontinue any subject from study drug administration or 
study participation.   Reasons for subject discontinuation may include, but are not limited 
to, the following: 
 
a)  Clinically significant deterioration of the subject’s condition; 
 
b)  Disease  progression; 
 
c)  Requirement for other anti-tumor therapy during the study; 
 
d)  Noncompliance; 
 
e)  Pregnancy; 
 
f) Significant AE; 
 
g)  Subject's  right  to  withdraw  from  the  study  at  any  time,  with  or  without 
stated reason; 


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h)  Significant protocol violation; 
 
i) Lost to follow-up; 
 
j) Death; 
 
Any other reason that, in the opinion of the principal investigator, would justify the removal 
of a subject from the study. 
 
The primary consideration in any determination to discontinue a subject’s participation must 
be the health and welfare of the subject. 
 
All subjects will be instructed on the importance of complying with the requirements of the 
study. It is expected that subjects will complete all of the necessary visits. If a subject does 
not    return   for   follow-up   visits   as   directed   or   does   not   adhere   to   the   study 
requirements,  the  investigator will determine if early withdrawal should occur. 
 
8.2 Documentation 
The primary reason for early removal of a subject from the study must be documented 
clearly, and must be completed for any subject who has received any amount of drug during 
the treatment period. If the reason for early withdrawal is an AE or an abnormal laboratory 
value,  the specific event  or test  result  must  also be recorded. 
 
8.3 Procedures for Subjects Who Withdraw Early 
Following early termination, the subject should be informed about which evaluations are 
necessary to monitor his or her safety.   In addition, subjects should be encouraged to 
complete any procedures or evaluations outlined in Section 5.4, Study Termination/Early 
Study Termination. 
 
8.4 Replacement of Subjects 
Subjects who have not received TH-302, or withdraw consent prior to any assessment of 
disease response (clinical or radiographic), will be replaced.  Subject enrollment numbers 
are unique and will not be re-assigned. 
 
9.  CONDITIONS FOR INITIATING,  MODIFYING,  OR  TERMINATING  THE 
STUDY 
 
9.1 Institution Review 
The investigator will  submit this  protocol,  any protocol  modifications, and  the subject 
consent form to be used in this study to the local Institutional Review Board (IRB)  for 
review   and   approval.   A   letter   confirming IRB approval of the protocol and subject 
consent form, and an IRB approved informed consent form must be forwarded to CTRC 
prior to  the enrollment  of subjects into the study. 
 
9.2 Informed Consent 
The investigator or his or her designee must explain to the  subject, in the presence of  a 
witness, the purpose and nature of the study, the study procedures, and the possible 
adverse effects, and all other elements of consent as defined in 21 CFR Part 50 and 
Clinical Trial Directive or ICH E6 guidelines before enrolling that subject in the study.  It 
is  the  investigator's  (or  designee's)  responsibility  to  obtain  informed  written  consent 


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from each subject, or if appropriate, the subject's parent or legal guardian. 
 
9.3 Modifications 
If any modifications in the experimental design, dosages, parameters, subject selection, or 
any other sections of the protocol are indicated or required, the investigator will consult 
with Threshold before  such changes are instituted. Modifications will be accomplished 
through formal amendments and approval from the appropriate IRB. 
 
9.4 Deviations 
The PI will  consider  any deviations  from  the  protocol  on  a  case-by-case  basis.  The 
investigator or other designated alternate in his absence will contact the local DSMB 
(DSMB2) as soon as possible to   discuss the   associated   circumstances.  The principal 
investigator and the DSMB will then decide whether the subject should continue to 
participate in the study. All protocol deviations and the reasons for such deviations must be 
noted in the source documents and will be reported to the IRB as per standard institutional 
policy. 
 
9.5 Termination 
Although  there   are   no   predefined   criteria   for   termination,   if   Threshold   or   the 
investigators) discover conditions during the course of the study that  indicate it  should be 
discontinued, an  appropriate procedure  for  terminating the  study will   be  instituted, 
including notification of  the appropriate regulatory agencies and  IRB. 
 
 
 
10.    INVESTIGATOR'S RESPONSIBILITIES 
 
10.1 Responsibilities/Performance 
The  investigator  will  ensure  that  this  study  is  conducted  in  accordance  with  all 
regulations  governing  the  protection  of  human  subjects.  The  investigator will adhere 
to the basic principles of "Good  Clinical Practice,"  as outlined  in  Title  21  of  the  Code 
of Federal  Regulations  (CFR),  Part  312,  Subpart D, "Responsibilities of Sponsors and 
 
Investigators";  2 1 CFR, Part 50, "Protection  of Human Subjects";  21  CFR, Part  56, 
"Institutional Review Boards";   and the   US   Food and Drug Administration     (FDA) 
guideline   entitled   "Good   Clinical   Practice:     Consolidated Guideline".  For  studies 
conducted outside of the USA, the investigator will ensure adherence to the principles 
outlined  in  the  International  Conference on  Harmonisation (ICH)  E6  "Guideline  for 
Good Clinical Practice". Additionally, this study will be conducted in compliance with 
the Declaration of Helsinki and with any local laws and regulations of the country in which 
the research is conducted. The investigator will ensure that all work and services described 
in or associated with this protocol  will  be   conducted  in  accordance  with  the 
investigational  plan,  applicable regulations,  and  the  highest  standards  of  medical  and 
clinical  research  practice.  The investigator is responsible for the control of drugs under 
investigation. The investigator will   provide   copies   of   the   study  protocol   and 
Investigator's  Brochure  to  all  sub- investigators, pharmacists, and other staff responsible 
for study conduct. 
 
