A Phase I/II Study of the Combination of Temozolomide and Pazopanib in Advanced Pancreatic Neuroendocrine Tumors (PNET)
Phase: PHASE1
Conditions: Pancreatic Alpha Cell Carcinoma, Pancreatic Beta Islet Cell Carcinoma, Pancreatic Delta Cell Carcinoma, Pancreatic G-cell Carcinoma, Recurrent Islet Cell Carcinoma
Sponsor: Northwestern University

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A Phase I/II Study of the Combination of Temozolomide and Pazopanib in 
Advanced Pancreatic Neuroendocrine Tumors (PNET) 
PRINCIPAL INVESTIGATOR:     Sheetal M.Kircher, MD
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
676 North Saint Clair, Suite 850
Chicago, IL-60611
Ph: 312-695-6180
Fax: 312-695-6189
Email: skircher@nm.org
 
SUB-INVESTIGATORS:
Northwestern University
University of Michigan
Al B. Benson, III, MD 
Mark Zalupski, MD
Mary F. Mulcahy, MD
U of M Comprehensive Cancer Center
Vahid Yaghmai, MD
1500 E. Medical Center Dr, Rm 3219
Michael J. Avram, PhD
Ann Arbor, MI 48109-5934
734-615-3969 (phone)
734-647-9647 (fax)
zalupski@med.umich.edu  
Fox Chase Cancer Center
Vanderbilt University
Crystal Denlinger, MD
Jordan D. Berlin, MD
Fox Chase Cancer Center
2220 Pierce Avenue
333 Cottman Avenue
777 Preston Building
Philadelphia, PA 19111
Nashville, TN 37232
215-214-1676 (phone)
615-936-8422 (phone)
crystal.denlinger@fccc.edu
jordan.berlin@Vanderbilt.edu
University of Washington
E. Gabriela Chiorean, MD
Fred Hutchinson Cancer Research Center
825 Eastlake Ave East, G4830
Seattle, WA 98109
Phone: 206-288-6248
gchiorea@seattlecca.org 
 
STATISTICIAN: 
Alfred Rademaker, PhD
Northwestern University
FUNDING AGENCY:
NCCN
IND STATUS:
EXEMPT
Robert H. Lurie Comprehensive Cancer Center
Clinical Research Office
676 N. St. Clair Street, Suite 1200
Chicago, IL 60611
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 SYNOPSIS
 Title
A Phase I/II Study of the Combination of Temozolomide and Pazopanib  
in Advanced Pancreatic Neuroendocrine Tumors (PNET) 
 Version Date
January 24, 2018
 Study Duration
3 Years
 Study Center(s)
Northwestern University, University of Michigan, Vanderbilt University,   
Fox Chase Cancer Center, University of Washington
 Objectives
Phase I Primary Objective: 
Determine the maximum tolerated dose (MTD) of temozolomide and  
pazopanib combination in patients with advanced PNET. 
Phase I Secondary Objectives:
1. Determine safety and toxicity profile. 
2. Describe the pharmacokinetics of temozolomide alone and in 
combination with pazopanib.
3. Observe the ORR.
Phase II Primary Objective:
Determine the ORR.
Phase II Secondary Objectives
1. Determine PFS and OS, DCR, and DOR.
2. Determine the safety and toxicity profile of the combination in a 
larger cohort of patients.
Exploratory/Correlative Objectives: 
1. Correlate the expression of tissue methyl–guanine methyl 
transferase (MGMT) as measured by immunohistochemistry (IHC) 
with ORR and PFS.
 Number of Subjects
Phase I:  9-18 patients + an additional 6 enrolled at the MTD to form a  
PK cohort
Phase II:  11-27 patients (includes the 6 from the PK cohort)
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Diagnosis and Main 
Inclusion Criteria
Inclusion Criteria:

Histologically confirmed islet cell carcinoma not amenable to 
surgical resection, with measurable disease (as defined by RECIST 
version 1.1 criteria)

Age 18 years or older

0-4 prior therapies allowed

ECOG performance status ≤ 2 

Life expectancy > 3 months

Controlled blood pressure

LVEF ≥ 50%

Adequate baseline organ and marrow function  
Exclusion Criteria

Known HIV infection 

Uncontrolled hypertension (≥ 140/90 mm Hg)

Symptomatic brain or bone metastasis

History of seizure disorder requiring antiepileptic medication

Active second malignancy other than non-melanoma skin cancer or 
cervical carcinoma in situ.  

Clinically significant GI abnormalities that may increase the risk 
for gastrointestinal bleeding or absorption

Cardiovascular conditions within the past 6 months

Corrected QT interval (QTc) > 480 msecs.  

Cerebrovascular accident including TIA, untreated PE or deep 
DVT within past 6 months.  

Recent hemoptysis 
Treatment Summary
Phase I:
One cycle = 28 days.  Starting doses (cohort 1) will be temozolomide   
150 mg/m2 orally on Days 1-7 and 15-21, and pazopanib 400 mg orally 
once daily continuously throughout cycle.  Dose escalation and de-
escalation will be conducted following a standard “3+3” design.  DLT 
period = 1st cycle (28 days)
Phase II:
Once MTD established, will proceed to the phase II portion.  Response 
will be assessed after every 2 cycles. 
 
(Note: The MTD has been identified at dose level -2 (75 mg/m2 per day 
p.o. days 1-7 and 15-21 of Temozolomide and 400 mg per day p.o. days 
1-28 of Pazopanib. 
As of 12.15.15 , all patients moving forward will be treated at this dose)
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Analysis Summary
The study design is a multicenter, phase I/II, open-label, non-randomized 
study.  Phase I will be a dose-escalation study to determine the MTD and 
the safety profile of the combination of temozolomide and pazopanib in 
patients with advanced pancreatic neuroendocrine tumors.  
Pharmacokinetic sampling for temozolomide and pazopanib will be 
performed in an additional 6 patients enrolled at the MTD.  The MTD 
will be the recommended Phase II dose.  Once the MTD is determined, 
the study will proceed to a single-arm, open-label phase II to evaluate 
efficacy endpoints.  Phase II analyses will include patients treated at the 
MTD in the PK cohort from phase I.  This protocol describes the phase 
I/II trial.  Data will be pooled from patients enrolled at all study sites. 
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TABLE OF CONTENTS
Synopsis
2
Schema
6
1.0  Introduction – Background & Rationale
7
2.0  Study Objectives
14
3.0  Patient Selection & Eligibility Criteria
15
4.0  Patient Registration
19
5.0  Treatment Plan
20
6.0  Endpoint Assessment
38
7.0  Study Parameters
45
8.0  Drug Formulation & Procurement
47
9.0  Statistical Considerations
51
10.0  Adverse Event Monitoring & Reporting
54
11.0  Study Management
61
12.0  Pathology Requirements
64
Appendices                                                                                                    68
References                                                                                                     92
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SCHEMA
Phase I – Dose Escalation
Phase II – Simon Two-Stage
1 Starting doses for Cohort 1:  temozolomide 150 mg/m2 orally – Days 1-7 and 15-21 of each cycle, 
pazopanib 400 mg orally daily continuously throughout each cycle (1 cycle = 28 days).  
2 The sample size for Stage 1 of the phase II portion will include the 6 patients from the PK cohort treated 
at the MTD.
(Note: The MTD has been identified at dose level -2 (75 mg/m2 per day p.o. days 1-7 and 15-21 of 
Temozolomide and 400 mg per day p.o. days 1-28 of Pazopanib. 
As of 12.15.15, all patients moving forward will be treated at this dose.) 
   
Eligible Patients 
with Advanced 
Pancreatic NET
“3+3” Dose 
Escalation
Temozolomide + 
Pazopanib 1
Identify MTD = 
Recommended 
Phase II Dose 
(RP2D)
PK testing in 6 
additional 
patients at MTD 
(PK cohort)
Stage 1: Treat 
11 patients at 
RP2D 2
If ≤ 2 patients have 
ORR, study will 
close; if > 2 pts 
have ORR, proceed 
to Stage 2
Stage 2: Treat 16 
additional patients 
(total of 27); if ≥ 8 
have ORR, suggest 
efficacy
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1.0
INTRODUCTION – BACKGROUND AND RATIONALE
1.1
Pancreatic Neuroendocrine Tumors:  Background and Standard Therapies
Pancreatic neuroendocrine tumors (NETs), also known as pancreatic endocrine 
tumors or islet cell carcinomas, are rare malignancies with a reported annual 
incidence of 0.32 cases per 100,000 in the Surveillance, Epidemiology, and End 
Results (SEER) Program registries.1  Advanced pancreatic NETs have a 
reputation for being more indolent than other pancreatic malignancies.  However, 
they can be aggressive and are most often diagnosed at an advanced stage (14% 
localized, 22% regional, and 64% distant).  Analyses from the SEER data from 
2000 to 2004 showed a median survival time of only 27 months among patients 
with advanced disease.2  Pancreatic NETs are sometimes divided into functioning 
and nonfunctioning tumors based on whether they cause clinical hormonal 
symptoms.  However, the functional status of these tumors may change over time 
or with treatment.  The introduction of somatostatin analogs has resulted in major 
advances in the management of hormonal syndromes from NETs and has recently 
been shown to prolong time to tumor progression in patients with advanced 
midgut NETs.3  
Pancreatic NETs are responsive to cytotoxic chemotherapy.  Streptozocin- based 
combination therapy has been an historical treatment standard for patients with 
advanced pancreatic NET.  In an early randomized trial, streptozocin 
plus doxorubicin had a combined biochemical and radiologic response rate of 
69% and a median survival of 2.2 years.4 A retrospective analysis of 84 patients 
with either locally advanced or metastatic pancreatic NETs treated with 
streptozocin, 5-FU, and doxorubicin reported a 39% objective radiographic 
response rate and a median survival duration of 37 months.5  The widespread 
adoption of streptozocin-based regimens has been limited by a relatively 
cumbersome administration schedule and by concerns about toxicity, including 
nausea, hair loss, and renal dysfunction.  More recently, novel approaches 
including vascular endothelial growth factor (VEGF) pathway inhibitors 
(including bevacizumab6, sorafenib7, sunitinib8, and pazopanib9) have shown 
preliminary evidence of activity in pancreatic NETs. 
 
1.2
Temozolomide in Pancreatic NETs
1.2.1
Clinical activity in Pancreatic NETs
Temozolomide is a cytotoxic alkalyting agent that has been specifically 
developed as an oral and less toxic alternative to dacarbazine.10  
Temozolomide and dacarbazine have similar mechanisms of action:  both 
agents are metabolized to the active agent 5-(3-methyl-triazeno) 
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imidazole-4-carboxamide (MTIC), an inhibitor of nucleoside 
incorporation.   Temozolomide is currently FDA approved for refractory 
anaplastic astrocytoma and newly diagnosed and recurrent glioblastoma 
multiforme (GBM).
Both temozolomide and dacarbazine have demonstrated activity in 
treatment of metastatic pancreatic NETs.  The Eastern Oncology Group 
(ECOG) evaluated the efficacy of dacarbazine in a phase II study in 
patients with advanced pancreatic NETs and reported an ORR of 33% and 
a median overall survival (OS) of 19.3 months.11  A combination of 
dacarbazine, vincristine, and cyclophosphamide in patients with 
pheochromocytoma was reported to result in a biochemical responses but 
was also associated with significant toxicity.12-14  The potential toxicity of 
dacarbazine precludes its use in treatment for advanced pancreatic NET.  
The efficacy of temozolomide monotherapy was reported in a phase II 
trial in patients with advanced pancreatic NETs, only one of 12 (8%) 
patients with pancreatic NET had a PR, while SD lasting at least 4 weeks 
was noted in 8 (67%) patients.15    A phase II study of 30 patients with 
metastatic pancreatic NETs investigated the combination of capecitabine 
plus temozolomide and reported ORR 70%.  Among these patients, 21 
(70%) achieved a PR, 8 (27%) had SD, and 1 (3%) had disease 
progression.16  
                        
                        1.2.2
Safety of temozolomide
In the phase II study of temozolomide monotherapy, toxicities were 
mainly hematologic, and dose reduction due to hematologic toxicity was 
necessary in 4 patients.  There were 2 patients with grade 3/4 fatigue.15  In 
the phase II study of temozolomide combined with capcitabine, Four 
patients (4%) experienced grade 3 or 4 adverse events (fatigue n=1, 
elevated AST n=1, anemia n=1, thrombocytopenia n=1).16   
1.3
Role of VEGF Pathway in Pancreatic NETs 
Neuroendocrine tumors are characterized by abundant vasculature and high levels 
of VEGF expression, and therefore are potentially susceptible to therapeutic 
strategies targeting pathways involved in angiogenesis.17 
                        
                        1.3.1
Preclinical studies of VEGF inhibition in Pancreatic NETs
Overexpression of VEGF and its receptor subtypes has been observed in 
preclinical models in both carcinoid and pancreatic endocrine tumors.  
This suggests that autocrine activation of the VEGF pathway may promote 
tumor growth.17-19  Casanovas et al showed that inhibition of VEGFR with 
antibodies disrupted tumor growth in a mouse pancreatic neuroendocrine 
tumor model, providing further support for this hypothesis.20 
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                       1.3.2
Clinical experience with VEGF inhibition in Pancreatic NETs
Recently, agents targeting VEGF pathway have shown promising results 
in phase II/III clinical trials in patients with advanced pancreatic NET.  
Sunitinib, a small molecule tyrosine kinase inhibitor targeting the VEGF 
receptor has been evaluated in a phase II study in patients with advanced 
NET.  Among 66 pancreatic NET enrolled patients, the overall response 
rate (ORR) was 16.7%, 68% had stable disease (SD), and the median time 
to progression was 7.7 months.8  Sunitinib was subsequently evaluated in 
a phase III randomized trial of sunitinib versus placebo in patients with 
pancreatic NET.  The primary end point was progression-free survival 
(PFS).  The trial was stopped early at the recommendation of the data 
safety and monitoring board.  The median PFS was 11.4 months in the 
sunitinib arm versus 5.5 months in the placebo arm (p = 0.0001); ORR 
with sunitinib was 9.3% (2 complete and 6 partial responses).21  Another 
phase II study of 93 patients with advanced NET evaluated the efficacy of 
sorafenib, a potent small molecule inhibitor of multiple tyrosine kinases 
including VEGFR 2, as well as FLT3, PDGFR, and fibroblast growth 
factor receptor-1 (FGFR1).  In a preliminary report, among the 43 
pancreatic NET patients enrolled, ORR was 11% with 32% exhibiting 
partial or minor response; the 6 month PFS was 60% .7  
 
1.4
Pazopanib in Pancreatic NETs
1.4.1
Clinical activity in Pancreatic NETs
Pazopanib is an oral, selective, small molecule inhibitor of the VEGFR-1, 
-2, and -3, PDGF-α, PDGFR-β, and c-kit tyrosine kinases.  Pazopanib 
selectively inhibits VEGF-mediated endothelial cell proliferation and is 
active in in vivo angiogenesis assays.22  In 2009, pazopanib was approved 
by the U.S. Food and Drug Administration (FDA) for the treatment of 
patients with advanced RCC [Votrient PI, 2012]. In 2012, pazopanib was 
FDA-approved for the treatment of patients with advanced soft tissue 
sarcoma who have received prior chemotherapy.  However, the efficacy of 
pazopanib for the treatment of patients with adipocytic soft tissue sarcoma 
or gastrointestinal stromal tumors has not been demonstrated [Votrient PI, 
2012].   This approval was based on a phase III randomized, double-blind 
trial in which 435 patients with locally advanced or metastatic RCC were 
randomly assigned 2:1 to receive oral pazopanib or placebo.  The primary 
end point was PFS.  PFS was significantly prolonged with pazopanib 
compared with placebo in the overall study population (median PFS of 9.2 
versus 4.2 months with a hazard ratio of 0.46, 95% confidence interval of 
0.34 to 0.62 and p = 0.0001) and the ORR was 30% in the pazopanib 
group compared to 0% in placebo.23
  