10.2 Confidentiality 


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The investigator must ensure that each subject's anonymity will be maintained and each 
subject's identity will be protected from unauthorized parties. A number will be assigned to 
each subject upon study entry and the number and the subject's initials will be used to 
identify the subject for the duration of the study.  Documents submitted to CTRC should 
not identify a subject by name.  Documents that are not submitted to CTRC (e.g, signed 
consent form) will be maintained by the investigator in strict confidence. 
 
10.3 Informed Consent and Permission To Use Protected Health Information 
It is the responsibility of the investigator to obtain written informed consent from each 
subject participating in this study after adequate explanation, in lay language, of the 
methods, objectives, anticipated benefits, and potential hazards of the study. The 
investigator must also explain that the subject is completely free to refuse to enter the study 
or to discontinue participation at any time (for any reason) and receive alternative 
conventional therapy as indicated. Prior to study participation, each  subject will sign an 
IRB approved informed consent form, which will be in form and substance acceptable 
to  Threshold,  and  receive  a  copy  of  same  (and  information  leaflet,  if appropriate). 
For subjects not qualified or able to give legal consent, consent must be obtained from a 
parent, legal guardian, or custodian. 
The investigator or designee must explain to the subject before enrollment into the study 
that for evaluation of study results, the subject’s protected health information obtained 
during the study may be shared with Threshold, regulatory agencies, and IECs/IRBs. It is 
the  investigator's  (or  designee's)  responsibility  to  obtain  permission  to  use  protected 
health information per HIPAA from each subject, or if appropriate, the subjects' parent or 
legal guardian 
 
10.4 SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
 
The investigator must maintain adequate and accurate records to fully document the 
conduct of  the  study and to  ensure that  study data can be  subsequently verified. These 
documents should be classified into 2 separate categories:  (1) investigator study file and 
(2) subject clinical source documents that corroborate data collected for case report forms. 
 
Subject   clinical   source   documents   would   include   hospital clinic   patient   records; 
physician's  and nurse's  notes; appointment book; original laboratory, ECG, EEG, 
radiology,  pathology,  and  special  assessment  reports;  pharmacy  dispensing  records; 
subject diaries; signed informed consent forms; consultant letters; and subject screening and 
enrollment logs. 
 
The following will be documented in source documents at the site: 
 
1)   Medical    history/physical    condition    and    diagnosis    of    the    subject   before 
involvement in the study sufficient to verify protocol entry criteria (if not already 
present); 
 
2)  Study   number  , assigned  subject  number,  and  verification  that  written  informed 
consent was obtained (each recorded in dated and signed notes on the day of entry into 
the study); 
 
3) Progress notes for each subject visit (each dated and signed); 


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4) Study drug dispensing and return; 
 
5) Review of laboratory test results; 
 
6) Adverse events (action taken and resolution); 
 
7) Concomitant medications (including start and stop dates); and 
 
8) Condition of subject upon completion of or early termination from the study. 
 
 
10.4.1 Exclusion Log 
The investigator must keep a record listing all patients considered for entry into the study 
but subsequently excluded. The reason for each exclusion will be recorded in the Subject 
Exclusion Log. 
 
 
 
11   DATA SAFETY MONTIORING PLAN 
 
Data and Safety Monitoring Oversight 
A Data and Safety Monitoring Plan is required for all an individual protocols conducted at 
CTRC. All protocols conducted at CTRC are covered under the auspices of the CTRC 
Institutional Data Safety Monitoring Plan (DSMP). 
 
The CTRC Institutional DSMP global policies provide individual trials with: 
 
• institutional policies and procedures for institutional data safety and monitoring, 
 
• an institutional guide to follow, 
 
• monitoring of protocol accrual by the CTRC Protocol Review Committee, 
 
• review of study forms and orders by the Forms Committee, 
 
• independent monitoring and source data verification by the CTRC QA 
Monitor/Auditor; 
 
• tools for monitoring safety events, 
 
• monitoring of UPIRSO’s by the Director of Quality Assurance and DSMC, 
 
• determining level of risk (Priority of Audit Level Score – PALS), 
 
• oversight by the Data Safety Monitoring Committee (DSMC),  and 
 
• verification of protocol adherence via annual audit for all Investigator Initiated 
Studies by the CTRC Quality Assurance Division. 
 
 
11.1 Monitoring Progress and Safety 
Due to the risks associated with participation in this protocol, the CTRC DSMB2 in 
conjunction with the Principal Investigator will perform assessment of adverse events, 
adverse event trends and treatment effects on this study.  The CTRC DSMB2 acts as an 
independent Data Safety Monitoring Board (DSMB) for IIS conducted at CTRC.  The 
CTRC DSMB2 will monitor data throughout the duration of a study to determine if 


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continuation of the study is appropriate scientifically and ethically.  An additional layer 
of review is provided by the CTRC Data Safety Monitoring Committee (DSMC) who 
will review the DSMB’s reports. 
 
Baseline events and adverse events will be captured using the CTRC Master Adverse 
Events Document for each patient using CTCAE V4.03 for the grading and attribution of 
adverse events. Usage of the CTRC Master Adverse Events Document centrally 
documents: 
 
• the event and grades the seriousness of the event, 
 
• if the event was a change from baseline, 
 
• the determination of the relationship between the event and study intervention, 
 
• if the event was part of the normal disease process, and 
 
• what actions were taken as a result of the event. 
 
 
Safety Definitions 
For this study, the following safety definitions will be applicable: 
Adverse Event 
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence in 
a human subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the subject’s 
participation in the research  For this study, all adverse events will be documented 
starting after the first dose of study drug and ending 30 days after the last dose of study 
drug is received. 
 
Serious Adverse Event 
 
Any adverse event that: 
 
1. results in death; 
 
2. is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
 
 
3. results in inpatient hospitalization or prolongation of existing hospitalization; 
 
4. results in a persistent or significant disability/incapacity; 
 
5. results in a congenital anomaly/birth defect; or 
 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition 


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Unanticipated Problems Involving Risks to Subjects or Others Definition (UPIRSO): 
Unanticipated problem involving risk to subjects or others includes any incident, 
experience or outcome that meets all of the following criteria: 
 
A.  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 (note: the unfounded 
classification of a serious adverse event as “anticipated” constitutes serious non- 
compliance); 
 
B.  definitely related or probably related to participation in the research; and 
 
C.  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 
 
11.2 Reporting Requirements 
 
For this study, the Master Adverse Events Documents collected on patients for this protocol 
will be reviewed by the Principal Investigator and discussed with the Dana Farber team on 
a monthly basis to determine if a serious safety problem has emerged that results in a 
change or early termination of a protocol such as: 
•   dose modification, 
•   suspending enrollment due to safety or efficacy, or 
•   termination of the study due to a significant change in risks or benefits. 
 
The PI will provide the DSMB2 with the quarterly findings for discussion and review 
during their quarterly meetings. 
 
Specific areas of concern that will be reported to the DSMB2 regarding this study that 
would qualify as an endpoint are: 
 
 
• evidence from interim evaluation suggesting TH302 would have no therapeutic benefit 
to patients on study 
• unacceptable  toxicity  that  would  prevent  patients  from  receiving  treatment  and 
therefore benefit 
 
As per the CTRC DSMP, any protocol modifications, problematic safety reports, 
unanticipated problems, and suspension or early termination of a trial must be reported to 
the DSMB2 and all members of the research team. Furthermore, the PI of this study will 
promptly notify all study affiliates, the UTHSCSA IRB, the CTRC DSMC, and the FDA 
via a FDA Form 3500A written IND safety report of any adverse events that are either 
serious and/or unexpected. 
 
Unanticipated Problem Involving Risk To Subjects Or Others (UPIRSO) is defined as: Any 
incident, experience or outcome that meets all of the following criteria: 
• 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- 


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approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied 
•   definitely related or probably related to participation in the research; and 
• 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. 
 
Suspension and early termination of a trial must also be reported immediately to the 
Director of Quality Assurance who will promptly notify the CTRC DSMC, FDA, all 
participating study sites, and the UTHSCSA IRB. 
 
The PI will review the Master Adverse Events documents to determine the significance of 
the reported events and will provide findings using the Investigator Initiated Study 
Quarterly DSMC Report Form on a quarterly basis with the DSMB2.  The DSMB2 will 
review the information provided by the PI and report to the CTRC DSMC on a quarterly 
basis unless an emergent issue has been identified. The Investigator Initiated Study 
Quarterly DSMC Report Form includes information on adverse events, current dose levels, 
number of patients enrolled, significant toxicities per the protocol, patient status (morbidity 
and mortality) dose adjustments with observed response, and any interim findings.  Any 
trend consisting of three or more of the same event will be reported to the CTRC DSMB 
for independent review outside of the quarterly reporting cycle, which begins three months 
after the first subject is enrolled. The DSMB2 will also provide its findings to the CTRC’s 
Regulatory Affairs Division so that it may be provided to the UTHSCSA IRB with the 
protocol’s annual progress report. Conflict of interest is avoided by the independent 
reviews of the CTRC DSMB2, CTRC DSMC and by ongoing independent review of 
UPIRSO’s by the Director of Quality Assurance. 
 
All SAE and UPRISO’s will be reported following CTRC, UTHSCSA institutional and 
FDA guidelines. 
 