In a phase II study, pazopanib was evaluated in two parallel cohorts of 
patients with carcinoid and pancreatic NET.  Pazopanib was administered 
at a dose of 800 mg p.o. daily in combination with octreotide LAR.  There 
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were no responses in the 20 carcinoid patients.  The study opened to a 
second stage of accrual for the pancreatic NET cohort only.  Of the 31 
evaluable pancreatic NET patients, there were 6 (19%) partial responses 
(PR), 5 (16%) minor responses (MR), and 21 (68%) SD; the 6-month PFS 
was 81%7.   A phase III trial evaluating pazopanib in patients with 
advanced pancreatic NET after progression from everolimus is currently 
underway.24 
1.4.2
Safety of pazopanib
In the hallmark article leading to the approval of pazopanib in the 
treatment of metastatic RCC, the most common grade 3/4 adverse events 
(AEs) in the pazopanib arm were hypertension (4%) and diarrhea (4%).  
Arterial thrombotic events occurred in 3% of pazopanib-treated patients 
[myocardial infarction/ischemia (2%), cerebrovascular accident (1%), and 
transient ischemic attack (1%)] compared with none in the placebo arm. 
The incidence of hemorrhagic events (all grades) in the pazopanib arm 
was 13% compared with 5% in the placebo arm.23  In the study of 
pazopanib in patients with neuroendocrine tumors, Grade 3/4 toxicities 
were relatively rare and included: anemia (n=1), neutropenia (n=3), 
hypertriglyceridemia (n=2), transaminitis (n=3), fatigue (n=3), 
hypertension (n=6), nausea (n=1), diarrhea (n=3), pain (n=1), rash (n=1), 
syncope (n=1), and confusion (n=1).9
(Note: please refer to updated IB version 14 dated 01.07.16 for more 
information.)
1.5 
Rationale for Current Study:  Combination of Temozolomide and Pazopanib
1.5.1
Preclinical evidence of temozolomide in combination with anti-
angiogenesis therapy
As seen in the above data, there is evidence to support the use of both anti-
angiogenesis therapy as well as cytotoxic therapy.  There is preclinical 
data to support that the combination of the two is promising.  Fisher and 
colleagues reported that 14 target genes of hypoxia-inducible factor (HIF-
1), were found to be up-regulated after temozolomide treatment to GBM 
cell lines, including VEGF.25  Sandström and colleagues reported ZD6474, 
a potent inhibitor of VEGFR-2, was evaluated in combination with either 
radiotherapy or temozolomide in an orthotopic glioma model; combination 
with temozolomide decreased tumor area by 74%.  Morphologically, these 
tumors had a much lower cellular density and they found that the 
proliferation index was decreased in tumors treated with ZD6474.26  Zhou 
and colleagues evaluated the combination of sunitinib with temozolomide 
in an orthotopic human glioma mouse model to investigate how sunitinib 
at different dose levels affects brain distribution of temozolomide.  In this 
study, they found that the effect of sunitinib on the brain tumor 
distribution of temozolomide was dose dependent.  Optimal tumor 
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exposure was achieved at the lower dose and was associated with a higher 
ratio of functioning vessels to normal vessels.  This research suggests that 
antiangiogenic therapy with sunitinib at an appropriate dose can positively 
alter the vasculature to improve penetration of temozolomide into the 
tumor.27  The results of these preclinical studies justify further 
investigation using combination therapy. 
1.5.2 Clinical evidence for temozolomide combination with anti-aniogenesis 
therapy
This preclinical data has translated into clinical success with the 
combination of temozolomide and anti-angiogenesis therapy.  
Thalidomide  is postulated to have anti-angiogenesis activity through its 
ability to interfere with VEGF and basic fibroblast growth factor (bFGF) 
pathways.28   A phase II study evaluated the combination of temozolomide 
and thalidomide in 29 patients with metastatic NET.  The results 
demonstrated an ORR of 45% in pancreatic NET versus only 7% in 
metastatic carcinoid; the median duration of response of 13.5 months and 
1 year survival was 79%.29  Another phase II study investigated the 
combination of temozolomide and bevacizumab in patients with advanced 
NET.  In a preliminary report, among 17 enrolled pancreatic NET patients, 
there were 4 (24%) PR, and 12 (70%) SD.30  
The combination of temozolomide with full dose anti-angiogenesis 
therapy has been successfully administered in multiple phase II trials.  In a 
phase II trial of temozolomide and sorafenib in advanced melanoma 
patients, standard dosing of temozolomide (150mg/m2 daily for 5 of every 
28 days) was given with sorafenib 400 mg orally twice per day.31
1.5.3
Safety of temozolomide combination with anti-antiogenesis therapy
In the phase II study of temozolomide and thalidomide, a total of 16 (55%) 
patients discontinued treatment because of treatment related toxicity.  
Neuropathy, a known toxicity of thalidomide, developed in 11 patients 
(38%).  Grade 2 or 3 thrombocytopenia occured in 4 patients (14%), 
resulting in treatment discontinuation.  Other toxicity resulting in study 
discontinuation included rash (n=1), neutropenia (n=1), and infection 
(n=4).  A total of 11 patients developed infections while receiving study 
treatment, including 3 opportunistic infections (1 case of Pnemocystis 
carinii pneumonia, 1 case of disseminated varicella zoster virus, and 1 
case of cutaneous herpes zoster).  Of these 3 patients, all had received 
more than 6 months of therapy and developed grade 3 or 4 lymphopenia; 
the study treatment did not include prophylactic antibiotics.29  
In the phase II study combining temozolomide and bevacizumab, grade 
3/4 toxicities included:  lymphopenia (n=21, 62%), leukopenia (n=2, 6%), 
thrombocytopenia (n=7, 21%), neutropenia (n=2, 6%), hyponatremia 
(n=1, 3%), vomiting (n=3, 9%), nausea (n=2, 6%), dehydration (n=1, 3%), 
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fatigue (n=2, 6%), constipation (n=1, 3%), and hypertension (n=1, 3%).  
Due to anticipated lymphopenia, patients received prophylaxis with 
trimethoprim/sulfamethoxazole (1 DS tablet every MWF) and acyclovir 
(400 mg p.o. TID).30  
In the phase I portion of another study (a phase I/II combining 
temozolomide and everolimus in metastatic pancreatic NET) 1 patient 
experienced dose-limiting toxicity (DLT) consisting of grade 4 
thrombocytopenia, and the cohort was expanded to 6 patients with no 
further observed DLTs.  A total of 24 patients were enrolled at the time of 
the analysis and the most common observed grade 3 or 4 toxicities were 
anticipated hematologic effects and included thrombocytopenia (n = 4), 
lymphopenia (n = 5), and neutropenia (n = 2).  Grade 3 or 4 non-
hematologic toxicities included hyperglycemia (n = 1), elevated 
transaminases (n = 1), elevated triglycerides (n = 1) and rash (n = 1).32 
The phase II study combining temozolomide with full-dose sorafenib was 
generally well tolerated, with grade 3/4 toxicity including lymphopenia 
(15%), hypertension (13%), hand-foot syndrome (13%), and fatigue 
(13%).31 A phase II study of sorafenib and temozolomide in patients with 
recurrent glioblastoma showed similar tolerability of full dose anti-
angiogenic therapy.  In this study, sorafenib 400 mg p.o. twice daily was 
given with continuous daily temozolomide 50mg/m2/day, and these doses 
were well tolerated with the most common grade 3 toxicities including an 
increase in amylase/lipase (13%), erythrodysesthesia (19%), and 
hypophosphatemia (9%).  Only 3 patients ultimately required any dose 
modification of sorafenib to 400 mg p.o. daily.33 
1.5.4
Rationale for current study design
Given the overexpression and activation of the VEGF pathway in 
pancreatic NET, and the established activity of temozolomide in PNET, 
we believe that the combination of temzolomide with a molecular-targeted 
therapy offers potential for additive or synergistic inhibition of shared 
targets.  We have chosen pazopanib as the anti-angiogenic agent for this 
trial, given the promising phase II data from Phan et al demonstrating both 
partial responses and stabilization of disease with pazopanib as 
monotherapy9.  We propose to conduct a phase I/II clinical trial of the 
combination of temozolomide and pazopanib in patients with advanced 
PNETs.  Phase I of the study will be an open-label dose escalation trial to 
determine maximum tolerated dose (MTD) and safety profile of the 
combination in this population.  The MTD will be the recommended Phase 
II dose.  Once the MTD is determined, that cohort will be expanded to 6 
additional patients to establish the pharmacokinetics (PK).The study will 
then proceed to a single-arm, open-label phase II trial to evaluate efficacy 
endpoints.    The phase II analyses will include the 6 patients treated at 
MTD for a PK cohort who will have MGMT expression and function CT 
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evaluation similar to the other phase II participants.  Please refer to 
Section 5 for a detailed description of the study design for both phases. 
Our hypothesis for this study is that the combination of temozolomide and 
pazopanib is safe and may be effective in patients with advanced PNET.  
This is backed by clinical and preclinical evidence as outlined above.
(Note: The MTD has now been identified at dose level -2 (75 mg/m2 per 
day p.o. days 1-7 and 15-21 of Temozolomide and 400 mg per day p.o. 
days 1-28 of Pazopanib.  As of12.15.15, all patients moving forward will 
be treated at this dose. ) 
1.5.5
Rationale for current study treatment doses
In the above phase II studies, studies, temozolomide was administered 
orally at 150 mg/m2 daily for 7 consecutive days every other week.30  The 
phase I/ II study of  the combination of everolimus and  temozolomide in 
metastatic PNET patients used a similar dose and schedule of 
temozolomide administration.32  Given that the activity and safety of this 
regimen has been rigorously evaluated in previous studies in PNET (as 
outlined above) we propose to use a similar dosage and schedule for 
temozolomide in our phase I/II trial of the combination of temozolomide 
and pazopanib.  The starting dose for the first cohort of the phase I portion 
will be temozolomide 150 mg/m2 orally on days 1-7 and 15-21 of each 
cycle (1 cycle = 28 days).      
The starting dose of pazopanib in our study is 400 mg orally on a daily 
basis throughout each cycle.  The rationale for this starting dose is based 
on the known metabolism of both of these drugs and the low likelihood of 
interactions.   Pazopanib metabolism is primary mediated by CYP3A4.  In 
contrast, the cytochrome P450 enzymes play only a minor role in 
metabolism of temozolomide or its metabolites, and therefore should not 
affect the metabolism of the pazopanib.  
1.5.6    Phase 1 summary: 
Eighteen patients have been treated with the Combination of 
Temozolomide and Pazopanib in the phase I portion of this trial. As per 
study design, once the MTD is determined, that cohort will be expanded to 
6 additional patients to establish the pharmacokinetics (PK).  MTD has 
now been identified at dose level -2 (75 mg/m2 per day p.o. days 1-7 and 
15-21 of Temozolomide and 400 mg per day p.o. days 1-28 of Pazopanib). 
Hence, all patients moving forward will be treated at this dose. (i.e. as of 
12.15.15) 
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1.6
Background and Rationale for Correlative Studies
     
     1.6.1    O6-methylguanine DNA methyltransferase (MGMT) Expression
In this study we will examine the predicitive role of MGMT expression in 
pancreatic NET to temozolomide therapy.  O6-methylguanine DNA 
methyltransferase (MGMT) is a DNA repair enzyme believed to induce 
cancer cell resistance to O6-alkylating agents such as temozolomide.  
Inactivation of the MGMT gene by promoter methylation is associated 
with longer survival in patients with GBM treated with temozolomide.37, 38 
Low MGMT expression, detected by immunohistochemistry (IHC), 
correlates with response to temozolomide treatment in low-grade 
oligodendroglioma, and MGMT immunostaining has been suggested as a 
marker for predicting tumor chemosensitivity.39 MGMT promoter 
hypermethylation has been described in small groups of NET including 
pancreatic NET and carcinoid.40   Ekeblad et al examined the role of 
MGMT expression in 27 patients with a variety of NET (12 PNET) treated 
with temozolomide monotherapy.  They found a low percentage of 
MGMT-positive tumor cell nuclei in 43% of tumors.  Four out of five 
patients with a radiologic response had tumors with low MGMT 
expressions.  This suggests a possible predictive value of MGMT IHC in 
NET and needs to be further investigated.15
2.0
STUDY OBJECTIVES
This will be a phase I/II study evaluating the combination of temozolomide and 
pazopanib in advanced PNET.  There will be separate objectives for the phase I and II 
portions, as outlined below, in addition to exploratory objectives.
2.1
Phase I
2.1.1
Phase I Primary Objective 
Determine the maximum tolerated dose (MTD) of temozolomide and 
pazopanib combination in patients with advanced PNET. 
2.1.2
Phase I Secondary Objectives
2.1.2.1 Determine safety and toxicity profile of the combination of 
temozolomide and pazopanib in this population.
2.1.2.2 Describe the pharmacokinetics of temozolomide alone and in 
combination with pazopanib.
2.1.2.3 Observe the ORR.
2.2
Phase II
2.2.1
Phase II Primary Objective
The primary objective for the phase II portion of this trial will be to 
determine the ORR.
2.2.2
Phase II Secondary Objectives
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2.2.2.1 Determine PFS and OS, disease control rate (DCR), and duration 
of response (DOR).
2.2.2.2 Determine the safety and toxicity profile of the combination in a 
larger cohort of patients. 
2.2.3
Exploratory/Correlative Objectives 
2.2.3.1 Correlate the expression of tissue methyl–guanine methyl 
transferase (MGMT) as measured by immunohistochemistry (IHC) 
with ORR and PFS. 
3.0
PATIENT SELECTION AND ELIGIBILITY CRITERIA
3.1
Population and Accrual Overview
The target population for this phase I/II trial is patients with advanced, 
unresectable pancreatic neuroendocrine tumor (PNET) with adequate 
performance status and organ function.  This will be a multicenter trial with the 
lead site being the Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University.  Participating sites will include the University of 
Michigan Comprehensive Cancer Center, Vanderbilt-Ingram Cancer Center, 
University of Washington and Fox Chase Cancer Center.  Patients from 
Northwestern University will be recruited from the Hematology-Oncology 
outpatient clinic of the Northwestern Medical Group. Patients may be referred to 
the Principal Investigator, Dr.Sheetal Kircher, at 312-695-0990.  Patients from the 
University of Michigan will be recruited from Hematology-Oncology outpatient 
clinic of the University of Michigan Comprehensive Cancer Center and may be 
referred to Dr. Mark Zalupski at 734-615-3969.  Patients from Vanderbilt 
University will be recruited from the Hematology-Oncology outpatient clinic and 
may be referred to Dr. Jordan Berlin at 615-936-8422.  Patients from Fox Chase 
will be recruited from the Hematology-Oncology outpatient clinic and may be 
referred to Dr. Crystal Denlinger at 215-214-1676.  Patients from University of 
Washington will be recruited from the Hematology-Oncology outpatient clinic 
and may be referred to Dr. E. Gabriela Chiorean at (206) 288-6248.
We anticipate an accrual rate of approximately 3 patients per month combined 
between the 5 study sites.  Based upon this rate of accrual and a DLT window of 
28 days, we anticipate completion of the phase I portion of this study in 6 to 14 
months, depending upon determination of the MTD.  Assuming a similar rate of 
accrual, we anticipate completion of stage I of the phase II portion in an 
additional 7 months.  If the study proceeds to stage II of the phase II, we 
anticipate completion of accrual within an additional 8 months, with assessment 
of the primary endpoint after 6 additional months (14 months total).  Accrual to 
both phases of the study and assessment of the primary endpoint for the phase II 
portion is estimated to be completed within approximately 3-4 years. 
 
3.2
Inclusion Criteria 
3.2.1
Patients must have histologically confirmed well –differentiated islet cell 
carcinoma (PNET) not amenable to surgical resection.
3.2.2
Patients must be age 18 years or older.
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3.2.3
Patients may have had 0-4 prior therapies.  
3.2.3.1 Prior chemoembolization or local ablative therapies are permitted 
if completed ≥ 6 weeks prior to study enrollment.  
3.2.3.2 Prior temozolomide is permitted.
3.2.4
Patients must have an ECOG performance status ≤ 2 (refer to Appendix I).
3.2.5
Patients must have a life expectancy > 3 months.
3.2.6
Patients must have radiographically measurable disease as defined by 
RECIST version 1.1 criteria.
3.2.7
Patients’ baseline blood pressure must be adequately controlled with or 
without antihypertensive medications prior to enrollment (systolic < 140 
mmHg, diastolic < 90 mmHg).
3.2.8
Patients must have LVEF ≥ 50 as measured by echocardiogram or 
MUGA.
3.2.9
Patients must have adequate baseline organ and marrow function as 
defined below: 
3.2.9.1   Absolute neutrophil count (ANC) ≥ 1,500/µL 
3.2.9.2   Platelets ≥ 100,000/µL
3.2.9.3   Hemoglobin ≥ 9.0 g/dL
3.2.9.4   Total bilirubin ≤ 2 mg/dL or ≤ 1.5 times upper limit of 
   normal (ULN)
3.2.9.5  AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN
3.2.9.6   INR ≤ 1.2 times ULN.  Subjects receiving anticoagulant 
  therapy are eligible if their INR is stable and within the    
  recommended range for the desired level of anticoagulation.
3.2.9.7   Activated partial thromboplastin time (aPTT) ≤ 1.2 x ULN
3.2.9.8   Albumin ≥ 2.8 g/dL
3.2.9.9   Serum creatinine ≤ 1.5 times ULN OR if serum creatinine 
  ≥ 1.5 mg/dL, calculated creatinine clearance ≥ 30 mL/min 
3.2.9.10 Urine protein to creatinine ratio < 1 OR 24-hour urine 
  protein < 1 g
3.2.10 Patients must be able to tolerate oral medications.
3.2.11 Females of child-bearing potential must have a negative pregnancy test 
within 14 days of study enrollment and must agree to use an effective 
method of birth control during treatment and for three months after 
receiving their last dose of study drug.  Males must agree to use an 
effective method of birth control during treatment and for three months 
after receiving their last dose of study drug.  All patients must notify 
treating provider immediately if any suspicion of pregnancy or conception. 
3.2.11.1 Child-bearing potential is defined as any woman 
(regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) who meets the following 
criteria:
3.2.11.1.1 Has NOT undergone a hysterectomy or bilateral 
oophorectomy; OR
3.2.11.1.2 Has NOT been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in 
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the preceding 12 consecutive months).
3.2.12 The eligibility of patients receiving any medications or substances known 
or with potential to affect the activity or pharmacokinetics of 
temozolomide and/or pazopanib will be determined following review of 
the case by the Principal Investigator.  Efforts should be made to switch 
patients who are taking enzyme-inducing agents to other medications.  A 
list of medications and substances known or with the potential to interact 
with selected relevant CYP450 isoenzymes is provided in Appendix II. 
3.2.13 Patients must have given signed, informed consent prior to registration on 
study.
 
3.3  
Exclusion Criteria
3.3.1
Patients with known HIV infection are NOT eligible for participation.
3.3.2
Patients with uncontrolled hypertension (≥ 140/90 mmHg) are NOT 
eligible for participation.
3.3.3
Patients who have had a transfusion within 7 days of screening are NOT 
eligible for participation.
3.3.4
Patients with symptomatic brain or bone metastasis are NOT eligible for 
participation.  Prior radiation and/or steroid therapy for brain or bone mets 
must be completed ≥ 2 weeks prior to study enrollment.
3.3.5
Patients with a history of seizure disorder requiring antiepileptic 
medication or brain metastases with seizures are NOT eligible for 
participation.
3.3.6
Patients with an active second malignancy (other than non-melanoma skin 
cancer or cervical carcinoma in situ) are NOT eligible for participation.  
Patients who have a history of malignancy are not considered to have a 
currently active malignancy if they have completed therapy and are now 
considered by their physician to be at < 30% risk for relapse.
3.3.7
Patients with clinically significant gastrointestinal abnormalities that may 
increase the risk for gastrointestinal bleeding are NOT eligible for 
participation.  These may include (but are not limited to):
3.3.7.1 Active peptic ulcer disease
3.3.7.2 Known intraluminal metastatic lesion/s with risk of 
bleeding 
3.3.7.3 Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s 
disease)
3.3.7.4 Other gastrointestinal conditions with increased risk of 
perforation 
3.3.8
Patients with a history of abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess within 28 days prior to beginning study treatment 
are NOT eligible for participation.
3.3.9
Patients with clinically significant gastrointestinal abnormalities that may 
affect absorption of the investigational product including are NOT eligible 
for participation.  These may include (but are not limited to):
3.3.9.1  Malabsorption syndrome
3.3.9.2  Major resection of the stomach or small bowel
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3.3.10 Patients with a history of any one or more of the following cardiovascular 
conditions within the past 6 months prior to study enrollment are NOT 
eligible for participation: 
3.3.10.1 Cardiac angioplasty or stenting
3.3.10.2 Myocardial infarction
3.3.10.3 Unstable angina
3.3.10.4 Coronary artery bypass graft surgery
3.3.10.5 Symptomatic peripheral vascular disease
3.3.10.6 Class III or IV congestive heart failure, as defined by the 
New York Heart Association (refer to Appendix III)
3.3.11 Patients with a corrected QT interval (QTc) > 480 msecs are NOT eligible 
for participation.
3.3.12 Patients with a history of transient ischemic attack (TIA) or 
cerebrovascular accident (CVA) within the past 6 months prior to study 
enrollment are NOT eligible for participation.
3.3.13 Patients with a history of any one or more of the following 
thromboembolic events within the past 6 months prior to study enrollment 
are NOT eligible for participation: 
3.3.13.1 Pulmonary embolism
3.3.13.2 Untreated deep venous thrombosis (DVT) 
 Subjects with recent DVT who have been therapeutically  
  coagulated for at least 6 weeks ARE eligible.
3.3.14 Patients who have undergone major surgery or trauma within 28 days 
prior to the first dose of investigational product and/or present with any 
non-healing wound, fracture, or ulcer are NOT eligible for participation. 
Procedures such as catheter placement not considered to be major surgery.
3.3.15 Patients with known endobronchial lesions and/or lesions infiltrating 
major pulmonary vessels that increase the risk of pulmonary hemorrhage 
are NOT eligible for participation.  
3.3.15.1 Lesions infiltrating major pulmonary vessels (contiguous 
 tumor and vessels) are excluded; however, the presence of a  
 tumor that is touching, but not infiltrating, the vessels is  
 acceptable.  CT with contrast is strongly recommended to  
 evaluate such lesions.  
3.3.15.2 Large protruding endobronchial lesions in the main or lobar 
 bronchi are excluded; however, endobronchial lesions in the  
  segmented bronchi are allowed.   
3.3.15.3Lesions extensively infiltrating the main or lobar bronchi 
 are excluded; however, minor infiltrations in the wall of the   
  bronchi are allowed.
3.3.16 Patients who have had recent hemoptysis (≥ ½ teaspoon of red blood 
within 8 weeks before first dose of study drug) are NOT eligible for 
participation.
3.3.17 Patients who have any history of allergic reaction(s) attributed to 
compounds of similar composition to temozolomide, pazopanib, their 
metabolites, or any component of their formulation are NOT eligible for 
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participation.
3.3.18 Females who are pregnant or lactating, fertile males, or females of child-
bearing potential who are not willing to comply with an effective double 
method of birth control are NOT eligible for participation.
3.3.19 Patients with a psychiatric illness, other condition or significant medical 
illness, or social situation which, in the investigator’s opinion, would limit 
compliance or ability to comply with study requirements are NOT eligible 
for participation.
3.3.20 Patients who have taken medications that are known strong inducers or 
inhibitors of CYP3A4 within 28 days prior to registration are NOT 
eligible for participation.
3.4  
Policy on Eligibility Waivers
The eligibility criteria listed above are interpreted literally and CANNOT be 
waived.
4.0
PATIENT REGISTRATION 
Patients may not begin protocol treatment prior to registration. 
4.1  
Overview
Eligible patients will be registered to the study via the Northwestern Oncology 
Trial Information System (NOTIS) using the web-based application, which can be 
found at:  https://notis.nubic.northwestern.edu. Please note that a password is 
required to use this program. One will be provided at the time of site activation, 
prior to training on the NOTIS system. Please contact the assigned Quality 
Assurance Monitor (QAM) or the QA Department 
(croqualityassurance@northwestern.edu) for questions regarding the registration 
process. In order for registrations to be processed efficiently, study teams are 
asked to inform the QAM of the date and time that potential patients will need to 
be registered.
4.2
Registration procedures: 
4.2.1 Registering a Patient for the Phase I Portion of the Study 
For potential patients for the phase I portion of this study, study teams are 
asked to inform the QAM of the date and time that the patient will need to be 
registered (croqualityassurance@northwestern.edu).  
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and 
keep original hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload 
to NOTIS)

Eligibility eCRF (complete in NOTIS)
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
Copy of the pathology report (upload to NOTIS)
The QAM will review all source documentation required to confirm eligibility 
that is readily available in the patient’s electronic medical record (EMR).  Any 
information that is not available in the EMR must be de-identified and emailed 
to the QAM. Once the QAM confirms the patient is eligible, he or she will 
register the patient, assign a subject identification number, provide a cohort 
assignment, and send a confirmation of registration to involved personnel. 
Registration will then be complete and the patient may begin study treatment. 
4.2.2   Registering a Patient to the Phase II Portion of the Study 
BEFORE a patient can be treated on study, please complete and submit 
the following items to confirm eligibility and receive a subject 
identification number: 
• Eligibility eCRF (complete in NOTIS) 
• Eligibility checklist (signed and dated by the treating physician – 
upload in NOTIS)
 • Signed and dated informed consent document (upload in 
NOTIS) 
• Pathology Report (upload in NOTIS) 
The QAM will review the registration, register the patient, assign an 
identification number, and send a confirmation of registration to involved 
personnel. Registration will then be complete and the patient may begin 
study treatment.
4.3
Notifying NCCN
This trial is supported by the National Comprehensive Cancer Network (NCCN), 
and as such, the NCCN requires notification of participant registration at the time 
of accrual. Accrual is defined as the point at which the informed consent is 
obtained and the participant has received the first dose of study treatment. At the 
time that registration is complete and the patient begins treatment, the Notification 
of Participant Registration form will be completed by the QAM. The QAM will 
then send completed forms to NCCN at the following email address:  
ORPRegistration@nccn.org.   
5.0 
TREATMENT PLAN
5.1 
Overview
This will be a phase I/II multicenter trial of the combination of temozolomide and 
pazopanib in patients with advanced PNETs.  The phase I portion will employ a 
standard 3+3 dose escalation schema.  The starting dose of temozolomide for 
cohort 1 will be 150 mg/m2 per day on days 1-7 and 15-21 of each 28-day cycle.  
The starting dose for cohort 1 of pazopanib will be 400 mg per day, taken 
continuously throughout each cycle.  Patients will be assessed for DLT during the 
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first 28-day cycle.  The frequency of DLTs observed in each cohort will 
determine whether and how the doses are adjusted (either up or down) in the next 
cohort.  Dose escalation rules and definitions are outlined below.  Once the MTD 
has been determined, that will be the recommended dose for the phase II portion 
of the trial.  In the phase I portion of the trial, once the MTD is reached, the 
cohort will be expanded to an additional 6 additional patients to perform PK 
studies. MTD has now been identified at dose level -2 (75 mg/m2 per day p.o. 
days 1-7 and 15-21 of Temozolomide and 400 mg per day p.o. days 1-28 of 
Pazopanib).  The phase II portion will be a Simon 2-stage design, with anywhere 
from 11 to 27 patients being enrolled to the phase II portion.  The 6 patients in the 
PK cohort treated at MTD in the phase I portion will be included in the phase II 
analysis.  
5.2 
Study Drug Administration
Both study drugs will be orally self-administered.  Patients will be provided a 
drug diary to record the date and time of each dose of temozolomide and 
pazopanib, as well as any skipped doses or doses intentionally held per the 
treating physician’s instructions. The study team will instruct patients on 
completing the diary, and will collect the completed diaries for the previous cycle 
on Day 1 of the subsequent cycle. 
5.2.1 Temozolomide
Patients will be instructed to take temozolomide orally once a day starting 
on Cycle 1 Day 1 of treatment.  The dose of temozolomide will depend on 
the phase and cohort onto which the patient is enrolled (refer to Section 
5.3 for dose escalation rules).  For phase I, the starting dose of 
temozolomide will be 150 mg/m2 per day.  Patients will continue 
temozolomide for 7 consecutive days at a time, every other week (Days 1-
7 and 15-21 of the cycle).  One cycle equals 28 days.  Patients will 
continue to take temozolomide every other week until study 
discontinuation (refer to Section 5.8 for duration of treatment and 
discontinuation rules).
Temozolomide tablets will be swallowed whole.  Patients will be 
instructed to fast at least 1 hour before and 1 hour after administration of 
temozolomide.  Water is allowed during the fasting period.  
Temozolomide may be taken before or after pazopanib (on days when 
both drugs are taken), but it is recommended that they be taken around the 
same time.  If a dose is missed, the patient should take the dose as soon as 
possible, but only if there are 12 or more hours remaining before the next 
dose is due.  If the next dose is due in less than 12 hours, the subject 
should skip the missed dose and take the next dose as scheduled.
If vomiting occurs after taking temozolomide, the patient should not take a 
replacement dose on that day.  The patient should resume taking 
temozolomide at the next scheduled dose on the following day.  
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(Note:  For patients in the PK cohort, please refer to the Study Parameters 
Table for PK Cohort for information regarding temozolomide doses on 
Cycle 1, Days 1-3.)
 
5.2.2
Pazopanib
Patients will be instructed to take pazopanib orally once a day starting on 
Cycle 1 Day 1 of study treatment.  The dose of pazopanib will depend on 
the phase and cohort onto which the patient is enrolled (refer to Section 
5.3 for dose escalation rules).  For phase I, the starting dose of pazopanib 
will be 400 mg per day.  Pazopanib will be taken daily continuously study 
discontinuation (refer to Section 5.8 for duration of treatment and 
discontinuation rules).
Pazopanib should be taken orally without food at least 1 hour before or 2 
hours after a meal.  The tablets should be swallowed whole and must not 
be crushed or broken.  The time of day the tablets are taken should be 
relatively constant.  Pazopanib may be taken before or after temozolomide 
(on days when both drugs are taken), but it is recommended that they be 
taken around the same time.  If a dose is missed, the patient should take 
the dose as soon as possible, but only if there are 12 or more hours 
remaining before the next dose is due.  If the next dose is due in less than 
12 hours, the subject should skip the missed dose and take the next dose as 
scheduled.
If vomiting occurs after taking pazopanib, the patient should not take a 
replacement dose on that day.  The patient should resume taking 
pazopanib at the next scheduled dose on the following day.  If vomiting 
persists, the patient should be instructed to notify the investigator.  
(Note:  For patients in the PK cohort, please refer to the Study Parameters 
Table for PK Cohort for information regarding pazopanib doses on Cycle 
1, Days 1-3.)
5.3 
Phase I Dose Escalation
5.3.1
Dose escalation schema
For cohort Level 1, starting doses will be temozolomide 150 mg/m2 per 
day (Days 1-7 and 15-21 of each cycle) and pazopanib 400 mg daily.  
Cycle length will be 28 days.  All patients in a given cohort must complete 
28 days (1 cycle) of therapy prior to proceeding with enrollment on the 
next cohort/dose level.  Dose escalation will be conducted according to the 
schema below starting at cohort Level 1 with dose escalation following the 
standard “3+3” design.
Table 1:  Phase I Dose Escalation Schema
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Cohort
Temozolomide
Pazopanib
Level -41
50 mg/m2 per day p.o.
Days 1-7 & 15-21
200 mg per day p.o. 
Days 1-28
Level -31
50 mg/m2 per day p.o.
Days 1-7 & 15-21
400 mg per day p.o.
Days 1-28
Level -21
75 mg/m2 per day p.o. 
Days 1-7 & 15-21
400 mg per day p.o. 
Days 1-28
Level -1 
100 mg/m2 per day p.o. 
Days 1-7 & 15-21
400 mg per day p.o. 
Days 1-28
Level 1   
(starting dose)
150 mg/m2 per day p.o. 
Days 1-7 & 15-21
400 mg per day p.o. 
Days 1-28
Level 22  
150 mg/m2 per day p.o.
Days 1-7 & 15-21
800 mg per day p.o. 
Days 1-28
   1 If DLTs occur at cohort Level -1, then a cohort Level -2 may be opened 
  as above. If DLTs occur at cohort Level -2, then a cohort Level -3 may be opened as   
  above. If DLTs occur at dose Level -3, then a cohort Level -4 may be opened as above. 
  Such decisions will be made after DMC review of the data and approval.  
2 If DLTs occur at cohort Level 2, then an additional cohort may be added 
with a pazopanib dose of 600 mg and temozolomide 150 mg/m2.  
This decision will be made following DMC review of the data 
and approval.
5.3.2 Dose escalation rules
If a DLT is encountered, the following rules in the table below will be 
applied (refer to Section 5.4.2 for definitions of DLT).  All patients on a 
given cohort must complete at least 28 days of treatment, and toxicity data 
must be available for review in order to determine whether accrual should 
proceed to the next cohort.  All toxicity data will be reviewed and dose 
level changes approved by the DMC prior to enrolling patients to 
subsequent cohorts.  
Table 2:  Phase I Dose Escalation Rules
# of Patients 
with DLT at a 
Given Cohort 
Level
Escalation Decision Rules
0 out of 3
Dose escalate to the next higher cohort level.
≥ 2 out of 3
Dose escalation will be stopped.  This dose level will be 
declared the maximum administered dose (MAD).  The 
next lower cohort will be expanded to 6 patients.  If no 
DLTs are observed, an intermediate dose level between this 
dose and the MAD dose may be considered.  The DMC 
must approve the creation of this intermediate dose level, 
and the protocol will be amended accordingly.
1 out of 3
Enter 3 more patients at this dose level.  If 0 of these 3 
patients experience a DLT, proceed to the next dose level.  
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If 1 or more of these 3 patients experience a DLT, then 
dose escalation is stopped and this will be declared the 
MAD.  
≤ 1 out of 6 at 
the highest dose 
level below the 
MAD
This is the MTD and the recommended phase II dose 
(RP2D).
If ≥ 2 patients in cohort Level -4 demonstrate DLT, the study will close.  
If 0 out of 3 patients in cohort Level 2 demonstrate DLT, an additional 3 
patients will be enrolled at this level.  If ≤ 1 out of 6 patients in cohort 
Level 2 demonstrate DLT, this will be considered the MTD and the RP2D 
without further dose escalation.   A dose level must have 6 evaluable 
patients to be defined as the MTD. 
(Note: The MTD has been identified at dose level -2 (75 mg/m2 per day 
p.o. days 1-7 and 15-21 of Temozolomide and 400 mg per day p.o. days 1-
28 of Pazopanib.  As of 12.15.15, all patients moving forward will be 
treated at this dose. ) 
5.4 
Dose Limiting Toxicity
5.4.1
DLT evaluation
Toxicities will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  A DLT will be 
defined as any of the following events (described below in 5.4.2), which 
are attributable to protocol treatment, occurring during the DLT window.  
The DLT window is defined as the first 28 days of therapy (or completion 
of 1 cycle of therapy).  Any exclusions from these are described in 5.4.3.
5.4.2
DLT definitions
DLT will be defined as the occurrence of any of the following felt to be 
related to study treatment during Cycle 1:
5.4.2.1 Grade 3 or higher non-hematologic toxicity (see exceptions below 
in 5.4.3).
5.4.2.2 Grade 4 thrombocytopenia or anemia.
5.4.2.3 Grade 4 neutropenia or Grade 3 febrile neutropenia associated with 
temperature > 38°C.
5.4.2.4 Inability to complete Cycle 1 due to toxicity related to study drug.
5.4.2.5 Delay in administration of scheduled doses of study drug greater 
than 2 weeks due to drug related toxicity of any grade.
5.4.3 DLT exclusions
5.4.3.1 Fatigue, nausea, and/or vomiting (any grade) will NOT be 
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considered DLTs.
5.4.3.2 Lymphopenia not associated with active infection or clinical 
disease will NOT be considered a DLT. 
5.4.3.3 Any grade non-hematologic toxicity will NOT be considered a 
DLT unless continued despite maximum supportive care beyond 
the 2 week delay allowed in section 5.4.2.5.  (see 5.5.8).
5.4.3.4 Grade 3 or higher non-hematologic toxicity will be considered a 
DLT EXCEPT in cases where the event existed at baseline.  In 
these cases, toxicity needs to increase in severity by 2 grades per 
CTCAE v. 4.03 before it is considered a DLT.  
5.4.4
DLT Terminology Clarifications
5.4.4.1 Unless otherwise noted, “clinically relevant” is defined as placing 
the patient at risk for other toxicity by the judgment of the treating 
investigator.   
5.4.4.2 “Optimal supportive care” is defined as standard of care measures 
that the treating physician deems appropriate and sustainable over 
multiple cycles of therapy.  Specific supportive care guidelines are 
given below in 5.5.  This definition relies upon the clinical 
judgment of the treating investigator.  This may include (but is not 
limited to) the following: 
5.4.4.2.1
Intravenous fluid hydration for dehydration
5.4.4.2.2
Electrolyte supplementation for low electrolytes
5.4.4.2.3
Loperamide for diarrhea
5.4.4.2.4
Antiemetics for nausea
5.4.4.2.5
Skin care for rash
5.4.4.2.6
Printed information as used in standard clinical care)  
5.5
Supportive Care Guidelines
Supportive medications to alleviate or mitigate adverse effects of protocol therapy 
may include the following agents at the discretion of the treating investigator and 
according to institutional standards of care.  
5.5.1
Antidiarrheal Agents  
Patients should be instructed to begin loperamide at the earliest signs of a 
poorly formed or loose stool.  Oral loperamide should be prescribed in the 
following manner: 4 mg at first onset of diarrhea then 2 mg 
every 2 hours until diarrhea-free for at least 12 hours up to 16 mg daily.
5.5.2
Antiemetic Agents
Drugs such as lorazepam, prochlorperazine, or serotonin antagonists may 
be used if clinically indicated.
5.5.3
Antihistamines
An antihistamine such as diphenhydramine may be used to manage 
dermatitis associated with therapy at the discretion of the treating 
physician. 
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5.5.4
Anti-diabetic Agents
For patients who develop clinically significant hyperglycemia on study 
protocol, anti-diabetic therapy and dietary modification are required.  The 
oral anti-diabetic agents, glyburide or metformin, may be instituted at the 
discretion of the treating physician, assuming no contraindication.  
Insulin may be instituted at the discretion of the treating physician to 
optimize glycemic control.  Management of complications of 
hyperglycemia should be performed by treating physician according to 
institutional standard practices.  All patients who develop clinically 
significant hyperglycemia on study protocol must receive diabetic 
teaching and education materials.   
 (Note:  Metformin must be temporarily discontinued for ≥ 48 hours before 
and after iodinated contrast imaging, with confirmation of stable renal 
function prior to resuming this agent after contrast exposure.)  
5.5.5
Antihyperlipidemic Agents
Patients who develop serum cholesterol > 350 mg/dL and/or triglycerides 
> 300 mg/dL while on therapy will require medication (assuming no 
contraindications and with standard precautions as appropriate for the 
class of agents chosen) and/or dietary modifications at the discretion of the 
treating investigator. 
Concomitant use of pazopanib and simvastatin (Zocor) increases the risk 
of ALT elevations and should be undertaken with caution and close 
monitoring.  If a subject receiving concomitant simvastatin develops ALT 
elevations, follow the Guidelines for Management of Treatment Emergent 
Hepatotoxicity and discontinue simvastatin.  Insufficient data are available 
to assess the risk of concomitant administration of alternative statins and 
pazopanib. 
Pravastatin or rosuvastatin is recommended if LDL and/or total cholesterol 
are elevated, with or without elevated triglycerides, because these agents 
are not CYP 3A4 substrates.  Atorvastatin may also be used with caution.  
If tryglycerides alone are elevated, fenofibrate may be considered.    
 
5.5.6
Antihypertensive Agents  
Patients who develop blood pressures ≥ 140/90 mm Hg on at least 2 
occasions should be managed with oral antihypertensives including 
amlodipine, hydrochlorothiazide, or metoprolol by their treating 
physician. 
5.5.7
Diuretics
Diuretics such as furosemide may be used for the management of 
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periorbital or lower extremity edema at the discretion of the treating 
physician.  Severe episodes of edema, such as congestive heart failure, 
pleural effusion, ascites, pericardial effusion, or pulmonary edema may 
require additional measures such as percutaneous drainage or 
hospitalization.  
5.5.8
Electrolyte Supplementation  
Electrolytes should be repleted according to standard institutional 
protocols.   
5.5.9
Growth Factors
Erythropoietin or darbopoietin are permitted at the discretion of the 
treating physician.  Filgrastim and PEG-filgrastim (Neulasta) should not 
be used in place of protocol-specified dose reductions or delays for 
myelosuppression, nor should they be used prophylactically because of 
concern for myelosuppression from a prior cycle of chemotherapy.  
For treatment of febrile neutropenia, the use of colony-stimulating factors 
should not be routinely instituted as an adjunct to appropriate antibiotic 
therapy.  The use of granulocyte colony-stimulating factors may be 
indicated, however, in subjects who have prognostic factors that are 
predictive of clinical deterioration such as pneumonia, hypotension, multi-
organ dysfunction, sepsis syndrome, or fungal infection.  Investigators 
should use discretion in initiating colony-stimulating factors in these 
settings. 
 