 
 
UTHSCSA SAE/UPIRSO REPORTING REQUIREMENTS 
For IIS that the PI holds the IND 
Type Event 
Report to 
Timeframe 
All AE, SAE and UPIRSO 
Regulatory Affairs and DQA 
ASAP 
SAE 
PI at UTHSCSA 
Within 24 hours 
SAE 
IRB 
Annually 
UPIRSO - all 
PI at UTHSCSA 
Within 24 hours 
UPIRSO - all 
FDA 
Within 7 days 
UPIRSO - life threatening 
UTHSCSA IRB/UTHSCSA OCR 
Within 48 hours 


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UPIRSO - non-life threatening 
UTHSCSA IRB/UTHSCSA OCR 
Within 7 days 
 
 
 
11.3 Assuring Compliance with Protocol and Data Accuracy 
As with all studies conducted at CTRC, the PI has ultimate responsibility for ensuring 
protocol compliance, data accuracy/integrity and responding to recommendations that 
emanate from monitoring activities.   Protocol compliance, data accuracy and reporting of 
events is further ensured by an annual audit conducted by the Data Safety Officer, whose 
audit report is shared with the PI, the research team and will be reviewed by the CTRC 
DSMC. 
 
CTRC DSMB Membership 
 
The CTRC has two DSMB’s with a primary set of members specific to the histology of the 
study consisting of UTHSCSA faculty and staff.  This Protocol will utilize DSMB#2. 
As per NCI guidelines and to eliminate conflict of interest (financial, intellectual, 
professional, or regulatory in nature), the CTRC DSMB specific to this study will not treat 
patients on this protocol.  Usage of the DSMB specific to the histology has been created to 
ensure that experts in that histology are represented on the DSMB assembled for this 
protocol, but may be expanded, at the PI’s discretion, to include other members which may 
include: 
 
• 
Experts in the fields of medicine and science that are applicable to the study (if not 
currently represented on the DSMB), 
 
• 
Statistical experts, 
 
• 
Lay representatives, 
 
• 
Multidisciplinary representation, from relevant specialties including experts such 
as bioethicists, biostatisticians and basic scientists, and 
 
• 
Others who can offer an unbiased assessment of the study progress. 
 
 
 
Additional or alternate membership of in the DSMB is selected by the DSMC chair, in 
conjunction with the PI of this protocol. 
 
CTRC DSMB Charter and Responsibilities 
The CTRC DSMB will provide information on the membership composition, including 
qualifications and experience to both the UTHSCSA IRB and CTRC PRC for review.  The 
CTRC DSMB for this study will act as an independent advisory board to the PI and will 
report its findings and recommendations to the PI, the UTHSCSA IRB and the CTRC 
DSMC.   CTRC DSMB reports will utilize the Investigator Initiated Study DSMC Report 
Form Once the protocol is activated, if not already established elsewhere in the protocol the 
CTRC DSMB will establish and provide: 
 
• procedures for maintaining confidentiality; 
 
• statistical procedures including monitoring guidelines, which will be used to monitor 
the identified primary, secondary, and safety outcome variables; 


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• consider factors external to the study when relevant information becomes available, 
such as scientific or therapeutic developments that may have an impact on the safety 
of the participants or the ethics of the study; 
 
• plans  for  changing  frequency  of  interim  analysis  as  well  as  procedures  for 
recommending protocol changes; 
 
• recommendation of dose escalation, MTD recommendation of early termination 
based on efficacy results; 
 
• recommendation of termination due to unfavorable benefit-to-risk or inability to 
answer study questions; 
 
• recommendation of continuation of ongoing studies; 
 
• recommend modification of sample sizes based on ongoing assessment of event 
rates; and 
 
• review of final results and publications. 
 
 
 
11.4 –Multi-Site Data Monitoring, Requirements and Expectations 
In order to assure timely review of data for safety and quality of data, CTRC requires 
participating institutions to submit participant source documents for review.   Data is 
expected to be updated in a timely manner to facilitate review. 
 
On-site and/or remote monitoring of case report forms will occur after the first subject is 
enrolled and treated on the protocol.  Additional monitoring may occur at the request of 
CTRC.  Participating institutions are required to provide access to source documents.  All 
source documents will be submitted to CTRC with the subject’s HIPAA information 
deidentified and only including the patient’s protocol subject ID number assigned at the 
time of patient registration. 
 
 
 
All data submitted to CTRC will be monitored for timeliness, accuracy, compliance with 
protocol and state/federal requirements.  Results from monitoring and audits will be 
 
shared with any participating sites and the CTRC PI in a timely manner. Any required 
corrections or responses to audit findings are expected to be received back to the CTRC QA 
Division within 30 days. 
 
CTRC, as the coordinating site, will distribute any protocol amendments and IND safety 
reports to the participating institution’s submission to their local IRB. Participating 
institutions are expected to submit and maintain local IRB approval.   Copies of the 
participating site’s IRB approval letter, consent documents and any subsequent amendments 
are required to be on file with CTRC prior to consent of a subject. 