5.5.10 Topical Agents
Topical steroid creams may be used to manage pruritic skin toxicity at the 
discretion of the treating physician.  Non-alcohol-based topical emollients 
such as Aquaphor may be used for hand-foot syndrome or desquamating 
rashes.  Non-alcohol-based moisturizers may be used for dry skin. 
5.5.11 Anti-viral Agents
It is recommended that patients be treated with prophylactic Valtrex 
(valacyclovir hydrochloride) 500 mg daily, however final decisions 
regarding this will be up to treating physician discretion.
5.6 
Concomitant Medications
Concomitant medications are any prescription medications or over-the-counter 
preparations used by the patient within 28 days of initiating study treatment, 
during study treatment, and up to 28 days following study termination.  
All patients will receive prophylaxis with trimethoprim-sulfamethaxazole double 
strength (sulfamethoxazole 800 mg and trimethoprim 160 mg) by mouth 3 times a 
week.  If a patient is allergic to this antibiotic it can be substituted per physician 
recommendation.  The details of all concurrent medications including vitamins 
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and alternative therapies will be recorded on the electronic case report forms 
(eCRFs).   
All medications must be reviewed for potential interaction with study drug 
therapy.  All concomitant medications and blood products, as well as supportive 
interventions (such as analgesic use, paracentesis, etc.) received by patients from 
screening until the end of study visit will also be recorded on the appropriate 
eCRFs. 
Concomitant use of pazopanib and simvastatin (Zocor) increases the risk of ALT 
elevations and should be undertaken with caution and close monitoring.  If a 
subject receiving concomitant simvastatin develops ALT elevations, follow the 
Guidelines for Management of Treatment Emergent Hepatotoxicity and 
discontinue simvastatin.  Insufficient data are available to assess the risk of 
concomitant administration of alternative statins and pazopanib (see section 8.2.8 
and Appendix II).
Concomitant use of any of the following is PROHIBITED while on this study:
5.6.1
Subjects may not receive other anti-cancer therapy [cytotoxic, biologic, 
radiation, or hormonal (other than leuprolide or other GnRH agonists)] 
while on treatment in this study.
5.6.2
Medications that inhibit CYP3A4 may result in increased plasma 
pazopanib concentrations; therefore, co-administration of strong CYP3A4 
inhibitors is PROHIBITED beginning 28 days prior to the first dose of 
study drug until discontinuation from the study.  Strong CYP3A4 
inhibitors include (but are not limited to):
5.6.2.1 Antibiotics: clarithromycin, telithromycin, troleandomycin
5.6.2.2 HIV: protease inhibitors (ritonavir, indinavir, saquinavir, 
nelfinavir, amprenavir, lopinavir)
5.6.2.3 Antifungals:  itraconzaole, ketoconazole, voriconazole
5.6.2.4 Antidepressants:  nefazodone.
Please refer to Appendix II for a more complete listing of these agents.  Those 
who have taken medications that are known strong inducers or inhibitors of 
CYP3A4 within 28 days before registration will be excluded from the study.   
Please refer to Section 8 for details regarding drug interactions for temozolomide 
and pazopanib.
5.7
Toxicity Management and Dose Modifications
5.7.1
Assessing toxicity
Toxicity will be graded according to the NCI CTCAE version 4.03.  
Toxicity will be formally assessed at scheduled clinic follow up 
appointments every one to two weeks, as well as by investigator review of 
weekly laboratory testing; in the interim, toxicity may be assessed via 
patient contact with the study coordinator and/or clinical staff should new 
symptoms arise between visits.  
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5.7.2
Treatment rules for toxicity for phase I AFTER the DLT period
Protocol therapy will be delayed, dose-reduced, or discontinued based 
upon the most severe toxicity encountered in the previous cycle and/or 
laboratory parameters on the scheduled day of treatment.  For treatment-
related delays in protocol therapy, the longest permitted interval of 
treatment interruption is 28 days to remain on study.  For non-treatment-
related delays, the maximum permitted interval is 8 weeks to remain on 
study.  General principles of toxicity management are as follows:
5.7.2.1 Temozolomide and pazopanib will be dose-adjusted according to 
attribution of toxicity.  In equivocal cases, the decision may be 
made by treating investigator with approval from the DMC.
5.7.2.2 Individual dose modifications will be made according to the 
system showing greatest degree of toxicity using NCI CTCAE 
version 4.03. 
5.7.2.3 Asymptomatic changes in laboratory values require dose 
modification only if assessed to be treatment-related, clinically 
relevant, and represent a change of ≥ 2 grades from baseline. 
5.7.2.4 If toxicity occurs, supportive care medications should be applied to 
ameliorate signs and symptoms (refer to Section 5.5) before 
toxicity grade is determined. 
5.7.2.5 A patient will be removed from protocol therapy if either of the 
two study drugs is discontinued.  
5.7.2.5.1
Temozolomide will be discontinued if it is not tolerated 
at a dose of 50 mg/m2 daily.
5.7.2.5.2
Pazopanib will be discontinued if it is not tolerated at a 
dose of 200 mg daily.
5.7.2.6 A patient will be removed from protocol therapy if treatment with 
either of the two study drugs is held for toxicity for longer than 28 
days (1 cycle).
5.7.2.7 Once a dose has been reduced for toxicity, it should not be re-
escalated. 
5.7.2.8 In obese patients, all dosing is to be determined by the patient’s 
actual body weight.  
5.7.2.9 If there is more than one indication for dose modification, use the 
more strict dose modification (i.e. modify according to the most 
severe toxicity). 
5.7.3
Patient dose level adjustments for toxicity in Phase II
For patients enrolled in the phase II portion, the following adjustments 
should be made in the appropriate drug (depending on attribution of 
toxicity) based upon the patient’s starting dose and the guidelines below in 
Section 5.7.4.  As stated above, if either study drug is discontinued, a 
patient will be removed from study. 
Table 4:  Patient Dose Level Adjustments for Toxicity: Temozolomide
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Patient Temozolomide Dose Level
Temozolomide Dose 
Modification
Level 1:  150mg/m2 per day p.o. 
↓ 100 mg/m2 per day p.o.
Level -1:  100 mg/m2 per day p.o.
↓ 75 mg/m2 per day p.o.
Level -2:  75mg/m2 per day p.o.
↓ 50 mg/m2 per day p.o 
Level -3:  50mg/m2 per day p.o.
Discontinue
Table 5:  Patient Dose Level Adjustments for Toxicity: Pazopanib
Patient Pazopanib Dose Level
Pazopanib Dose Modification
Level 3 800 mg per day p.o.
↓ 600 mg per day p.o.
Level 2 600 mg per day p.o.
↓ 400 mg per day p.o.
Level 1 400 mg per day p.o.
↓ 200 mg per day p.o.
Level -1 200 mg per day p.o.
Discontinue
5.7.4
Dose modifications for toxicity
Held doses of either drug will be considered as omitted.  For example, if 
pazopanib is held for one week starting cycle 2 day 8, the next dose of 
temozolomide the following week will still be considered cycle 2, day 15 
(rather than delaying the cycle and repeating the day 8 dose).  
5.7.4.1 Temozolomide dose modifications 
Please refer to Table 6 below for a summary of dose modifications 
for temozolomide for both hematologic and non-hematologic 
toxicities.  Toxicities that are judged to be unrelated to study drug 
will not require dose modifications.
Table 6:  Summary of Hematologic & Non-Hematologic Dose Modifications for 
Temozolomide
Toxicity
Grade (NCI CTCAE v 4.03)
Temozolomide (TMZ) Adjustment
HEMATOLOGIC
Grade 1
ANC 1500 to < 2000/mm3
No change
Neutropenia
Grade 2
ANC 1000 to < 1500/mm3
No change
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Toxicity
Grade (NCI CTCAE v 4.03)
Temozolomide (TMZ) Adjustment
Grade 3
ANC 500 to < 1000/mm3
Hold TMZ, repeat CBC weekly until ≤ grade 2, 
then decrease 1 level
Grade 4
ANC < 500/mm3
Hold TMZ, repeat CBC weekly until ≤ grade 2, 
then decrease 1 level
Lymphopenia
Any Grade
No dose reductions
Grade 1
Plts 75,000 to < LLL/mm3
No change
Grade 2
Plts 50,000 to 75,000/mm3
No change
Grade 3
Plts 25,000 to < 50,000/mm3
Hold TMZ, repeat CBC weekly until ≤ grade 2, 
then decrease 1 level
Thrombocytopenia
Grade 4 
Plts < 25,000/mm3
Hold TMZ, repeat CBC weekly until ≤ grade 2, 
then decrease 1 level
Anemia
Any Grade
No dose reductions or delays will be performed for 
anemia; transfusions and/or growth factor support 
may be used at the discretion of the investigator
ALL OTHER NON-HEMATOLOGIC TOXICITY
Grade 1
No change
Grade 2
No change
Grade 3
Hold TMZ until ≤ grade 2, then decrease 1 level
Other toxicity
(despite optimal care)
Grade 4
Discontinuation of therapy and removal from study
5.7.4.2 Pazopanib dose modifications
There will be no dose modifications of pazopanib for hematologic 
toxicity of any grade. There will be no dose modifications for 
grade 1 or 2 non-hematologic toxicities.  For grade 3 and/or 4 non-
hematologic toxicities, please see Table 7 below.
Table 7:  Summary of Hematologic & Non-Hematologic Dose Modifications for Pazopanib
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Toxicity
Grade (NCI CTCAE v 4.03)
Pazopanib (PAZ) Adjustment
GASTROINTESTINAL (EXCLUDING HEPATIC DYSFUNCTION)
Grade 1
No change
Grade 2
No change
Grade 3
Hold PAZ and monitor until ≤ grade 2, then 
decrease 1 level
Nausea/vomiting, 
constipation, or 
mucositis
(despite optimal 
supportive care)
Grade 4
Hold PAZ and monitor until ≤ grade 2, then 
decrease 1 level
Grade 1
No change
Grade 2
No change
Grade 3
Hold PAZ and monitor until ≤ grade 2, then 
decrease 1 level
Diarrhea
(despite optimal 
supportive care)
Grade 4
Hold PAZ and monitor until ≤ grade 2, then 
decrease 1 level
CARDIOVASCULAR AND VASCULAR
Scenario A:
Asymptomatic and persistent 
SBP of ≥ 140 and < 170 
mmHg, or DBP ≥ 90 and < 
110 mmHg, or a clinically 
significant increase in DBP of 
20 mmHg (but still below 110 
mmHg)
1.
Continue PAZ at the current dose.
2.
Adjust current or initiate new 
antihypertensive medication(s).
3.
Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-
controlled BP. If BP is not well-controlled 
within 2 weeks, consider referral to a 
specialist and go to Scenario B.
Hypertension
Scenario B:
Asymptomatic SBP ≥ 170 
mmg Hg or DBP ≥ 110 
mmHg, or failure to achieve 
well-controlled BP within 2 
weeks under Scenario A.
1.
Consider reducing or interrupting PAZ, as 
clinically indicated.
2.
Adjust current or initiate new 
antihypertensive medication(s).
3.
Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-
controlled BP.
4.
Once BP is well-controlled, restart PAZ at 1 
dose level (200 mg) lower if PAZ was 
interrupted.
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Toxicity
Grade (NCI CTCAE v 4.03)
Pazopanib (PAZ) Adjustment
Scenario C:
Symptomatic hypertension 
or recurring SBP ≥ 170 
mmHg or DBP ≥ 110 
mmHg, despite modification 
of hypertensive 
medication(s)
Interrupt PAZ.
Adjust current or initiate new antihypertensive 
medication(s).
Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled 
BP. Referral to a specialist for further evaluation 
and follow-up is recommended.
Once BP is well-controlled, restart PAZ at 1 dose 
level (200 mg) lower if PAZ was interrupted.
Scenario D:
Refractory hypertension 
unresponsive to above 
interventions.
Discontinue PAZ and follow-up per protocol.
Arterial Thrombus
[Cardiac 
ischemia/infarction, 
CNS ischemia (TIA, 
CVA), any peripheral 
or visceral arterial 
ischemia/thrombus]
 ≥ Grade 3
Discontinue PAZ
Venous Thrombus
Grade 3/4
Hold PAZ.  If the planned duration of full-dose 
anticoagulation is <2 week, PAZ should be held 
until this is over
If the planned duration of the full-dose 
anticoagulation is >2 weeks, PAZ can be resumed 
once criteria are met:
Subject must have in-range INR (usually 2-3) on 
a stable dose of warfarin or be on a stable dose of 
heparin and the subject must not have pathologic 
conditions that carry high risk of bleeding.  If 
thromboembolic disease worsens, discontinue 
PAZ
DERMATOLOGIC
Grade 1
No change
Grade 2
No change
Grade 3
Hold PAZ until ≤ grade 2, then decrease 1 level
Hand-foot syndrome 
(despite optimal 
supportive care)
Grade 4
Hold PAZ until ≤ grade 2, then decrease 1 level
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RENAL AND URINARY
UPC < 3
Continue PAZ at the current dose; monitor as 
clinically indicated.
Proteinuria
UPC ≥ 3 or 24-hr urine 
protein ≥ 3g
1.
Interrupt PAZ
2.
Weekly UPC or 24-hr urine protein 
monitoring until UPC is < 3 or 24-hr urine 
protein is < 3g. Then restart PAZ at 1 dose 
level (200 mg) lower. 
3.
If UPC ≥ 3 or 24-hr urine protein ≥ 3g 
recurs, repeat steps 1 and 2.
4.
If UPC ≥ 3 or 24-hr urine protein ≥ 3g recurs 
and the PAZ dose can no longer be reduced, 
discontinue PAZ and follow-up per protocol.
CARDIAC
QTc ≥ 480 < 500 msec
Continue PAZ; monitor as clinically indicated.
Prolongation of QTc 
Interval
QTc ≥ 500 msec
Discontinue PAZ and follow-up per protocol.
HEMORRHAGE/BLEEDING
Grade 1
For hemoptysis, interrupt PAZ and contact the 
NOVARTIS Study Physician to discuss whether 
further treatment with PAZ is appropriate.
For other Grade 1 hemorrhage/bleeding events, 
continue PAZ at the current dose; monitor as 
clinically indicated.
Grade 2
1.
If pulmonary or GI bleed (other than 
hemorrhoidal bleeding), discontinue PAZ 
and continue follow-up per protocol. 
Otherwise, interrupt PAZ until resolved to ≤ 
Grade 1.
2.
Restart PAZ; consider reducing dose and 
monitor as clinically indicated.
Hemorrhage/Bleeding
Grade 3 or 4
or
Recurrent ≥ Grade 2 event 
after dose 
interruption/reduction
Discontinue PAZ and follow-up per protocol.
ALL OTHER NON-HEMATOLOGIC TOXICITY
Grade 1
No change
Grade 2
No change
Grade 3
Hold PAZ and monitor until ≤ grade 2, then 
decrease 1 level
Other toxicity
(despite optimal care)
Grade 4
Discontinue PAZ
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HEPATIC DYSFUNCTION
Event 
Dose Modification Algorithms
(A). ALT of ≤ 3.0 x ULN
Continue pazopanib at current dose with full panel 
LFTsError! Reference source not found. monitored 
as per protocol.
(B). ALT >3.0 x ULN to ≤8.0 x ULN without 
bilirubin elevation (defined as total bilirubinError! 
Reference source not found. <2.0 x ULN or direct 
bilirubin ≤35%) and without hypersensitivity 
symptoms (e.g., fever, rash)
Liver Event Monitoring Criteria:
(1) Continue pazopanib at current dose levels. 
(2) Monitor subject closely for clinical signs and  
    symptoms; perform full panel LFTsa weekly or 
    more frequently if clinically indicated until 
    ALT/AST is reduced to Grade 1.
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(C). ALT >8.0 x ULN without bilirubin elevation 
(defined as total bilirubinb <2.0 x ULN or direct 
bilirubin ≤35%) and without hypersensitivity 
symptoms (e.g., fever, rash)
1st occurrence – Liver Event Interruption 
CriteriaError! Reference source not found.:
(1) Interrupt pazopanib until toxicity resolves to 
Grade 1 or baseline.  Report the event to 
NOVARTIS as an SAE within 24 hours of learning 
of its occurrence  and complete the eCRF liver 
event forms.  Make every reasonable attempt to 
have subjects return to the clinic within 24 to 72 
hours for repeat liver chemistries and liver event 
follow up assessments.
(2) Liver imaging and other laboratory investigations 
should be considered as clinically appropriate.
(3) Monitor subject closely for clinical signs and 
symptoms; perform full panel LFTs a weekly or 
more frequently if clinically indicated until 
ALT/AST is reduced to Grade 1.  
(4) If the potential benefit for reinitiating pazopanib 
treatment is considered to outweigh the risk for 
hepatotoxicity, then reintroduce pazopanib at a 
reduced dose and measure serum liver tests weekly 
for 8 weeks..d  
Re-treatment may be considered if ALL following 
criteria are met: 
- ALT/AST reduced to Grade 1
- Total bilirubin <1.5 x ULN or direct bilirubin 
35%
- No hypersensitivity signs or symptoms
- Subject is benefiting from therapy. 
If approval for re-treatment is granted, the subject 
must be re-consented (with a separate informed 
consent specific to hepatotoxicity). 
Recurrence – Liver Event Stopping CriteriaError! 
Reference source not found.:
Discontinue pazopanib permanently and monitor 
subject closely for clinical signs and symptoms; 
perform full panel LFTs a weekly or more frequently 
if clinically indicated until ALT/AST is reduced to 
Grade 1.  At the time of the recurrence, complete the 
eCRF liver event forms.  
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(D). ALT >3.0 x ULN with concomitant elevation 
in bilirubinError! Reference source not found. 
(defined as total bilirubin 2.0 x ULN; with direct 
bilirubin >35%) or with hypersensitivity symptoms 
(e.g., fever, rash).
Liver Event Stopping CriteriaError! Reference 
source not found.:
(1) Discontinue pazopanib immediately, report the 
event to NOVARTIS as an SAE within 24 hours 
of learning of its occurrence , and complete the 
eCRF liver event forms.  Make every reasonable 
attempt to have subjects return to the clinic within 
24 hours for repeat liver chemistries and liver event 
follow up assessments.
(2) Consult a gastroenterologist / hepatologist, collect 
PK sample  and perform the following assessments 
to identify potential co-factors:
- Eosinophil count
- Viral serology for hepatitis A, B, C and E, 
cytomegalovirus, Epstein-Barr virus (IgM 
antibody, heterophile antibody, or monospot 
testing) 
- Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies.
- Serum creatinine phosphokinase for possible 
muscle injury caused LFT elevation
- Liver imaging
-Consider toxicological blood screen for possible 
contributing chemical/medical entities 
(3) Monitor subject closely for clinical signs and 
symptoms; record the appearance or worsening of 
clinical symptoms of hepatitis, or hypersensitivity, 
such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever rash or 
eosinophilia as relevant on the AE report form.  
Perform full panel LFTs a weekly or more 
frequently if clinically indicated until LFTs are 
reduced to Grade 1.  
For isolated total bilirubinError! Reference source 
not found. elevation without concurrent ALT 
increases (defined as ALT <3 X ULN).
(1) Isolated hyperbilirubinemia (i.e., in the absence of 
elevated ALT or other signs/symptoms of liver 
injury) does not require dose modification.  
Pazopanib inhibits UGT1A1 and OATP1B1, which 
can cause elevation of indirect (unconjugated) 
bilirubin in the absence of liver injury.
(2) If bilirubin is >1.5 x ULN in the absence of ALT 
elevation, fractionation of bilirubin elevation should 
be performed.  If bilirubin is >35% direct 
(conjugated), further evaluation for underlying 
cause of cholestasis should be performed.
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a.
Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.  Coagulation tests should 
be performed as clinically indicated.
b.
Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject 
meets the criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported as an SAE.
c.
When a liver chemistry event meets the Liver Event Interruption Criteria, or Liver Event Stopping Criteria, 
blood samples should be obtained for PK and for clinical laboratory testing by the central laboratory (Liver 
Event Kits will be provided for this purpose).   
d.
Please refer to Investigator’s Brochure, Summary of Data and Guidance for Investigator, Warnings and 
Precautions, Hepatic Effects for information about rechallenge dose.
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; eCRF electronic case report form; 
IP investigational product; LFT liver function tests; PK pharmacokinetics; SAE serious adverse event; ULN upper 
limit of normal
5.7.4.5 For any toxicity (regardless of grade), despite optimal supportive 
care, that is felt by the treating investigator to represent a risk to 
the patient’s safety, additional dose reduction, treatment delay, or 
treatment discontinuation is permitted at the discretion of the 
treating investigator with approval from the Principal Investigator 
and DMC. 
5.8
Duration of Therapy
Patients will receive 2 cycles of protocol therapy prior to radiographic assessment 
for response or progression.  Patients with clinical signs or symptoms of rapid 
disease progression prior to completing 2 cycles of protocol therapy may be 
removed from the study by the treating physician.  Patients without disease 
progression at the time of response assessment will continue on the study, with 
repeat assessments after every 2 cycles (8 weeks +/- 7 days) until one of the 
criteria for treatment discontinuation is met. It is recommended that 
temozolomide treatment be discontinued after 1 year, due to risk of 
Myelodysplastic syndrome (MDS) . Patients can continue on Pazopanib.  If 
patient is receiving benefit from combination treatment after one year, it is up to 
the treating physician’s discretion whether or not the patient continues 
Temozolomide.
5.8.1
Criteria for discontinuing study treatment
When a patient is discontinued from treatment, the reason(s) for 
discontinuation will be documented on the appropriate eCRFs.  Individual 
patients will continue on study therapy until any of the following occurs:
5.8.1.1 Unacceptable toxicity despite optimal supportive care and dose 
modifications (refer to Sections 5.6 and 5.7),
5.8.1.2 Disease progression by RECIST (version 1.1),
5.8.1.3 The patient or his/her legally authorized representative requests to 
discontinue protocol therapy or withdraws consent.
5.8.1.4 The decision is made by the treating physician to discontinue 
treatment due to one of the following:
5.8.1.4.1 Patient non-compliance or lack of follow-up.
5.8.1.4.2 Patient requires exclusionary concurrent treatment.
5.8.1.4.3 Physician assessment that continuation of protocol 
   therapy would be detrimental to the patient.
5.8.1.5 Death
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5.8.2
Unacceptable toxicity
Patients must be removed from the study and protocol therapy 
discontinued for toxicities deemed by the treating investigator as 
unacceptable.  These toxicities include but are not limited to: 
5.8.2.2 Recurrent grade 3 or any grade 4 hemorrhage.
5.8.2.3 Gastrointestinal perforation requiring medical or surgical therapy.
5.8.2.4 Wound dehiscence requiring medical or surgical therapy.
5.8.2.5 Grade 4 hypertension despite optimal medical management
5.8.2.6 Grade 4 hypersensitivity reaction to either study drug, or Grade 3 
reaction that recurs despite optimal supportive care.
5.8.2.7 Any Grade 3 or 4 toxicity that is deemed serious and/or life-
threatening by the treating investigator after review with the 
Principal Investigator.
5.8.2.8 Any irreversible (lasting ≥ 2 weeks despite optimal supportive 
care) Grade 3 or 4 toxicity (excluding nausea, vomiting, 
asymptomatic Grade 3 hypophosphatemia or Grade 3 
hyponatremia, anemia, lymphopenia, or fatigue)
5.8.2.9 Any toxicity requiring treatment delay for > 28 days or 
discontinuation of either study drug.
5.9
Follow-Up
After treatment discontinuation, patients will be followed every 6 months for 1 
year in clinic and/or via phone for survival follow-up.  The study will end 30 days 
after the last patient discontinues therapy and completes the protocol-defined 
follow-up period.
  