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Stupp,  R.,  et  al.,  Radiotherapy  plus  concomitant  and  adjuvant  temozolomide  for 
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p. 169-74. 
13. 
Kraus-Berthier, L., et al., Histology and sensitivity to anticancer drugs of two human non- 
small cell lung carcinomas implanted in the pleural cavity of nude mice. Clin Cancer Res, 
2000. 6(1): p. 297-304. 
14. 
Newman,  H.F.,  et  al.,  A  comparative  study  of  Ro  03-8799:  racemic  mixture  and 
enantiomers. Br J Radiol, 1986. 59(706): p. 997-9. 
15. 
Roberts, J.T., et al., A phase I study of the hypoxic cell radiosensitizer Ro-03-8799. Int J 
Radiat Oncol Biol Phys, 1984. 10(9): p. 1755-8. 
16. 
Keunen, O., et al., Anti-VEGF treatment reduces blood supply and increases tumor cell 
invasion in glioblastoma. Proc Natl Acad Sci U S A, 2011. 108(9): p. 3749-54. 
17. 
Whitmore, GF, Varghese, AJ, The Biological Properties of Reduced Nitroheterocyclics and 
Possible, Underlying Biochemical Mechanisms. Biochem Pharmacol, 1986. 35: 97-103. 
18. 
Bruehlmeier, et al., J Nucl Med, 2004. 45: 1851-1859. 
19. 
Swanson, et al., J Nucl Med, 2009. 50: 36-44 
20. 
Narayana, et al., Human Brain Mapping, 2010. 31(2): 222-236 
21. 
Yee, et al., Nucl Med Comm. 2006. 27(7): 573-81 
22. 
Ibaraki, et al., J Nucl Med. 2008. 49(1): 50-9 


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23. 
Raichle, et al., J Nucl Med. 1984. 25: 177-187 
 
 
 


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Appendix A: Schedule of Assessments 
Study Procedures 
Screening 
(w/in 21 
days of 
C1D1) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
EOTG 
Day 
Day 
1 
Day 
15 
Day 
29 
Day 
1 
Day 
15 
Day 
29 
Day 
1 
Day 
15 
Day 
29 
Day 
1 
Day 
15 
Day 
29 
Informed Consent 
X 
Demographics 
X 
Med/Surg History 
X 
Physical Exam (to 
include Adverse 
events and conc 
meds)F,H 
X 
XA 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
X 
Vital signs 
X 
XA 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
X 
Height 
X 
XA 
Weight 
X 
XA 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
X 
ECOG 
X 
XA 
XB 
XB 
XB 
XB 
XB 
XB 
X 
ECG 
X 
Xk 
Xk 
Hematology labs 
X 
XA 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
X 
Chemistry labs 
X 
XA 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
X 
Coagulation labsC 
X 
XA 
X 
UrinalysisD 
X 
XA 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
X 
Pregnancy test 
X 
XA 
XB 
X 
TH-302F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BevacizumabF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI-BT 
Questionairre 
X 
Xj 
Xj 
Xj 
X 
Tumor AssessmentE 
X 
XA,E 
XB,E 
XB,E 
XB,E 
Serum/Whole Blood 
Sampling for 
BiomarkersH 
XA 
XB 
XB 
XB 
X 
18F-FMISO-PET 
XB, L 
XB,I, L 


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Footnotes for Appendix A 
 
A: May be done up to 5 days prior to visit. 
B: May be done up to 3 days prior to visit. 
C: INR only if pt is on warfarin 
D: Screen & EOT: UA with micro. Other visits, urine dipstick for protein & glucose. If positive or change from BL, complete urinalysis w/ micro. 
E: Tumor Assessments: At screening & after every cycle (within 3 days). 
F: Plus or minus 2 days. 
 
G: Occurs 3-4 weeks after the last dose of TH-302 for subjects who terminate early. 
 
H: Testing includes hypoxia biomarkers (GLUT-1, HIF-1a, LDH-A, VEGF) as well as angiogenesis/vasculogenesis 
biomarkers(SDF1, bFGF1, circulating endothelial cells/ progenitor circulating cells). Done pre-dose on Day 1. 
I:  Optional assessments 
 
J:  Done prior to dosing 
 
K: Triplicate ECG done within 30 minutes prior to TH-302 infusion within 30 minutes after the end of TH-302 infusion 
 
L: To include plasma pharmacokinetic collection to assess decay of 18F-FMISO 


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APPENDIX B: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE SCORE SCALE 
 
 
 
 
 
Grade 
Description 
 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead. 


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APPENDIX C: RANO TUMOR RESPONSE 
 
 
 
 
 
 
 


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Appendix D: TH-302 Skin and Mucosal Toxicity Treatment Algorithms 
 
 
Severity (CTCAE v.4) 
Intertriginous Rash Intervention 
 
 
Grade 0 
 
Asymptomatic 
 
Prophylaxis - Apply Preparation H to perineal area, under arms and areas where one skin folds 
touch15 minutes before TH-302 infusion. Apply a cool pack to the  inguinal region during TH-302 
infusion. After infusion apply maximum strength Desitin cream bid  to perineal areas and after 
bowel movement. Gentle skin care instructions given. 
 
 
  
Grade 1  
 
 
Lesions covering <10% 
BSA with or without 
symptoms 
 
Continue TH-302 at current dose and monitor for  change in severity 
 
Apply Preparation H to perineal area, around the  anus, under arms and areas  where one skin 
surface touches another skin surface 15  minutes before TH-302 infusion . Also apply a cool pack to 
the  inguinal region during TH-302 infusion. Apply Silvadene 1% cream AND triamcinolone 0.1% 
cream bid  to affected areas. 
 
Reassess after 2 weeks (either by  healthcare professional or patient self-report); 
if reactions worsen proceed to next step 
 
 
Grade 2 
 
Lesions covering 10-30% 
BSA with or without 
symptoms; limiting 
instrumental ADL 
 
First obtain bacterial/viral cultures if infection is suspected and continue with TH- 
302 infusion and treatment of skin reaction with the  following: 
Silvadene 1%  cream AND triamcinolone 0.1% cream bid 
Reassess after 2 weeks (either by  healthcare professional or patient self-report); 
if reactions worsen or do  not  improve, proceed to next step 
 
 
Grade 3 
Severe, generalized 
erythroderma or 
eruption;desquamation 
covering ≥30% BSA 
with or without 
symptoms; limiting self 
care ADL 
 
Interrupt TH-302 until severity decreases to grade 0-1; obtain bacterial/viral 
cultures if infection is suspected and continue treatment with the  following: 
 
Silvadene 1%  cream bid  and triamcinolone 0.1% cream 
 
Reassess after 2 weeks; if reactions worsen or do  not  improve, dose interruption 
or discontinuation per  protocol may be  necessary 


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Hand-Foot Skin  Reaction 
 
Severity (CTCAE v.4)  
Intervention 
 
Grade 0 
 
Asymptomatic 
Prophylaxis with Ammonium lactate 12% cream  (Amlactin®) twice  daily 
OR heavy  moisturizer (e.g. vaseline) twice  daily 
 
 
Grade 1 
 
Minimal skin  changes or 
dermatitis (e.g., 
erythema, edema or 
hyperkartosis) without 
pain 
Continue TH-302 at current dose  and monitor for change in severity 
 
Prophylaxis with  cryotherapy for hands and  feet 
Ammonium lactate 12%  cream twice daily  AND 
clobetasol 0.05% cream once daily 
Reassess after  2 weeks (either by healthcare professional or patient self- 
report); if reactions worsen proceed to next  step 
 
 
Grade 2 
 
Skin  changes (e.g., 
peeling, blisters, 
bleeding, edema or 
hyperkeratosis) with 
pain, not  interfering with 
function 
Continue TH 302 and   begin treatment of skin reaction with  the following: 
Ammonium lactate 12%  cream twice daily 
AND  clobetasol 0.05% cream once  daily 
 
Reassess after  2 weeks (either by healthcare professional or patient self- 
report); if reactions worsen or do not improve, proceed to next  step 
 
 
Grade 3 
Severe skin  changes 
(peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with 
pain; limiting self  care 
ADL 
Interrupt TH-302 until  severity decreases to grade 0-1;  continue treatment of 
skin reaction with  the following: 
Clobetasol 0.05% cream twice daily 
AND  pain  control with  NSAIDs/CGRP inhibitors/Narcotics 
 
Reassess after  2 weeks; if reactions worsen or do not improve, dose 
interruption or discontinuation per protocol may  be necessary 


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Intervention 
Anal  Mucositis 
Severity (CTCAE v.4) 
 
 
Grade 0 
 
Asymptomatic 
Prophylaxis - Apply Preparation H to perineal area, around the anus, under arms and  areas 
where one  skin  surface touches another skin  surface 15 minutes before TH-302 infusion . 
Also  apply a cool  pack to the inguinal region during TH-302 infusion. After infusion apply 
Maximum strength Desitin cream bid to perineal areas and  after bowel movement. 
Gentle skin  care  instructions given 
 
 
Grade 1 
 
Asymptomatic or mild 
symptoms; 
intervention not 
indicated 
 
Continue TH-302 at current dose  and monitor for change in severity 
 
Continue Prophylaxis above AND pain  control 
 
Reassess after 2 weeks (either by healthcare professional or patient self-report); if 
reactions worsen proceed to next step 
 
 
 
Grade 2 
 
Symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL 
Continue with  treatment with TH 302 and  recommend physician evaluation and 
treatment of skin reaction with the following: 
 
Continue Preparation H and Desitin and local  cryotherapy during infusiion 
Apply  silvadene 1% and triamcinolone 0.1% creams bid AND  pain control 
 
Reassess after 2 weeks (either by healthcare professional or patient self-report); if 
reactions worsen or do not improve, proceed to next step 
 
 
 
Grade 3 
 
Severe symptoms; 
limiting self  care  ADL 
Interrupt TH-302 until severity decreases to grade  0-1; Assess/manage pain and 
recommend evaluation; continue treatment of mucosal reaction with the following: 
 
Continue local  cryotherapy, silvadene 1% and triamcinolone 0.1% creams 
AND  Pain  control measures 
 
Reassess after 2 weeks; if reactions worsen or do not improve, dose  interruption 
or discontinuation per protocol may be necessary 
 
*Encourage limiting self  care  ADL 


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Protocol CTRC# 12-0105  
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Severity (CTCAE v.4) 
 
Oral  Mucositis 
 
 
Intervention 
 
Grade 0 
 
Asymptomatic 
 
Prophylaxis with  oral cryotherapy during infusion 
 
 
Grade 1 
 
Asymptomatic or mild 
symptoms; 
intervention not 
indicated 
Continue TH-302 at current dose  and monitor for change in severity; 
Recommend dental evaluation 
 
Oral cryotherapy during infusion AND  Pain  control AND  Elixir 
(Hydrocortisone 200mg, Nystatin 2 million units, tetracycline 1500mg,Benadryl 
equal to 250cc); Swish & Swallow 1 tsp tid 
Reassess after 2 weeks (either by healthcare professional or patient self-report); if 
reactions worsen proceed to next step 
 