6.0 
ENDPOINT ASSESSMENT
6.1 
Phase I
6.1.1
Primary Endpoint
The primary objective for the phase I portion of this trial will be to 
determine the MTD of temozolomide and pazopanib combination in 
patients with advanced PNET.  The primary endpoint will be toxicity, as 
assessed after 28 days of treatment (or completion of 1 cycle of therapy).  
Toxicity will be assessed at scheduled clinic follow up appointments every 
one to two weeks, as well as by investigator review of weekly laboratory 
testing; in the interim, toxicity may be assessed via patient contact with 
the study coordinator and/or clinical staff should new symptoms arise 
between visits.  The MTD will be the level at which ≤ 1 out of 6 patients 
experience a DLT (the highest dose level below the MAD).  This will be 
the dose for the phase II portion of the study.  Toxicity will be assessed 
according to the NCI CTCAE version 4.03.
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6.1.2
Secondary Endpoints
6.1.2.1 Determine the safety and toxicity profile
One secondary objective for the phase I portion of this trial will be 
to determine safety and toxicity profile of the combination of 
temozolomide and pazopanib in this population.  The endpoint for 
this objective will be toxicity, which will be assessed at scheduled 
clinic follow up appointments every one to two weeks, as well as 
by investigator review of weekly laboratory testing; in the interim, 
toxicity may be assessed via patient contact with the study 
coordinator and/or clinical staff should new symptoms arise 
between visits.  Toxicity will be graded according to the NCI 
CTCAE version 4.03.
6.1.2.2 Describe the pharmacokinetics (PK) of the combination of 
temozolomide and pazopanib
Once the MTD is reached in the phase I portion of the study, this 
cohort will be expanded to include an 6 additional patients who 
will have PK studies performed.  We will examine the effect of 
pazopanib on the pharmacokinetics of temozolomide.  Full PK 
profiles will be taken after a single dose of temozolomide on Day 1 
and again on Day 2 after administration of the combination of 
temozolomide and pazopanib.  On Day 1, Cycle 1, the patient will 
have a time = 0 sample, take their dose of temozolomide, and then 
have samples drawn at the following times:
6.1.2.2.1 Day 1, Cycle 1
Time = 0 (prior to temozolomide dose) 10 min (+/- 5 
minutes), 30 min (+/- 5 min), 1 hour (+/- 5 min), 2 
hours(+/- 5 min), 3 hours(+/- 5 min), 4 hours (+/- 30 min) , 
6 hours(+/- 30 min), 8 hours(+/- 30 min), and 24 hours(+/- 
1 hour) post-dose.(drawn on Day 2.This will be the same 
sample as the pre-dose PK sample of Day 2 provided Day 
2 drug administration is done within 1 hour of sample 
collection. One 3 ml sample is needed).
6.1.2.2.2 Day 2, Cycle 1
 Time = 0 (prior to both pazopanib and temozolomide. 
This will be the same sample as the 24 hour post-dose PK 
sample of Day 1, provided Day 2 drug administration is 
done within 1 hour of sample collection. If this drug 
administration is delayed beyond one hour, then another 3 
ml PK sample has to be collected for the pre-dose PK of 
Day 2), 10 min(+/- 5 minutes), 30 min(+/- 5 min), 1 
hour(+/- 5 min), 2 hours(+/- 5 min), 3 hours(+/- 5 min), 4 
hours(+/- 30 min), 6 hours(+/- 30 min), 8 hours(+/- 30 
min), and 24 hours(+/- 1 hour)  (done on Day 3) post dose.
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Plasma temozolomide concentrations will be measured using our 
triple quadruple API3000 LC-MS/MS after sample preparation by 
solid-phase extraction.  The plasma temoxolamide concentration 
versus time relationships will be modeled using the SAAM II 
software system (SAAM Institute, Seattle, WA) implemented on a 
WindowsTM-based PC as described by Argiris et al.  Cmax and 
Tmax will be taken as the observed values.
These 6 patients in the PK cohort will be included in the phase II 
analysis.  These patients will have correlative studies including 
MGMT.  These 6 patients will be evaluated for phase II endpoints. 
6.1.2.3 Observe the ORR
For all patients enrolled in the phase I portion of the study, we will 
describe the ORR as the best overall response recorded from the 
start of the study treatment until the end of treatment based on 
RECIST (version 1.1) criteria.
6.2
Phase II
6.2.1
Primary Endpoint
The primary objective for the phase II portion of this trial will be to 
determine the ORR.  All enrolled patients will undergo contrast-enhanced 
CT or MRI imaging at baseline and after every 2 cycles of protocol 
therapy until study discontinuation. Patients will be assessed 
radiographically for response or progression after 2 cycles (8 weeks ± 7 
days) of study treatment. After 1 year of protocol therapy, patients may 
switch to imaging every 12 weeks (+/- 7 days) per treating physician 
discretion. Centralized RECIST measurements may be performed for 
some sites, depending upon feasibility.  The schedule and methods of 
radiographic evaluation are described in Section 7.0.  
6.2.2
Secondary Endpoints
6.2.2.1 Determine PFS, OS, DCR, and DOR.
For these endpoints, all enrolled patients will undergo contrast-
enhanced CT or MRI imaging at baseline and after every 2 cycles 
of protocol therapy until study discontinuation.  Please see Section 
6.3 for definitions.  
6.2.2.1.1 PFS will be defined as will be defined as the time from 
the first study treatment to the first occurrence of 
progression or death.
6.2.2.1.2 OS will be defined as the time from first study treatment 
until death from any cause.
6.2.2.1.3 DCR will be defined as CR + PR +SD
6.2.2.1.4 DOR will be defined as the time from documented 
overall response to time of documented disease 
progression.
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6.2.2.2 Determine the safety and toxicity profile of the combination in 
a larger cohort of patients.
All patients enrolled in the phase II portion of the trial will be 
evaluated for toxicity throughout the course of their participation 
on study and through 30 days after the last dose of study treatment.
 
6.2.3
Exploratory/Correlative Endpoints
Exploratory objectives of this study will look at different types of 
correlations.  We will examine the relationship between tumor blood flow 
(as measured by perfusion functional computed tomography) and overall 
response.  We will also correlate the expression of tissue MGMT as 
measured by immunohistochemistry with PFS. 
6.2.3.1 Correlate the expression of tissue MGMT with PFS.
Immunohistochemistry for MGMT expression will be performed 
on all patients enrolled in the phase II portion of the study (the 6 
patients in the PK cohort will also be included in these exploratory 
studies).  
MGMT expression will be measured in a blinded fashion utilizing 
mouse monoclonal antibodies to MGMT.  Nuclear MGMT will be 
scored as either present or absent in tumor cells and correlated with 
treatment outcome (PFS).
6.3
Definitions
Target and non-target lesions will be defined by RECIST guidelines (version 1.1).
6.3.1
Measureable disease
Measurable lesions are defined as measurable in at least one dimension 
with clearly defined margins; at least one diameter must be greater than 
0.5 cm.  Bone lesions are excluded.
6.3.2
Non-measureable disease
All other lesions (or sites of disease), including small lesions and bone 
lesions, are considered non-measurable disease.
6.3.3
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs should be identified 
as target lesions and recorded and measured at baseline.    Target lesions 
should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either 
by imaging techniques or clinically).  A sum of the longest diameter (LD) 
for all target lesions will be calculated and reported as the baseline sum 
diameters.  The baseline sum diameters will be used as reference by which 
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to characterize the objective tumor.  Pathological lymph nodes: nodes with 
a short axis of ≥ 15 mm are considered measurable and assessable as 
target lesions.  The short axis measurement should be included in the sum 
of lesions in calculation of tumor response. Nodes that shrink to < 10 mm 
short axis are considered normal. 
6.3.4
Non-target lesions
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
6.4  Evaluation of response to therapy
The following criteria (RECIST version 1.1) will be used to define disease 
response to therapy based upon radiographic measurements using contrast-
enhanced CT or MRI imaging with contiguous cuts of 10 mm or less in slice 
thickness:41
Table 8:  Definitions & Evaluation of Response
Evaluation of Target Lesions
Complete Response 
(CR)
Disappearance of all target lesions. 
Partial Response (PR)
At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum 
diameters.
Progressive Disease 
(PD)
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum 
recorded on study 
AND
an absolute increase in the sum of at least 5 mm OR 
the appearance of one or more new lesions.  
 Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum of diameters while on 
study 
Evaluation of Non-Target Lesions
Complete Response 
(CR)
Disappearance of all non-target lesions and 
normalization of tumor marker level. 
Incomplete Response/ 
Stable Disease (SD)
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease 
(PD)
Appearance of one or more new lesions and/or 
unequivocal1 progression of existing non-target 
lesions2.
 1 For unequivocal progression on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. The designation of overall 
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progression solely on the basis of change in non-target disease in the face of SD 
or PR of target disease will be extremely rare.42
2 In the uncommon scenario of a mixed response with response or stable disease in target 
lesion(s) but progression in non-target lesions only, assessment of overall 
response will be made by the treating investigator and confirmed with the 
Principal Investigator and DMC. 
 
6.5
Evaluation of best overall response
At study completion, each patient’s case will be reviewed to determine a best 
overall response to therapy.  Based on RECIST, the best overall response is the 
best response recorded from the start of the study treatment until the end of 
treatment, taking into account any requirement for confirmation.41, 42  In general, 
the patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.  Patients with a global deterioration of 
health status requiring discontinuation of treatment without objective evidence of 
disease progression at that time should be classified as having “symptomatic 
deterioration.”  Every effort should be made to document objective tumor 
progression even after discontinuation of treatment.  The best overall response 
will be defined as follows: 
Table 9:  Best Overall Response Definitions
Best Overall Response
Target Lesion
Non-Target Lesion New Lesion 
Overall Response
CR
CR
No
CR
CR
Non CR/Non-PD
No 
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
6.6
Confirmation of disease response or progression
The main goal of confirmation of objective response is to avoid overestimating 
the response rate observed.  The Principal Investigator will confirm the objective 
response for each patient, and the confirmed responses will be reviewed by the 
DMC prior to reporting the results.  
In cases where confirmation of response is not feasible, it will be made clear 
when reporting the outcome that the responses are not confirmed.  To be assigned 
a status of PR or CR by RECIST, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks 
after the criteria for response are first met.41, 42  In the case of SD, follow-up 
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measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 8 weeks (± 7 days).  
6.7
Criteria for study completion
6.7.1
Phase I
The phase I portion of the study will close to accrual when the MTD is 
confirmed in a cohort of at least 6 patients and the additional 6 patients for 
the PK cohort have been enrolled.  The study may also be closed 
prematurely if more than 1 of 3 patients at cohort Level -3 experience a 
DLT so that the MTD cannot be determined.  At the discretion of the 
Principal Investigator and the DMC, the study may be terminated early for 
failure to enroll an adequate number of patients or for significant, 
unexpected toxicities.
6.7.2
Phase II
The phase II portion of the trial will be completed when all patients have 
been enrolled and all data for the study endpoints have been collected.   At 
the discretion of the Principal Investigator and the DMC, the study may be 
terminated early for failure to enroll an adequate number of patients or for 
significant, unexpected toxicities.
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7.0          STUDY PARAMETERS 
 Table 10:  Schedule of Events
Screening
Cycle 1 20
Cycles 2 & 320,
Cycle 4+ 11,20
Follow-Up 12
Assessments
Baseline 1
D1 17
D8
D15
D22
D1
D15
D1
D1521
Off 
Treatment
Post-Treatment
Informed Consent
X
History and physical 2
X
X
X
X
X
X
X
X
X
Toxicity assessment 3
X
X
X
X
X
X
X
X
X
WBC, ANC, hemoglobin, platelet
X
X
X
X
X
X
X
X
X23
X
Electrolytes & renal function tests 
(Na, K, Cl, CO2, BUN, 
Creatinine, Mg, Phos)
X
X
X
X
X
X
X
X
X23
X
Liver function tests (AST, ALT, 
alk phos, total bilirubin)
X
X
X
X
X
X
X
X
X23
X
Albumin, INR, PTT
X
Serum chromogranin A
X18
X
X
Serum creatinine 4
X
Urine protein/creatinine 5
X
X
X
X
Serum pregnancy test 6
X
EKG 19
X
X
X
Echocardiogram or MUGA
X
Pathology review 15
X
Imaging 7
X
X
X
X
Temozolomide 8
X
(D1-7)
X
(D15-21)
X
(D1-7)
X
(D15-21)
X
(D1-7)
X
(D15-21)
Pazopanib 9
Continuous daily administration beginning Cycle 1 Day 1
Sulfamethoxazole prophylaxis 10
Administered 3 times per week while on treatment
Drug Diary collection 22
X
X
Survival Follow-up
X
X
Correlative Studies 14
PK sampling (PK cohort only) 13
X
(D1-3)
IHC for MGMT expression 16
X
1 Baseline studies should be completed within 14 days of initiating treatment except for imaging, which must be within 28 days.
2 A complete history and physical exam [including weight, height, vital signs (pulse, temperature, respiratory rate, blood pressure, oxygen saturation) and ECOG PS] will be 

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conducted at baseline.  Subsequent visits require physical exam including vital signs, weight and ECOG PS.  
3 Toxicity will be assessed using the NCI CTCAE version 4.03.
4 If serum creatinine ≥ 1.5 mg/dL, then creatinine clearance should be calculated and ≥ 30 mL/min
5 For baseline, patients must have urine protein to creatinine ratio < 1 OR a 24-hour urine protein < 1 g.  For treatment cycles, only a urine protein/creatinine ratio is required.
6 Required for females of childbearing potential (within 14 days) – see definition of child-bearing potential in Section 3.2.
7 Imaging with CT or MRI (whichever test is used for a particular patient at baseline should be the same that is used throughout for disease assessment).  Response will be assessed 
every 2 cycles (8 weeks +/- 7 days). After 1 year of protocol therapy, patients may switch to imaging every 12 weeks (+/- 7 days) per treating physician’s discretion.
8 Temozolomide will be administered on Days 1-7(+/-1 day) and 15-21(+/-1day) of each cycle.  Please refer to Section 5.2 for further details.
9 Pazopanib will be administered continuously starting Cycle 1, Day 1 until study discontinuation.  Please refer to Section 5.2 for further details.
10 All patients will receive prophylaxis with trimethoprim-sulfamethaxazole double strength (sulfamethoxazole 800 mg and trimethoprim 160 mg) by mouth 3 times a week.
11 Patients will continue on treatment until disease progression (or until removed from study for other reasons, as outlined in Section 5.8.1).  
12 Patients removed from the study for disease progression who have no ongoing toxicity will undergo one last off-treatment visit for response.  Survival follow-up will continue 
every 6 months for 1 year in clinic and/or via phone ; survival follow-up may occur either in clinic or via phone contact.  Additional follow-up may be required for patients 
experiencing toxicity at the time of treatment discontinuation.  .
13 Patients in the PK cohort only will have PK samples drawn on Days 1-3 of Cycle 1.  Please refer to Sections, 6.1.2.2and 12.1 for details.
14 Correlative studies will only be done on the 6 patients in the PK cohort, as well as all patients enrolled to the phase II portion of the study.  
15 Copy of pathology report is sufficient for registration.  However a sample of tissue from a recent biopsy will be required for the 6 patients enrolled in the PK cohort and all 
patients in the phase II portion of the trial
16 Please refer to Section 12 for details regarding tissue requirements.  Tissue from the most recent biopsy will be obtained for study purposes – patients will not undergo repeat biopsy for 
correlative studies. This applies to both PK cohort and Phase II patients 
17 If baseline labs (chemistries, Mg, Phos, and CBC) were completed within 48 hours prior to start of treatment, they do not need to be repeated for Cycle 1 Day 1.
18 If serum chromogranin is completed within 14 days of treatment, it does not need to be repeated for Cycle 1 Day 1.
19 EKG will be performed at baseline (within 14 days of initiating study treatment) and then Day 1 of every cycle beginning with Cycle 2 – EKG does NOT need to be repeated at Cycle 1 
Day 1.
20 Assessments will be completed +/- 3 day from treatment Days 1, 8, 15, and 22 unless otherwise noted. Imaging will be assessed every 2 cycles (8 weeks +/- 7 days). 
21 For Cycle 4 and beyond, Day 15 labs may be completed at a local facility if more convenient for patients, per treating investigator’s discretion.
22 The drug diary (completed by the patient during each cycle) should be collected on Day 1 of the next cycle. Patients should be instructed to complete the drug diary every day and bring 
it to their visit on Day 1 of the next cycle.
23For patients who discontinue Temozolamide  after 1 year of treatment, D15 laboratory tests  (WBC, ANC, hemoglobin, platelet, Electrolytes & renal function tests [Na, K, Cl, CO2, 
BUN, Creatinine, Mg, Phos] and AST, ALT, alk phos, total bilirubin)  are not required to be done.