 
 
 
Grade 2 
 
Moderate pain; not 
interfering with oral 
intake; modified diet 
indicated 
Continue TH-302 infusion; Assess/manage oral pain and recommend dental 
evaluation and continue treatment of skin  reaction with  the following: 
 
Oral cryotherapy during infusion AND 
Pain  control AND  Elixir  (Hydrocortisone 200mg, Nystatin 2 million units, 
tetracycline 1500mg, Benadryl equal to 250cc); Swish & Swallow 1 tsp tid 
 
Reassess after 2 weeks (either by healthcare professional or patient self-report); if 
reactions worsen or do not improve, proceed to next step 
 
 
 
 
Grade 3 
 
Severe pain; interfering 
with oral  intake 
Interrupt TH-302 until severity decreases to grade 0-1; Assess/manage oral pain 
and recommend dental evaluation; continue treatment of mucosal reaction with  the 
following: 
 
Oral cryotherapy during infusion AND 
Pain  control AND  Elixir  (Hydrocortisone 200mg, Nystatin 2 million units, 
tetracycline 1500mg, Benadryl equal to 250cc); Swish & Swallow 1 tsp tid 
 
Reassess after 2 weeks; if reactions worsen or do not improve, dose  interruption 
or discontinuation per protocol may  be necessary 
 
*Encourage use  of soft  toothbrush 


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Injection site reaction 
 
Severity (CTCAE v.4)  
Intervention 
 
Grade 0 
 
Asymptomatic 
 
Observe for correct placement and infusion rate 
 
 
Grade 1 
 
Asymptomatic or Mild 
Pain, Itching or 
Erythema; intervention 
not indicated 
Continue TH-302 at current dose  using alternate access and monitor for 
change in severity 
 
Extremity elevation AND  daily warm compresses 
 
Reassess after  2 weeks (either by healthcare professional or patient self- 
report); if reactions worsen proceed to next  step 
 
 
 
Grade 2 
 
Moderate pain  or 
swelling, with 
inflammation or 
phlebitis; limiting 
instrumental ADL 
Continue TH-302 at current dose  using alternate access and monitor for 
change in severity; continue treatment of skin reaction with  the following 
 
Extremity elevation AND  daily warm compresses 
 
Reassess after  2 weeks (either by healthcare professional or patient self- 
report); if reactions worsen or do not improve, proceed to next  step 
 
 
Grade 3 
 
Ulceration or necrosis 
that  is severe; 
hospitalization or 
operative 
intervention indicated; 
limiting self care ADL 
 
Continue TH-302 at current dose  using alternate access and monitor for 
change in severity; continue treatment of skin reaction with  the following: 
 
Plastic surgery/wound care  team  consultation AND  oral antibiotics 
 
Reassess after  2 weeks; if reactions worsen or do not improve, dose 
interruption or discontinuation per protocol may  be necessary 


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CTRC at UTHSCSA 
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Hyperpigmentation 
Severity (CTCAE v.4)  
Intervention 
 
 
Grade 0 
 
Asymptomatic 
 
Prophylaxis with sunscreen SPF 30 to face, ears, neck, arms and 
hands when exposed to sun, use  of hats and  protective clothing 
 
 
 
 
 
Grade 1 
 
 
Covering <10% BSA; no 
psychosocial impact 
Continue TH-302 at current dose and  monitor for  change in severity 
 
 
Ensure that  there is no associated dermatitis (erythema, rash, edema) 
that  should be treated with triamcinolone 0.1% cream; 
treat with ammonium lactate 12% cream bid AND use  sunscreen 
 
Reassess after 2 weeks (either by healthcare professional or patient self- 
report); if reactions worsen proceed to next step 
 
 
 
 
 
Grade 2 
 
Covering >10% BSA; 
associated psychosocial 
impact 
Continue TH-302 infusion and  begin treatment of skin reaction 
with the  following: 
 
Hydroquinone 4%  cream bid  to affected areas AND 
strict sun  protection 
 
Reassess after 2 weeks; if reactions worsen or do not  improve, dose 
interruption or discontinuation per  protocol may be necessary 


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Appendix E: MD. Anderson Symptom Inventory-Brain Tumor (1\IDASI-BT) 
Date: r;:Qt QJ/ 
 
Subjec t Jnldals:o::IJ 
 
 
Study Name: -------- 
Prototol#:-------- 
P : ---------   
- 
MD Anderson # j  I I I I I I PDMS # j I I 
 
M. D. Anderson Symptom Inventory - Brain Tumor (MDASI- Bli) 
 
Part I.How sewre are )'0\W symptoms? 
People with cancer frequent y have symptoms that are caused by theri disease or by their treatment. We 
ask you to rate how severe the following symptoms l'lave beenIn the last 24 hours.Pleue flO in the 
circl e below from 0 (symptom has not been present) to 10 (the symptom was as bad as you can Imagine 
H could be) for each Item. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 0 0 
 
 
 
Page 1 of 2 
CopyrighC 2000 The University of TexasM.D. AndersonCancer Center 
AllIS "'serwd. 