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8.0
DRUG FORMULATION AND PROCUREMENT
8.1
Temozolomide
8.1.1
Other Names
Temodar®, TMZ, Temodal®, methazolastone
8.1.2
Classification – type of agent
Temozolomide is a cytotoxic alkalyting agent.
8.1.3
Mode of Action
Temozolomide is not directly active but undergoes rapid non-enzymatic 
conversion at physiologic pH to the reactive compound MTIC.  The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA.  
Alkylation (methylation) occurs mainly at the O6 and N7 positions at 
guanine.
8.1.4
Storage and Stability
Temozolomide capusles are packaged in amber glass bottles and should be 
stored at 25°C (temperature excursions between 15-30°C are permitted).  
Refer to the product label for storage and stability information.  
8.1.5
Protocol Dose
The starting dose for the phase I portion of this trial will be 150 mg/m2 
taken orally on days 1-7 and 15-21 of each cycle (1 cycle = 28 days).  The 
dose will be escalated (or de-escalated) according to the toxicities 
observed in each cohort of patients.  The MTD, once determined in the 
phase I portion, will be the recommended dose for the phase II portion of 
the trial. The MTD has been identified at dose level -2: Temozolomide 75 
mg/m2 per day p.o. days 1-7 and 15-21. As of 12.15.15, all patients 
moving forward will be treated at this dose.
8.1.6
Preparation
Temozolomide is supplied in white opaque, preservative-free capsules in a 
variety of dosage strengths.
8.1.7
Protocol Administration
Temozolomide will be administered orally on days 1-7 and 15-21 of each 
28-day cycle.  Capsules should be swallowed whole with a glass of water. 
Absorption is affected by food.  Temozolomide may be administered on 
an empty stomach or at bedtime to reduce nausea and vomiting.  A dose 
should not be repeated if vomiting occurs after administration.  Capsules 
should not be opened or chewed.  Contact with skin should be avoided if 
capsules are accidentally opened or damaged.
8.1.8
Incompatibilities
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Administration of valproic acid decreases oral clearance of temozolomide 
by about 5%.  The clinical implication of this effect is not known.
8.1.9
Availability
Temozolomide is FDA-approved for the treatment of anaplastic 
astrocytoma and GBM.  Locally-obtained, commercial supplies of 
temozolomide will be prescribed for this study.   
8.1.10 Side Effects
The most common grade 3 or 4 toxicities reported with standard dosing 
include: 
8.1.10.1 Lymphopenia < 5%
8.1.10.2
 Thrombocytopenia < 5% 
8.1.10.3
 Nausea/vomiting < 10%
8.1.10.4
 Elevated liver enzymes < 10%
8.1.10.5
 Elevated BUN/Cr < 10%
8.1.10.6
 Constipation < 10%
8.1.10.7
 Rash 5%
8.1.10.8
 Headache < 5%
8.1.10.9
 Alopecia < 5% 
8.1.10.10 Lethargy < 1% 
8.1.11 Nursing Implications
8.1.11.1Monitor CBC carefully and report any significant changes to the 
treating physician.  Instruct patients to report signs/symptoms of 
infection, unusual bruising and bleeding to health care team.
8.1.11.2Instruct patients to report any fever, cough, chest pain, or other 
signs of infection to the health care team.
8.1.11.3Advise patients that a mild-moderate rash may be experienced.
8.1.11.4Work with patients in energy conserving lifestyle methods to 
combat fatigue.
8.1.11.5Encourage patients to increase fluid intake.  Administer stool 
softeners or laxatives as ordered and monitor for their 
effectiveness.
8.2
Pazopanib
8.2.1
Other Names
None
8.2.2
Classification – type of agent
Pazopanib is an ATP-competitive tyrosine kinase inhibitor of VEGFR.
8.2.3
Mode of Action
Pazopanib is an orally-bioavailable, ATP-competitive tyrosine kinase 
inhibitor of VEGFR (-1, -2, and -3), PDGFR (-α and -β) –Kit. 
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8.2.4
Storage and Stability
Keep in tightly closed containers or packages away from moisture and 
away from sources of ignition.  Avoid direct sunlight.
8.2.5
Protocol Dose
The starting dose for the phase I portion of this trial was 400 mg taken 
orally on a daily basis for each cycle (1 cycle = 28 days).  The dose was 
escalated (or de-escalated) according to the toxicities observed in each 
cohort of patients. The MTD has been identified at dose level -2; 
Pazopanib 400 mg per day p.o. days 1-28. 
As of 12.15.15, all patients moving forward will be treated at this dose. 
8.2.6
Preparation
For clinical supply, Pazopanib is supplied as a series of aqueous film-
coated tablets containing 200 mg or 400 mg of the freebase:
8.2.6.1 200 mg, oval-shaped, white, packaged in bottles containing 34 
tablets each
8.2.6.2 400 mg, oval-shaped, white, packaged in bottles containing 68 
tablets each.
For commercial supply,
                                   8.2.6.3 200mg, gray, oblong-shaped tablets, packaged in bottles 
containing 120 tablets each.
                                    Votrient (Pazopanib) commercial available supply with auxiliary 
label will also be provided by Novartis. The study drug should be 
administrated and stored according to the instructions specified on 
the drug labels. 
                                   (Note: Sites will start using the commercial supply when they finish the 
previous clinical supply).
8.2.7
Protocol Administration
Pazopanib should be taken orally without food at least 1 hour before or
2 hours after a meal. The tablets should be swallowed whole and must not 
be crushed or broken. The time of day the tablets are taken should be 
relatively constant. If a dose is missed, the patient should take the dose as 
soon as possible, but not if there are less than 12 hours before the next 
dose is due. If the next dose is due in less than 12 hours, the patient should 
skip the missed dose and take the next dose as scheduled.  If vomiting 
occurs after taking pazopanib another dose is not permitted on that day. 
The patient should resume taking pazopanib at the next scheduled dose.  If 
vomiting persists, the subject should be instructed to notify the 
investigator.
8.2.8
Incompatibilities
Results from drug-drug interaction studies conducted in cancer patients 
suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and 
CYP2D2 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19.  
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The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, 
ritonavir, clarithromycin) may increase pazopanib concentrations and 
should be avoided.  Grapefruit juice should be avoided as it inhibits 
CYP3A4 activity and may also increase plasma concentrations of 
pazopanib. A list of CYP3A4 inhibitors is provided in Appendix II.  
The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may 
decrease pazopanib concentrations and should be avoided.  Pazopanib 
should not be used in patients who cannot avoid chronic use of strong 
CYP3A4 inducers.  A list of CYP3A4 inducers is provided in Appendix II.  
Concomitant use of pazopanib with agents with narrow therapeutic 
windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not 
recommended.  A list of these agents is provided in the Appendix II.
Concomitant use of pazopanib and simvastatin (Zocor) increases the risk 
of ALT elevations and should be undertaken with caution and close 
monitoring.  If a subject receiving concomitant simvastatin develops ALT 
elevations, follow the Guidelines for Management of Treatment Emergent 
Hepatotoxicity and discontinue simvastatin.  Insufficient data are available 
to assess the risk of concomitant administration of alternative statins and 
pazopanib.
Please refer to the development core safety information in the current 
Investigator’s Brochure for detailed information about interactions with 
simvastatin, CYP3A4 inhibitors, impact on drugs eliminated through 
UGT1A1 and OATP1B1, and the use of pazopanib with drugs known to 
increase the gastric pH. Please also refer to Appendix II of this protocol.
8.2.9
Availability
Votrient (Pazopanib) commercial available supply with auxiliary label will 
be provided by Novartis. The study drug should be administrated and 
stored according to the instructions specified on the drug label.
Pazopanib will be provided by study supporters Novartis and 
NCCN.  All requests for study drug should be submitted via email to 
Desiree Hiraman (desiree.hiraman@novartis.com), Quincy Chau 
(quincy.chau@novartis.com), and Donna Scharff (Scharff@nccn.org) and 
should include the following information:
8.2.9.1 Quantities needed
8.2.9.2 Protocol number
8.2.9.3 PI’s name and shipping address
8.2.10 Side Effects
8.2.10.1 Very common (≥ 1 in 10): anorexia, headache, 
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  hypertension, diarrhea, nausea, vomiting, abdominal pain, 
  increases in ALT, AST, hair depigmentation, fatigue,  
              asthenia.
8.2.10.2 Common (≥ 1 in 100 and < 1 in 10): thrombocytopenia, 
  neutropenia, hypothyroidism, decreased weight, dysgeusia, 
  transient ischemic attack, myocardial ischemia, QT 
              prolongation, epistaxis, hematuria, dyspepsia, hepatic  
              function abnormalities, hyperbilirubinemia, rash, alopecia, 
              skin depigmentation, Palmar-plantar erythrodysaesthesia  
              syndrome, proteinuria, chest pain 
8.2.10.3 Uncommon (≥ 1 in 1000 and < 1 in 100): ischemic stroke, 
  Torsade de Pointes, atrial fibrillation, pulmonary hemorrhage, GI 
hemorrhage,  
  cerebral hemorrhage, GI perforation, GI fistula
(Note: please refer to updated IB version 14 dated 01.07.16 for 
more information.)
8.2.11 Nursing Implications
8.2.11.1 Take without food.  
8.2.11.2 Monitor liver function tests at baseline while on treatment.
8.2.11.3 Monitor blood pressure.
9.0
STATISTICAL CONSIDERATIONS 
The study design is a phase I/II, open-label, non-randomized dose-escalation study to 
determine the MTD, safety profile, pharmacokinetics, response rate, and overall survival 
with the combination of temozolomide and pazopanib in patients with advanced 
pancreatic neuroendocrine tumor.  
The MTD determined in phase I will be the recommended Phase II dose.  Once the MTD 
is determined, the study will proceed to a single-arm, open-label Phase II to evaluate 
efficacy endpoints.  Data will be pooled from patients enrolled at both study sites. 
9.1
Phase I Endpoints
The primary endpoint in Phase I is MTD and RP2D determination for the 
combination of temazolamide and pazopanib in patients with advanced pancreatic 
neuroendocrine tumor.  This will be achieved using a standard “3+3” dose 
escalation as detailed in Section 5.2.  Secondary endpoints in Phase I include 
determining the safety and toxicity profile of the combination of temozolomide 
and pazopanib, describing the pharmacokinetics, and observing the ORR.  
Patients who are removed from study for reasons other than disease progression 
(i.e. for toxicity or patient preference) will be censored for measurement of 
secondary endpoints at the time of their latest objective tumor assessment. 
9.1.1
Sample Size of Phase I
Between 9 and 12 patients will be accrued in phase I.  The MTD of the 
regimen will be determined using standard “3+3” phase I methodology. 
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9.1.2
Phase I Statistics
Safety will be assessed through a summary of adverse events and 
laboratory test results.  Safety analyses will include all patients who 
receive at least one dose of study regimen.  Verbatim description of 
treatment-related adverse events will be mapped to thesaurus terms.  
Adverse events assessed as related to study drug and serious adverse 
events will be summarized similarly.  Adverse events leading to treatment 
discontinuation will also be summarized.  The safety analysis will include 
a tabulation of all toxicities by grade.  The frequency of toxicities will be 
tabulated separately for each treatment dose level.  Treatment safety and 
toxicity will be evaluated using NCI CTCAE v 4.0 with scheduled 
assessments every week for the first cycle and then biweekly thereafter.  
The statistical analysis for the secondary objectives of phase I will be 
descriptive in nature.  The pharmacokinetics of temozolomide alone 
(Cycle 1 Day 1) and in combination with pazopanib (Cycle 1 Day 2) will 
be described in a population of 6 patients enrolled at the MTD.  Cmax and 
Tmax will be taken as the observed values.  At a minimum, for 
temozolomide, the following PK parameters will be determined:  maximal 
serum concentration (Cmax); observed time to achieve Cmax (Tmax); 
minimum (trough) serum concentration (Cmin); elimination half-life (t1/2); 
elimination clearance (CLE); volume of distribution at steady-state (VSS), 
and area under the concentration-time curve extrapolated to infinity 
(AUCinf).  These parameters will be summarized for each person and each 
day, and each constant will be compared between Day 1 and Day 2 using a 
Wilcoxon signed rank test.  The plasma temozolomide concentration 
versus time relationships will be modeled using the SAAM II software 
system.  The 6 patients enrolled at the MTD to form the PK cohort will be 
included in the phase II analysis for all other endpoints. 
9.2
Phase II Endpoints
9.2.1
Sample Size of Phase II
The sample size estimate for phase II is based upon a two-stage Simon’s 
optimal design.  The primary efficacy endpoint will be the objective 
response rate (partial or complete response).  A Simon (1989), optimum 
two-stage design will be employed.  A 19% response rate precludes 
further study whereas a 39% response rate would indicate that further 
investigation of the treatment is warranted (i.e., P0=0.19 and P1=0.39 in 
the Simon terminology).  Using α and β errors of 0.10 and 0.20, 
respectively, 11 patients will be enrolled in the first stage and this will 
include the 6 patients in the PK cohort.   If 2 or fewer responses are 
observed, the trial will be terminated.  Otherwise, an additional 16 patients 
will be enrolled in the second stage and if ≤ 7 responses are observed 
among the 27 patients, the agents will not be considered worthy of further 
testing; whereas, if 8 or more responses are observed the drugs will be 
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considered sufficiently active to justify further study.  This design has 
80% power under the alternative hypothesis and provides a 65% 
probability of early stopping if the true response rate is only 19%.   
Therefore, a maximum of 27 patients will be accrued to the phase II 
portion of the study.  
9.2.2
Response Rate Statistics
Radiological response will be analyzed using an intent-to-treat approach 
of including all enrolled patients.  After every 2 cycles of protocol therapy, 
patients will undergo imaging studies to assess for response to therapy 
using RECIST.  At study termination, each patient’s case will be reviewed 
to determine a best overall response to therapy by RECIST.  A descriptive 
analysis of evidence of antitumor activity will be provided based on 
radiographic assessments of activity.  The proportion with PFS at 6 
months will also be calculated based on RECIST criteria.
9.2.3
Toxicity Profile Statistics
Safety will be assessed through a summary of adverse events and 
laboratory test results.  Safety analyses will include all patients who 
receive at least one dose of study regimen.  Verbatim description of 
treatment-related adverse events will be mapped to thesaurus terms.  
Adverse events assessed as related to study drug and serious adverse 
events will be summarized similarly.  Adverse events leading to treatment 
discontinuation will also be summarized.  The safety analysis will include 
a tabulation of all toxicities by grade.  The frequency of toxicities will be 
tabulated separately for each treatment dose level.  Treatment safety and 
toxicity will be evaluated using NCI CTCAE v 4.03 with scheduled 
assessments every week for the first cycle and then biweekly thereafter.  
9.3
Exploratory Endpoints
Exploratory endpoints in this phase I/II trial will be assessed in all patients 
enrolled in the phase II portion of this study.  As noted above, patients who are 
removed from study for reasons other than disease progression (i.e. for toxicity or 
patient preference) will be censored for measurement of secondary endpoint, PFS 
at 6 months, at the time of their latest objective tumor assessment.  Exploratory 
endpoints include:

Correlate the expression of tissue MGMT as measured by IHC with PFS. 
9.3.1 Exploratory Study Statistical Analyses
9.3.1.1 MGMT expression
Changes in MGMT over time will be assessed using repeated 
measures analysis of variance; pre-treatment levels and changes in 
levels from baseline to day 30 will be related to response using a 
Wilcoxon rank sum test, and to PFS and OS using a proportional 
hazards regression model. 
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9.4 
Replacement Policy
A patient may be replaced if protocol therapy is discontinued due to early disease 
progression, defined as occurring within the first 28 days of therapy.  Patients will 
not be replaced if taken off study due to toxicity, however, if a patient is taken off 
study during their DLT period for a reason unrelated to study treatment, another 
patient may be added to that cohort. 
9.5
Statement of Feasibility
The Northwestern University GI Oncology program derives study patient 
populations from patients currently undergoing treatment or evaluation at the 
Robert H. Lurie Comprehensive Cancer Center (RHLCCC), as well as from a 
broad referral base in the Chicago and Midwest area.  The weekly 
multidisciplinary GI Tumor Board at RHLCCC provides additional means to 
identify potential study subjects.  Based upon these resources, we anticipate 
monthly accrual of approximately 2-3 patients with advanced PNET.  Estimated 
time of study completion is 2.5 years.  Dr. Halla Nimeiri, the Principal 
Investigator of this proposal, has experience leading and designing clinical trials 
in GI oncology. She is also an active member of the ECOG GI committee. She 
has received an NCCN grant in the past for evaluating temsirolimus and sorafenib 
in HCC. As of June2017, she is being replaced by Dr.Sheetal Kircher as Principal 
Investigator of this study. The co-investigators on this study proposal are all 
members of the RHLCCC with strong clinical research backgrounds in the 
development and implementation of clinical trials in gastrointestinal 
malignancies. Dr. Benson is the director of the GI oncology program and the chair 
of the ECOG Gastrointestinal and Data Monitoring Committees.  The group 
includes well developed research infrastructure including research nurses and 
nurse practitioners, data managers, biostatisticians, and research pharmacists. 
Safety monitoring and oversight will be provided by the RHLCCC Data 
Monitoring Committee (DMC) in accordance with the Data Safety Monitoring 
Plan (DSMP) of the RHLCCC. Additional details regarding how this study will 
be monitored can be referenced in Appendix IV. 
10.0
ADVERSE EVENT MONITORING & REPORTING 
This trial will be conducted in accordance with the DSMP of the RHLCCC
((http://cancer.northwestern.edu/CRO/data/Data andSafetyMonitoringPlanMay2014.pdf). 
The level of risk attributed to this study requires High Intensity Monitoring, as outlined in 
the DSMP.  
10.1
Adverse Event Monitoring
Collection and reporting of adverse event (AE) data is required as part of every 
clinical trial, and is done to ensure the safety of patients enrolled in this study as 
well as those who will enroll in future studies using similar agents.  Toxicity will 
be assessed daily during treatment, and at least twice weekly (if not more 
frequently) after treatment until count recovery (as described in Section 7.0).  All 
adverse events will be reported on the appropriate eCRF (as outlined in 
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Appendices V and VI).  Additionally, certain serious adverse events (SAEs) will 
be reported in an expedited manner to allow for optimal monitoring of patient 
safety and care.  
All patients experiencing an AE, regardless of its relationship to study drug, will 
be monitored until one of the following occurs: 
10.1.1 The AE resolves or the symptoms or signs that constitute the AE return to 
baseline.
10.1.2 Any abnormal laboratory values have returned to baseline.
10.1.3 There is a satisfactory explanation other than the study drug for the 
changes observed.
10.1.4 Death.
10.2
Definitions & Descriptions
10.2.1 Adverse Event
An AE is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease 
temporarily associated with the use of an experimental intervention, 
whether or not related to the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or 
measurements, but should reflect the reason for the procedure or the 
diagnosis based on the abnormal measurement. Preexisting conditions that 
worsen in severity or frequency during the study should also be recorded 
(a preexisting condition that does not worsen is not an AE). Further, a 
procedure or surgery is not an AE; rather, the event leading to the 
procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the 
diagnosis should be provided. For example, if clinically significant 
elevations of liver function tests are known to be secondary to hepatitis, 
“hepatitis” and not “elevated liver function tests” should be recorded. If 
the cause is not known, the abnormal test or finding should be recorded as 
an AE, using appropriate medical terminology (e/g/ thrombocytopenia, 
peripheral edema, QT prolongation).
10.2.2 Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html
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If no CTCAE grading is available, the severity of an AE is graded as 
follows:
10.2.2.1 Mild (grade 1): the event causes discomfort without 
  disruption of normal daily activities.
10.2.2.2 Moderate (grade 2): the event causes discomfort that affects 
  normal daily activities.
10.2.2.3 Severe (grade 3): the event makes the patient unable to 
  perform normal daily activities or significantly affects his/her 
  clinical status.
10.2.2.4 Life-threatening (grade 4): the patient was at risk of death at 
  the time of the event.
10.2.2.5 Fatal (grade 5): the event caused death.
10.2.3 Serious Adverse Event
An SAE is any untoward medical occurrence i.e. an undesirable sign or 
symptom or medical condition that at any dose results in one of the 
following outcomes: 
10.2.3.1Death; if death results from progression of the disease, the disease 
progression should be reported as an SAE itself.
10.2.3.2A life-threatening adverse event; the patient was at risk of death 
at the time of the event (this does not refer to an event that 
hypothetically might have caused death if it were more severe).
10.2.3.3A congenital anomaly/birth defect.
10.2.3.4A persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions.
10.2.3.5 An adverse event that requires inpatient hospitalization or 
prolongation of existing hospitalization for ≥ 24 hours, unless 
hospitalization is for:
10.2.3.5.1 Routine treatment or monitoring of the studied 
       indication, not associated with any deterioration in 
       condition (specify what this includes).
10.2.3.5.2 Elective or pre-planned treatment for a pre-existing 
condition that is unrelated to the indication under study 
and has not worsened since the start of study drug.
10.2.3.5.3 Treatment on an emergency outpatient basis for an 
event not fulfilling any of the definitions of a SAE 
given above and not resulting in hospital admission.
10.2.3.5.4 Social reasons and respite care in the absence of any 
deterioration in the patient’s general condition.
10.2.3.6 Is medically significant or is an important medical event, 
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              Important medical events are those that may not meet any of the 
above criteria, but that are clearly of major clinical significance in 
the judgment of the investigator.  They may jeopardize the subject, 
and/or may require intervention to prevent one of the other serious 
outcomes noted above.  
Examples might include:  
allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, convulsions that may not result in hospitalization, or 
development of drug abuse or drug dependency.
10.2.5 Exceptions to AE & SAE Definitions
Generally speaking, any adverse event that results in hospitalization or 
prolonged hospitalization should be documented and reported as an SAE, 
as described above.  Likewise, any condition responsible for surgery 
should be documented as an AE if the condition meets the criteria for an 
AE.  However, for the purposes of this study, neither the condition, 
hospitalization, prolonged hospitalization, nor surgery are reported as AEs 
or SAEs under the following circumstances:
10.2.5.1Hospitalization or prolonged hospitalization is for a diagnostic or 
elective surgical procedure for a preexisting condition.  Surgery 
should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome 
was uneventful.
10.2.5.2Hospitalization or prolonged hospitalization is required to allow 
efficacy measurement for the study.
10.2.5.3Hospitalization or prolonged hospitalization is required for study-
directed therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as 
judged by the principal investigator.
10.2.5.4Hospitalization or prolonged hospitalization is due to social 
reasons (i.e. awaiting transport home).
10.2.6 Unanticipated Problem Involving Risk to Subject or Others (UPIRSO)
In order for an adverse event to be reported to the Northwestern University 
IRB, it must qualify as a UPIRSO.  In order to qualify as a UPIRSO, the 
event must meet all three of the following criteria:  
10.2.5.1The event must be unanticipated in terms of nature, severity, or 
frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the investigators 
brochure, etc.).  
10.2.5.2The event must place the research subject or others at a different 
or greater risk of harm (including physical, psychological, 
economic, or social harm).
10.2.5.3The event must be at least possibly related to participation in the 
study.
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 10.3
Reporting of SAEs
All SAEs, regardless of attribution, occurring during the study or within 30 days 
of the last administration of temozolomide and/or pazopanib must be reported to 
the principal investigator upon discovery or occurrence.  Additional expedited or 
routine reporting may be required, depending on the nature of the SAE (as 
outlined below). Please also refer to Table 7 – Summary of Hematologic & Non-
Hematologic Dose Modifications for Pazopanib – for additional information 
regarding toxicities that should be reported as SAEs.
10.3.1 Reporting to the QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE form is 
required (available as stand-alone document).
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include:
10.3.1.1
 Protocol description and number
10.3.1.2
 The patient’s identification number
10.3.1.3
 A description of the event, severity, treatment, and 
outcome (if known)
10.3.1.4
 Supportive laboratory results and diagnostics
10.3.1.5
 The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
10.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site (Northwestern 
University). Additional participating sites should follow their local IRB guidelines for 
reporting to their local IRBs.
10.3.2.1
 Any death of an NU subject that is unanticipated in nature 
and at least possibly related to study participation will be 
promptly reported to the Northwestern University IRB within 24 
hours of notification.  
10.3.2.2
 Any death of an NU subject that is actively on study 
treatment (regardless of whether or not the event is possibly 
related to study treatment)
10.3.2.3 The following SAEs will be reported to the NU IRB within 5 
working days of notification:
10.3.2.2.1 Death of a non-NU subject that is unanticipated in 
nature and at least possibly related to study 
participation
10.3.2.2.2 Other UPIRSOs
10.3.2.4 The following SAEs will be reported to the NU IRB at   the 
  time of annual continuing review:
10.2.3.4.1 All deaths of NU subjects that were not previously 
reported.
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10.2.3.4.2All deaths of non-NU subjects that are deemed to be 
unanticipated in nature and unrelated to participation.
10.2.3.4.3All other SAEs not previously reported to the IRB as 
UPIRSOs
10.3.3 Reporting to Novartis
The principal investigator has the obligation to report all serious adverse 
events to Novartis Pharmaceuticals Drug Safety and Epidemiology 
Department (DS&E). 
All events reported to the FDA by the investigator are to be filed utilizing 
the Form FDA 3500A (MedWatch Form). 
To ensure patient safety, every SAE, regardless of suspected causality, 
occurring:
10.3.3.1After the patient has provided informed consent and until atleast 
30 days after the patient has stopped study treatment/participation.
10.3.3.2After protocol-specified procedures begin (e.g., placebo run-in, 
washout period, double-blind treatment, etc.) and 30 days after the 
patient has stopped study treatment.
10.3.3.3After the start of any period in which the study protocol interferes 
with the standard medical treatment given to a patient (e.g., 
treatment withdrawal during washout period, change in treatment 
to a fixed dose of concomitant. medication) and until 30 days after 
the patient has stopped study treatment.
All events must be reported to Novartis within 24 hours of learning of its 
occurrence. Information about all SAEs is collected and recorded on a 
Serious Adverse Event Report Form (NU SAE form); all applicable sections 
of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the relationship of each SAE 
to each specific study treatment (if there is more than one study treatment), 
complete the SAE Report Form (NU SAE form) in English, and send the 
completed, signed form by fax to (fax: 877-778-9739) within 24 hours 
to the oncology Novartis DS&E department with the provided FAX 
cover sheets (available as stand-alone documents).
This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or 
within 30 days following completion of active protocol therapy must be 
reported within 24 hours.
Any SAEs experienced after this 30 days period should only be reported to 
Novartis if the investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must 
be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.  The 
end date of the first event must be provided.
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The original copy of the SAE Report and the fax confirmation sheet must 
be kept within the Trial Master File at the study site.
Follow-up information is sent to the same fax number as the original SAE 
Report Form was sent, using a new fax cover sheet, stating that this is a 
follow-up to the previously reported SAE, and giving the date of the original 
report. Each re-occurrence, complication, or progression of the original 
event should be reported as a follow-up to that event regardless of when it 
occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was 
broken or not (if applicable), and whether the patient continued or withdrew 
from study participation.
If the SAE is not previously documented in the Pazopanib Investigator 
Brochure or Package Insert (new occurrence) and is thought to be related to 
the Novartis study drug, a DS&E associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis 
may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as 
per national regulatory requirements in participating countries.
To ensure patient safety, each pregnancy occurring while the patient is on 
study treatment must be reported to Novartis within 24 hours of learning of 
its occurrence.
The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects, congenital abnormalities or maternal and 
newborn complications.
Pregnancy should be recorded on a Clinical Study Pregnancy Form and 
reported by the investigator to the oncology Novartis Drug Safety and 
Epidemiology (DS&E) department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the 
SAE Report Form (NU SAE form).
10.3.4  Reporting to NCCN
10.3.4.1All SAEs must also be reported to NCCN via fax at 215-358-7699 
or e-mailed to ORPReports@nccn.org
10.3.4.2The NU CRO SAE form will be used to report SAEs to  NCCN. 
This form will include a full written summary, detailing relevant 
aspects of the adverse events in question. Where applicable, 
information from relevant hospital case records and autopsy 
reports should be included. 
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10.3.4.3In addition, the Investigators will adhere to the safety reporting 
requirements and timelines described in the Clinical Trial 
Agreement with National Comprehensive Cancer Network 
(NCCN).
11.0 
STUDY MANAGEMENT 
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB 
approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol 
and/or informed consent. All amendments will be subject to the review and 
approval of the appropriate local, institutional, and governmental regulatory 
bodies, as well as by Janssen Scientific Affairs. Amendments will be distributed 
by the lead institution (Northwestern) to all affiliate sites upon approval by the 
Northwestern University IRB.
11.3 
Registration Procedures
The items detailed in section 4.2.1 (for phase I patients) and 4.2.2 (for phase II 
patients) must be submitted in order for the patient to be registered and an 
identification number assigned.
11.4 
Data Submission:   
Once a subject is confirmed and registered to the study, eCRFs should be 
submitted according to the detailed data submission guidelines (provided in a 
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separate document).  Generally, all data for phase I patients during the time period 
patients are evaluated for Dose Limiting Toxicities (DLTs) must be submitted on 
a weekly basis.   Generally, for all phase II patients, data are due at the end of 
every cycle.  
To develop your data submission guideline, contact 
croqualityassurance@northwestern.edu.
11.5 Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:

Signed and completed Letter of Invitation to participate in the study.

Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.

Draft informed consent form should for review/approval prior to submission 
to the local IRB

A copy of the official IRB approval letter for the protocol and informed 
consent. 

CVs and medical licensure for the local PI and any sub-investigators who will 
be involved in the study at the site.

Form FDA 1572 appropriately filled out and signed with appropriate 
documentation.
Additional activities may be required prior to site activation (i.e. contract 
execution, study-specific training). Full requirements will be outlined in a memo 
upon receipt of the signed Letter of Invitation.
11.6 Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to Appendices for additional information). The level of risk 
attributed to this study requires high level of monitoring as outlined in the 
DSMP(http://cancer.northwestern.edu/CRO/data/Data 
andSafetyMonitoringPlanMay2014.pdf). The assigned QAM, with oversight from 
the Data Monitoring Committee, will monitor this study in accordance with the 
study phase and risk level. Please refer to the Appendices for additional data 
submission instructions.
11.7
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol. 
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11.7.1 Emergency Modifications
Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior 
IRB approval. 
For any such emergency modification implemented, an IRB modification 
form must be completed within 5 business days of making the change, and 
the QAM must be notified within 24 hours of such change. 
11.7.2 Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned 
QAM using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved 
protocol that: 

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
A protocol deviation may be considered an instance of Reportable New 
Information (RNI) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the 
investigator(s).

Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.
11.8
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The PI is responsible for personally overseeing the 
treatment of all study patients. The PI must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study 
protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical 
trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected, entered onto the appropriate 
eCRFs, and submitted within the study-specific timeframes. Periodically, 
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monitoring visits may be conducted and the Principal Investigator will provide 
access to his/her original records to permit verification of proper entry of data. 
The study may also be subject to routine audits by the Audit Committee, as 
outlined in the DSMP. 
11.9
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with 
the policies and processes set forth in the Lurie Cancer Center DSMP. For trials 
that require high intensity monitoring, the assigned QAM will prepare a 
preliminary data summary (to be approved by the DMC) no later than 3 months 
after the study reaches its primary completion date (the date that the final subject 
is examined or receives an intervention for the purposes of final data collection 
for the primary endpoint). If the investigator’s wish to obtain DMC-approved data 
prior to this point (or prior to the point dictated by study design), the PI must send 
a written request for data to the QAM which includes justification. If the request 
is approved, data will be provided no later than 4 weeks after this request 
approval. The data will be presented to the DMC at their next available meeting, 
and a final, DMC-approved dataset will be released along with any DMC 
decisions regarding publication. The investigators are expected to use only DMC-
approved data in future publications. The investigators should submit a copy of 
the manuscript to the biostatistician to confirm that the DMC-approved data are 
used appropriately.  Once the biostatistician gives final approval, the manuscript 
may be submitted to external publishers.
 
12.0 
PATHOLOGY REQUIREMENTS – CORRELATIVE STUDIES
12.1
Pharmacokinetics (PKs)
12.1.1 Timing
After determination of the MTD, the last cohort of the phase I portion will 
be expanded to include an additional 6 patients who will undergo PK 
testing to evaluate the effect of pazopanib on the pharmacokinetics of 
temozolomide.  The MTD has now been identified at dose level -2 (75 
mg/m2 per day p.o. days 1-7 and 15-21 of Temozolomide and 400 mg per 
day p.o. days 1-28 of Pazopanib). As of 12.15.15,all patients moving 
forward will be treated at this dose. As stated above, the PKs are 
mandatory for this cohort. 
The schedule and dosing for these 6 patients will be as follows: 
12.1.1.1Day 1, Cycle 1
 Patients will not take either study drug prior to arriving to the 
clinic.  Patients will have a time = 0 sample drawn, and then be 
instructed to take their dose of temozolomide.  Patients will then 
have PK samples drawn at 10 min (+/-5 min), 30 min (+/-5 min), 
1 hour (+/-5 min), 2 hours (+/-5 min),, 3 hours (+/-5 min),4 
hours(+/-30 min), 6 hours (+/-30 min), 8 hours(+/-30 min),, and 
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24 hours(+/-1 hour) post-dose (drawn on Day 2. This will be the 
same sample as the pre-dose PK sample of Day 2 provided Day 2 
drug administration is done within 1 hour of sample collection. 
One 3 ml sample is needed).
Pazopanib will be held on this day.  
12.1.1.2Cycle 1, Day 2:  
  Patients will continue to take temozolomide as instructed but will 
not take pazopanib until instructed to do so in clinic.  Patients will 
have a time = 0 sample drawn and then be instructed to take their 
dose of pazopanib. This will be the same sample as the 24-hour 
post-dose PK sample of Day 1, provided Day 2 drug 
administration is done within 1 hour of sample collection. If this 
drug administration is delayed beyond one hour, then another 3 ml 
PK sample has to be collected for the pre-dose PK of Day 2).  
Patients will then have PK samples drawn at 10 min(+/- 5 min), 30 
min(+/- 5 min), 1 hour(+/- 5 min), 2 hours(+/- 5 min), 3 hours(+/- 
5 min), 4 hours(+/- 30 min), 6 hours(+/- 30 min), 8 hours(+/- 30 
min), and 24 hours(+/-1 hour) (done on Day 3) post-dose.
12.1.1.3Cycle 1, Day 3: 
 Patients will not take either study drug prior to arriving to the 
clinic.  Patients will have 1 PK sample drawn (the 24 hours[+/- 1 
hour] post-pazopanib dose sample from Day 2) and then continue 
to take both temozolomide and pazopanib as instructed per 
protocol. 
12.1.2 Sample collection
PK samples will be drawn in the outpatient setting.  Collect each blood 
sample (3 mL) in an evacuated blood tube containing lithium heparin.  
Invert the tube gently 4 or 5 times (avoid shaking).  Care must be taken to 
ensure that blood does not come in further contact with the stopper on the 
evacuated tube.  Blood samples should be kept in an ice water bath from 
the time of collection to the time of centrifugation, which should occur 
within 30 minutes of sample collection.  Samples at Northwestern 
University should be picked up by the Pathology Core Facility Clinical 
Trials Technician for processing and storage until they are ready to be 
analyzed.  Samples should be labeled with the patient’s study ID number 
and initials, as well as the date and collection time point (i.e. 30 min post-
dose).
12.1.3 Processing
Centrifuge samples in a laboratory centrifuge designed for separating 
plasma from cells at  approximately 3,000 rpm for 10 min at 4°C.  
Transfer the plasma to 2 polypropylene tubes ( a primary and a back-up 
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tube, approximately 0.75 mL per tube).  After aliquoting, 30 uL 8.5% 
phosphoric acid should be added to each mL of plasma being stored in the 
polypropylene tubes before freezing the samples (22.5 microL/0.75 mL).
Computer-printed labels will be generated at each study site for the 
polypropylene (storage) tubes detailing study ID number, patient study ID, 
date of collection, time of collection, and protocol therapy time point.  If it 
should be necessary to handwrite the information, only indelible ink 
should be used.  Apply the labels along the length of the tube.  Secure the 
labels by wrapping with clear tape.  
Apply the preprinted labels to the polypropylene tubes at room 
temperature at least 2 hours before refrigerating or freezing.  Adequate 
adhesion cannot be guaranteed if the labels are applied to cold tubes.  
Blood samples must be kept frozen at approximately -80°C after 
collection and until delivery/shipment is initiated.  
Sample collection details (i.e., patient study ID, date of collection, time of 
collection, and protocol therapy time point) should be indicated on a log 
sheet along with the times of last study drug dose(s).  A copy of the sheet 
should be submitted with the samples.   
12.1.4 Shipment
Plasma samples for the PK portion of the study will be shipped directly 
from study sites to Northwestern University for bioanalysis.  Samples 
should be stored as referenced above until shipment.  All samples for all 
patients on study may be batched and shipped upon completion of the 
enrollment phase to the PK cohort.  
One specimen from each pair of a sample should be included in the initial 
shipment.  Samples will be shipped overnight along with a copy of the log 
sheet via FEDEX on dry ice to Northwestern University at the address 
provided below.  The remaining set of samples will be saved at each study 
site until receipt of the first set of samples has been confirmed, then 
shipped to Northwestern University separately (in case of lost shipment or 
other complication).  
Shipment should only be initiated on Mondays, Tuesdays, or Wednesdays 
to ensure arrival of samples within working hours Tuesdays through 
Thursday (excluding holiday dates).  Dr. Michael Avram should be 
contacted prior to shipment to confirm shipment date and to notify of 
expected time and date of delivery.
The address and contact for shipments is as follows:
Michael J. Avram, Ph.D.
Northwestern University Feinberg School of Medicine
Department of Anesthesiology
Tarry Building Room 4-735
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303 E. Chicago Avenue 
Chicago IL 60611
Phone: 312-908-0636
mja190@northwestern.edu 
Please refer to laboratory manual for further details (available as stand-
alone document)
12.2
MGMT Analysis
12.2.1 Tissue requirements
From each patient, 5 unstained slides will be obtained.  Paraffin-embedded 
sections of 4 μm from the most recent biopsy will be used for 
immunohistochemistry.  
12.2.2 Processing
For antigen retrieval, sections will be subjected to pretreatment with 45-
min pressure boiling in citrate buffer (pH 6.0).  Immunohistochemistry 
will be done using an autostainer (Dako Cytomation).  Sections will be 
incubated with a mouse monoclonal MGMT antibody, diluted in antibody 
diluent (Dako Cytomation), at room temperature for 60 min.  The reaction 
product will be revealed using Dako kit 50087 (Dako Cytomation). 
Sections will be counterstained with Mayer’s hematoxylin.  Initial 
experiments will be done with omission of the primary antibody.  Nuclear 
MGMT will be scored as either present or absent in tumor cells and 
correlated with treatment outcome (PFS).
All staining and analysis will take place in the Pathology Core 
Facility at Northwestern University.
12.2.3 Shipment
Pathology samples from biopsy will be shipped to:
Northwestern University
Pathology Core Facility
710 N. Fairbanks Ct, Olson 8421
Chicago, IL 60611
312-908-5546
  
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APPENDIX I - ECOG Performance Status
Grade
ECOG
0
Fully active; no performance restrictions
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
As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
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APPENDIX II – P450 Drug Interactions: Substrates, Inhibitors, and Inducers
Please note that these lists are not exhaustive. If investigators are unsure of potential for drug-drug interaction, the Investigational 
Pharmacist should be consulted, along with the current version of the Investigator’s Brochure. For the most up to date table of 
cytochrome P450-related drug interactions, please refer to the Indiana University drug interaction table at the following website: 
http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx. Below is an abbreviated table of clinically relevant substrates, inhibitors, 
and inducers. Inhibitors are classified as Strong, Moderate, Weak, or Other. A strong inhibitor is one that causes a > 5-fold increase in 
the plasma AUC values or more than 80% decrease in clearance. A moderate inhibitor is one that causes a > 2-fold increase in the 
plasma AUC values or 50-80% decrease in clearance. A weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the 
plasma AUC values or 20-50% decrease in clearance.
SUBSTRATES
1A2
2B6
2C8
2C9
2C19
2D6
2E1
3A4,5,7
clozapine
bupropion
paclitaxel
cyclobenzaprine
Cyclophospha-
mide
torsemide
duloxetine
efavirenz
amodiaguine
fluvoxamine
ifosfamide
cerivastatin
haloperidol
methadone
repaglinide
NSAIDs:

diclofenac

ibuprofen

piroxicam
PPIs:

lansoprazole

omeprazole

pantoprazole

rabeprazole
Beta blockers:

S-metoprolol

propafenone

timolol
Anesthetics:

enflurane

halothane

isoflurane

methoxyflurane

sevoflurane
Macrolide 
antibiotics:

clarithromycin

erythromycin 
(not 3A5)