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5& 
 
 
 
 
 
Caw:    unthl/ 
I w 
Subjtet nltlols: 
 
 
 
Study Name:---   -- - - 
Protocol:   - - -- - - - 
PI: 
- - ---- 
MD Anderson# j I  I  I  I I I POMS # j  
I I I 
 
 
 
 
0 
 
0 
 
 
 
 
 
 
 
 
 
 
 
 
Port M.How havo yo.. symptoms lntoo<foo.., 
 
Symptom& froquontly intarforo with 
with the following items in 
 
 
How muchhave your oymptoms lntarforod 
 
 
 
 
 
 
2•. Mood?  
0 o :  o  0 0· 0 0 0: 0 0 0 
 
 
 
 
 
 
27   - 
 
28. Enjoymonl lifo? 
 
 
 
 
 
 
Page 2 of 2 
Cclpjrighl2000 The U ri¥M"'
ilr
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lg
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M..-
D. 
c.,_ COlli« 


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APPENDIX F: PET IMAGING PROCEDURES 
 
TRACER: 
Molecular Characterization: 
 
Storage Conditions: 20 mL Sterile Syringe at room temperature. 
Handling Procedures:  According to established Institutional guidelines for safe handling of radioactive 
material 
Dilution: Diluted with normal saline to an activity of 3.7 MBq/kg (0.1 mCi/kg) (maximum 260 MBq, 7 mCi) 
with a final volume of < 15 mL. 
Dosimetry Assessment:  gamma-ray dose calibrator as described 
 
 
PET Scan Acquisition and Reconstruction 
All PET imaging will be performed on a research-dedicated Siemens/CTI HR+. This PET system acquires 63 
simultaneous axial (horizontal) planes over a transaxial field of view of 15.5 cm, sufficient to cover the 
entire brain. The in-plane resolution is 4.1 mm FWHM (full-width at half maximum), equal to that used in 
the fMRI studies. Emission scans will be obtained for FMISO (see details in the following paragraphs). 
Transmission scans will be performed with a rotating 10 mCi pin source.  Emission images will be 
reconstructed using a standard filtered back-projection algorithm with a 6 mm FWHM high-resolution 
Hahn filter, including attenuation correction computed from the transmission scans.  Reconstructed 
images are transferred to an image analysis workstation for further processing in MATLAB 7. 
 
BF Computational Strategy 
Hypoxia imaging using 18FMISO. Patients will not be required to fast. Venous access lines will be 
established in each arm, one for FMISO injection and the other for blood sampling. A transmission scan 
will be obtained for 15 min with the patient in the supine position. Patients will be injected intravenously 
with 3.7 MBq/kg (0.1 mCi/kg) of 18FMISO, maximum 370 MBq (10 mCi). Images will be acquired in three 
dimensional mode with 63 slices covering a 15.5-cm axial field of view. A single field of view emission 
scan (30 min) of the brain with tumor will be obtained approximately 120 min post-injection. During 
emission tomography, four venous blood samples will be collected at intervals of 5 min. Whole blood 
samples of 1 mL each will be counted in a calibrated well counter. 18FMISO blood activity will be averaged 
and then expressed as mCi/mL (or MBq/ml) of decay corrected to time of injection. Reconstructed 
18FMISO PET images will be scaled to the average venous blood concentration of 18FMISO activity to 
produce tumor-to-blood (T/B) values. A three dimensional pixel by pixel T/B calculation will be 
performed. The number of pixels in the brain with a T/B ratio of ≥1.2, indicating viable hypoxic tissue, will 
be determined and converted to cubic millimeters to assess hypoxic volume (HV). This cut-off value of 1.2 
has been used to determine HV in previous studies exploring 18FMISO PET[2-6]. Various T/B ratios will be 
used to determine HV in order to confirm and verify that a T/B ratio of 1.2 is reasonable to determine HV. 


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References for Appendix F 
 
1. 
Powers, W.J., et al., Extracranial-intracranial bypass surgery for stroke prevention in 
hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA, 
2011. 306(18): p. 1983-92. 
2. 
Rajendran, J.G., et al., Hypoxia and glucose metabolism in malignant tumors: evaluation by 
[18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. 
Clin Cancer Res, 2004. 10(7): p. 2245-52. 
3. 
Swanson, K.R., et al., Complementary but distinct roles for MRI and 18F-fluoromisonidazole PET in 
the assessment of human glioblastomas. J Nucl Med, 2009. 50(1): p. 36-44. 
4. 
Spence, A.M., et al., Regional hypoxia in glioblastoma multiforme quantified with 
[18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with 
time to progression and survival. Clin Cancer Res, 2008. 14(9): p. 2623-30. 
5. 
Szeto, M.D., et al., Quantitative metrics of net proliferation and invasion link biological 
aggressiveness assessed by MRI with hypoxia assessed by FMISO-PET in newly diagnosed 
glioblastomas. Cancer Res, 2009. 69(10): p. 4502-9. 
6. 
Kawai, N., et al., Correlation of biological aggressiveness assessed by 11C-methionine PET and 
hypoxic burden assessed by 18F-fluoromisonidazole PET in newly diagnosed glioblastoma. Eur J 
Nucl Med Mol Imaging. 38(3): p. 441-50.