NOT 
azithromycin

telithromycin
imipramine
mexiletine
nabumetone
naproxen
olanzapine
riluzole
tacrine
Oral 
hypoglycemic:

tolbutamide

glipizide
Anti-epileptics:

diazepam

phenytoin

phenobarbitone
Antidepressants:

amitriptyline

clomipramine

desipramine

imipramine

paroxetine
Others:

acetaminophen

aniline

benzene

chloroxazone

ethanol

N,N-dimethyl

formamide

theophylline 8-
OH
Anti-arrhythmics:

quinidine 3-OH 
(not 3A5)
theophylline
tizanidine
triamterene
Angiotensin II 
blockers:

losartan

irbesartan
Others:

amitriptyline

clomipramine

clopidogrel
Antipsychotics:

haloperidol

risperidone

thioridazine
Benzodiazepines:

alprazolam

diazepam 3OH

midazolam

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zileuton

cyclophosphamid
e

progesterone

triazolam
zolmitriptan
Others:

celecoxib

fluvastatin

naproxen

phenytoin

rosiglitazone

sulfamethox
azole

tamoxifen

tolbutamide

torsemide

warfarin
Others:

aripiprazole

codeine

dextromethor
phan

duloxetine

flecainide

mexiletine

ondansetron

tamoxifen

tramadol

venlafaxine
Immune 
modulators:

cyclosporine

tacrolimus 
(FK506)
HIV antivirals:

indinavir

ritonavir

saquinavir
Prokinetics:

cisapride
Antihistamines:
astemizole
chlorpheniramine
Calcium channel 
blockers:

amlodipine

diltiazem

felodipine

nifedipine

nisoldipine

nitrendipine

verapamil
HMG CoA 
reducutase 

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inhibitors:

atorvastatin

lovastatin

NOT 
pravastatin

NOT 
rosuvastatin

simvastatin
Others:

aripiprazole

boceprevir

buspirone

gleevec

haloperidol

methadone

pimozide

quinine

sildenafil

tamoxifen

telaprevir

trazodone

vincristine
INHIBITORS
1A2
2B6
2C8
2C9
2C19
2D6
2E1
3A4,5,7
thiotepa
fluoxetine
ticlopidine
fluvoxamine
ketoconazole
lansoprazole
omeprazole
ticlopidine
Weak 
inhibitors:

cimetidine
Strong 
inhibitors:

gemfibrozil
Strong 
inhibitors:

fluconazole
Strong inhibitors:

bupropion

fluoxetine

paroxetine

quinidine
disulfiram
Strong inhibitors:

indinavir

nelfinavir

ritonavir

clarithromycin

itraconazole

ketoconazole

nefazodone
Other inhibitors:

fluoroquinol
ones
Other 
inhibitors:
montelukast
Moderate 
inhibitors:

amiodarone
Moderate 
inhibitors:

duloxetine
Moderate 
inhibitors:

erythromycin

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
fluvoxamine

ticlopidine

grapefruit juice

verapamil

diltiazem
Other inhibitors:

isoniazid
Weak inhibitors:

amiodarone

cimetidine
Weak inhibitors:

cimetidine
Other inhibitors:

chlorphenira
mine

clomipramine

doxepin

haloperidol

methadone

mibefradil

ritonavir
Other inhibitors:

amiodarone

NOT 
azithromycin

fluvoxamine

mibefradil

troleandomycin
INDUCERS
1A2
2B6
2C8
2C9
2C19
2D6
2E1
3A4,5,7
tobacco
phenobarbital
rifampin
ethanol
carbamazepine
phenytoin
secobarbital
isoniazid
phenobarbital
rifampin
phenytoin
pioglitazone
rifabutin
rifampin
St. John’s wort
troglitazone
http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx 

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APPENDIX III – NY Heart Association Classifications
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnea.
Class III (Moderate)
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased.
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Appendix IV – NCI CTCAE Version 4.03
All toxicities in this protocol will be graded according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE) version 4.0, which can be found at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
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Appendix V – History of Changes
Original Protocol as Approved by Scientific Review Committee – June 7, 2011
Update 1 (1st version submitted to IRB) – June 28, 2011
Scientific Review Committee  Approval: June 29, 2011
Section (s) Affected
Prior Version
Update 1 Changes
Rationale
Synopsis, Schema, 
1.5.5 (Rationale for 
current study 
treatment doses), 5.1 
(Treatment 
Overview), 5.2.2 
(Pazopanib 
administration), 5.3.1 
& Table 1, (Phase I 
dose escalation 
schema), 8.2 (Drug 
Information: 
pazopanib)
Starting dose for pazopanib 
was to be 600 mg. 
Revises starting dose for 
pazopanib to be 400 mg and 
adjusts dose escalations and 
de-escalations accordingly; 
indicates that if cohort Level 
2 (pazopanib = 800 mg) is 
too toxic, an additional 
cohort (pazopanib 600 mg) 
may be added upon DMC 
review and approval.
Upon review, the study 
collaborators (NCCN and 
GSK) recommended that 
the starting dose for 
pazopanib be 400 mg.
Amendment 1 – January 10, 2012
Scientific Review Committee Approval:  February 24, 2012
Section (s) Affected
Prior Version
Update 1 Changes
Rationale
Cover-page
1.
Dr. Mark Zalupski listed 
as the local PI for 
University of Michigan; 
Dr. Sheetal Kircher listed 
as a sub-investigator at 
Northwestern University.
2.
No mention of IND status.
1.
Replaces Dr. Zalupski 
with Dr. Kircher as the 
local PI for University of 
Michigan and removes 
Dr. Kircher from the list 
of sub-investigators at 
Northwestern.
2.
Indicates that study is 
IND exempt.
Administrative
3.2.12 (Inclusion 
criteria)
Inclusion criterion indicated 
that “eligibility of patients 
receiving any medications or 
substances known or with 
potential to affect the activity 
or pharmacokinetics of 
temozolomide and/or 
pazopanib” would be 
determined by the PI and the 
Data Monitoring Committee.
Removes “and the Data 
Monitoring Committee” from 
the statement.
Although it is understood 
that any questions 
regarding eligibility may 
ultimately be brought to 
the DMC for review and 
confirmation, it is not 
necessary to state this 
specifically for this 
criterion only.  Thus, it 
was removed for clarity.
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4.0 (Patient 
Registration)
n/a
Adds a new section 4.4 to 
describe the procedures for 
notifying the study supporter 
(NCCN) when a new subject 
is registered to the study.
Administrative – per 
request from NCCN.
8.2.9 (Availability of 
pazopanib)
Ordering instructions not 
included in drug procurement 
section.
Adds contact information and 
details to be included when 
ordering drug supply.
Administrative
10.3 (Reporting of 
SAEs)
Gave timeframes and 
indicated that SAEs would be 
reported to the FDA as 
required for IND studies.
Removes reporting to FDA 
since it was determined that 
the study is IND exempt.
Administrative/clarity.
Amendment 2 – October 10, 2012
Scientific Review Committee Approval – October 17, 2012
Updated Amendment SRC approved on February 6, 2013
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
Cover-page
n/a
Adds Dr. E. Gabriela 
Chiorean (University of 
Washington) as a sub-
investigator/participating 
site. Adds Dr. Hidayatullah 
Munshi as a sub-investigator. 
Removes Lisa Marshall, RN 
as a sub-investigator. 
Administrative
Section 1.4.1
Pazopanib has been approved 
by the FDA for treatment of 
metastatic renal cell carcinoma 
(RCC).
Adds the following: In 2009, 
pazopanib was approved by 
the U.S. Food and Drug 
Administration (FDA) for the 
treatment of patients with 
advanced RCC [Votrient PI, 
2012]. In 2012, pazopanib 
was FDA-approved for the 
treatment of patients with 
advanced soft tissue sarcoma 
who have received prior 
chemotherapy.  However, the 
efficacy of pazopanib for the 
treatment of patients with 
adipocytic soft tissue 
sarcoma or gastrointestinal 
stromal tumors has not been 
demonstrated [Votrient PI, 
2012].
The additional language 
provides more data on the 
FDA approval of 
pazopanib. 
Synopsis and 3.2 
(inclusion criteria)
Patients may have 0-2 prior 
therapies. 
Patients may have 0-3 prior 
therapies.
Broadens the patient 
population. 
Section 5.5.5 
(Antihyperlipidemic 
Agents), 5.6 
(Concomitant 
n/a
Adds information about 
pazoparib standards for 
concomitant medications and 
that using it with simvastatin 
Added to fully disclose all 
information about 
concomitant medications.
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Medications) & 8.2.8 
(Incompatibilities)
increases the risk of ALT 
elevations. 
5.7.2 (Treatment 
rules for toxicity for 
phase II)
Stated that “regardless of the 
reason for delay” the 
maximum permitted interval 
for delay was 28 days.
Revises the allowed delay 
timeframe to specify 28 days 
for treatment related delays 
and up to 8 weeks for non-
treatment-related delays.
This clarification is 
necessary to allow patients 
who are responding to 
treatment to continue to 
receive treatment 
following necessary 
delays longer than 28 days 
for non-study-related 
issues.  
Table 7 - Summary 
of Hematologic & 
Non-Hematologic 
Dose Modifications 
for Pazopanib
Hepatic Dysfunction table 
Replaces the table for hepatic 
dysfunction provided by the 
NCCN.
Changes requested by the 
NCCN & provided more 
specific dose 
modifications related to 
liver enzyme changes with 
or without 
hyperbiliruinemia
Appendix II - - 
Substrates, 
Inhibitors, and 
Inducers of CYP3A4
CYP3A4,5,7 Substrates table
Replaces previous table with 
a table that includes the 
following: 
CYP3A4,5,7 Substrates 
CYP3A4,5,7 Inducers 
CYP3A4,5,7 Inhibitors
Also adds table for substrates 
of CYP2B6, CYP2C8, and 
CYP2C9
The original version 
included only a portion of 
the information.  The 
additions should have 
been included, but were 
inadvertently omitted. 
Also provides 
updated/corrected website 
reference.
Amendment 3 – May 15, 2013
Scientific Review Committee Approval – May 29, 2013
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Cover-page
Listed Dr. Sheetal Kircher as 
the local PI for University of 
Michigan.
Replaces Dr. Kircher with 
Dr. Mark Zapulski at U of M. 
Adds Dr. Kircher to the list 
of sub-investigators at 
Northwestern.
Administrative – Dr. 
Kircher has left U of M 
and is now back at 
Northwestern.
Cover-page
Listed Dr. Hidayatullah 
Munshi as a sub-investigator 
at Northwestern.
Removes. Dr. Munshi.
Dr. Munshi is no longer an 
active member of the GI 
research team at 
Northwestern.
Section 3.2 
(Inclusion Criteria)
Allowed patients with 0-3 
prior therapies.
Expands inclusion criteria to 
allow patients with 0-4 prior 
therapies.
Changed in order to 
increase accrual to the 
study.
Section 3.3 
(Exclusion Criteria)
Excluded patients taking 
immunosuppressive 
medications (including 
systemic corticosteroids unless 
Removes this exclusion 
criterion entirely.
It will be up to the 
discretion of the treating 
investigator to determine 
whether or not any 
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used for adrenal replacement), 
appetite stimulants, acute 
therapy for asthma or acute 
bronchitis exacerbation, or 
antiemetics.
concomitant medications 
are a concern for 
interactions with study 
therapy.
Section 5.7.4 (Dose 
modifications for 
toxicity) – Table 7: 
Table 7:  Summary 
of Hematologic & 
Non-Hematologic 
Dose Modifications 
for Pazopanib
In the event of a 1st occurrence 
of liver event interruption, 
protocol stated to contact GSK 
Medical Monitor regarding 
possible re-challenge. Gives 
criteria to be met for re-
treatment.
Revises this to state: 
If the potential benefit for 
reinitiating pazopanib 
treatment is considered to 
outweigh the risk for 
hepatotoxicity, then 
reintroduce pazopanib at a 
reduced dose and measure 
serum liver tests weekly for 8 
weeks. 
Criteria to be met for re-
treatment remain the same. 
Adds a footnote directing 
investigators to the IB for 
further information.
Changed per request from 
GSK and NCCN.
Sections 7.0 (Study 
Parameters) & 7.2.2 
(Study Visits)
Perfusion CT required for all 
subjects.
Perfusion CT required only 
as feasible. 
Some participating sites 
do not have perfusion CT 
capability. Since this is a 
secondary endpoint, this is 
not required to meet the 
study objectives.
Sections 7.0 (Study 
Parameters) & 7.2.2 
(Study Visits)
Required labs, physical exam, 
and toxicity assessment on 
days 1 and 15 of all cycles 
after cycle 1 (indefinitely).
Revises schedule to require 
these on both days only for 
cycles 2 and 3. Starting with 
cycle 4 and beyond, physical 
exam and toxicity assessment 
may be done only on day 1 of 
each cycle. Labs will still be 
required on days 1 and 15, 
but day 15 labs may be 
drawn at a local facility, per 
treating investigator’s 
discretion. 
This was changed to 
accommodate feasibility 
for patients who are on 
treatment and tolerating it 
well for several cycles.
Section 8.2.8 
(Pazopanib 
incompatibilities)
n/a
Adds language referring 
investigators to thecurrent IB 
for detailed information 
about interactions with 
simvastatin, CYP3A4 
inhibitors, impact on drugs 
eliminated through UGT1A1 
and OATP1B1, and the use 
of pazopanib with drugs 
known to increase the gastric 
Administrative
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pH. Also refers them to an 
updated Appendix.
Section 10.3 
(Reporting of SAEs)
n/a
Adds language referring 
investigators to Table 7 in the 
protocol (Summary of 
Hematologic & Non-
Hematologic Dose 
Modifications for Pazopanib) 
for additional information 
regarding toxicities that 
should be reported as SAEs.
Administrative
Section 11.0 
(Records to Be Kept)
Stated that “Treatment and 
Summary eCRFs” were to be 
completed at the end of study 
therapy.
Clarifies that “Treatment 
eCRF” should be completed 
at the end of each cycle of 
study therapy.
Administrative
Appendix II
Outdated and incomplete list 
of P450 drug interactions.
Updates the entire listing to 
include an expanded table of 
inducers, inhibitors, and 
substrates. Updates the 
website link for 
additional/current 
information.
Administrative
Amendment 4 – October 16, 2013
Scientific Review Committee Approval – October 22, 2013
Section (s) Affected
Prior Version
Amendment 4 Changes
Rationale
Throughout
n/a
Updates numbering of 
appendices and website links 
for the NU CRO & the NCI’s 
CTCAE v. 4.0.
Administrative
Section 3.2 
(Inclusion Criteria)
Baseline parameters require 
AST/ALT ≤ 5 x ULN.
Changed to AST/ALT ≤ 2.5 
x ULN.
Changed to match grantor 
requirements and to 
Section 4.0 (Patient 
Registration)
Contained old standard 
language for registering 
patients via NOTIS.
Updates language to outline 
new procedures and 
requirements for reserving 
slots on a cohort, registering 
patients in NOTIS, and 
confirming eligibility for 
phase I vs. phase II patients. 
Also clarifies the procedure 
for notifying NCCN of new 
enrollments.
Administrative – NU is 
implementing new study-
specific procedures and 
plans.
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Section 5.2 (Study 
Drug Administration) 
& Section 7.1 Table 
10:  Schedule of 
Events
n/a
Adds reference to the drug 
diary that patients will be 
asked to complete and that 
study teams will be required 
to collect each cycle.
A drug diary was already 
in use but procedures were 
not explicitly stated in the 
protocol.
Section 5.3.1 Table 
1:  Phase I Dose 
Escalation Schema
Cohort -1 included 
temozolomide at a dose of 150 
mg/m2 q day PO and 
pazopanib at a dose of 200 mg 
q day PO.
Revises dosing for ohort -1 
and -2, and adds a cohort -3, 
as follows:
Level -1: 
Temozolomide 100 mg/m2 + 
pazopanib 400 mg
Level -2: 
Temozolomide 75 mg/m2 + 
pazopanib 400 mg
Level -3: 
Temozolomide 75 mg/m2 + 
pazopanib 200 mg
Changes made based on 
review of data from recent 
patients in conjunction 
with the Data Monitoring 
Committee.
5.4.3 (DLT 
Exclusions)
n/a
Adds the following as an 
exclusion to the definition of 
DLT:
Any grade of 
hypophosphatemia or other 
metabolic 
abnormality…unless 
continued despite maximum 
supportive care.
Added to clarify the DLT 
definition.
Section 5.5 
(Supportive Care 
Guidelines)
n/a
Adds prophylactic treatment 
with Valtrex 500 mg q day.
This was added given the 
higher incidence of herpes 
zoster that has been 
observed in recent patients 
(likely due to 
lymphopenia).
Section 5.6 
(Concomitant 
Medications)
n/a
Adds a specific list of 
prohibited concomitant 
medications (previously only 
referenced in the 
Appendices).
Added to comply with 
grantor requirements.
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Section 5.7 (Toxicity 
Management and 
Dose Modifications – 
Table 7)
Did not list specific dose 
modifications for proteinuria, 
hemorrhage, or prolongation 
of the QTc interval.
Added specific dose 
modifications for proteinuria, 
hemorrhage, and 
prolongation of the QTc 
interval. Also modified 
instructions for hypertension.
Added/revised to comply 
with grantor requirements 
and recommendations.
Section 10.3 
(Reporting  of 
SAEs), Appendices
Reporting requirements varied 
based on type of SAE (death 
of a subject vs. UPIRSO vs. 
other) and timeframes for 
reporting to the NU IRB were 
based on previous policy.
Updates and simplifies SAE 
reporting language. Requires 
ALL SAEs to be reported to 
the QAM within 24 hours of 
notification. Updates NU 
IRB reporting timeframes. 
Adds that the new NU CRO 
SAE form will be used to 
report all SAEs.
Administrative and to 
improve clarity.
Section 11.0 
(Records to be Kept)
Contained old standard 
language.
Updates and simplifies 
language.
Administrative
Section 12.1 
(Pharmacokineticsc)
n/a
Update some processing 
instructions and details (tube 
type, centrifugation 
requirements, and shipping 
address) for PK samples.
Administrative updates
Appendices
n/a 
Adds newly implemented, 
study and phase-specific 
monitoring procedures and 
data submission 
requirements. 
Administrative – NU is 
implementing new study-
specific procedures and 
plans for each phase of the 
study to help improve 
compliance and patient 
safety.
Amendment 5 – April 15, 2015
Scientific Review Committee Approval – April 15, 2015
Section (s) Affected
Prior Version
Amendment 5 Changes
Rationale
Study Synopsis & 3.1
n/a
University of Washington
Additional site added
3.1 (Population and 
Accrual overview)
“Accrual to both phases of the 
study and assessment of the 
primary endpoint for the phase 
II portion is estimated to be 
completed within 
approximately 2.5 years.”
Revised to “Accrual to both 
phases of the study and 
assessment of the primary 
endpoint for the phase II 
portion is estimated to be 
completed within 
approximately 3-4 years.”
Revised to account for 
Phase I enrolling 9-18 
patients
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3.2.1 (Inclusion 
Criteria)
“Patients must have 
histologically confirmed islet 
cell carcinoma (PNET) not 
amenable to surgical 
resection.”
Revise to “Patients must 
have histologically 
confirmed well –
differentiated islet cell 
carcinoma (PNET) not 
amenable to surgical 
resection.”
Revised to clarify patient 
eligibility
3.2.3.2 (Inclusion 
Criteria)
n/a
Revised to add “Prior 
temozolomide is permitted.”
Revised to clarify patient 
eligibility
5.3.1(Dose escalation 
schema)
Phase I  Level-3 cohort at 
Temozolomide  75 mg/m2 per 
day p.o.
Days 1-7 & 15-21 and 
Pazopanib 200 mg per day p.o. 
Days 1-28
Revised to add dose level -4: 
Temozolomide 50 mg/m2 per 
day p.o. Days 1-7 & 15-21 
and Pazopanib 400 mg per 
day p.o. Days 1-28
Revision of dose levels 
after DMC review of data
5.3.1(Dose escalation 
schema) 
n/a
Dose level -3 revised to: 
Temozolomide 50 mg/m2 per 
day p.o. Days 1-7 & 15-21 
and Pazopanib 200 mg per 
day p.o. Days 1-28
Addition of reduced dose 
level after DMC review of 
data
5.3.1(Dose escalation 
schema)
n/a
Footnote 1 revised to add “ If 
DLTs occur at dose Level -3, 
then a cohort Level -4 may 
be opened as above.”
Revised to accommodate 
dose level -4
5.4.2 (DLT 
definitions)
n/a
Revised to “Inability to 
complete Cycle 1 due to 
toxicity related to study 
drug.”
Clarification
5.4.3.3 (DLT 
Exclusions)
Any grade of 
hypophosphatemia, or other 
metabolic abnormality will 
NOT be considered a DLT, 
unless continued despite 
maximum supportive care.”
Revised to “Any grade non-
hematologic toxicity will 
NOT be considered a DLT 
unless continued despite 
maximum supportive care 
beyond the 2 week delay 
allowed in section 5.4.2.5.  
(see 5.5.8).”
Clarification
5.4.3.4 (DLT 
Exclusions)
n/a
Added “Grade 3 or higher 
non-hematologic toxicity will 
be considered a DLT 
EXCEPT in cases where the 
event existed at baseline.  In 
Clarification
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these cases, toxicity needs to 
increase in severity by 2 
grades per CTCAE v. 4.0 
before it is considered a 
DLT.  ”
4.4.4.2.2 (DLT 
Terminology 
Clarifications)
“Electrolyte supplementation 
for hypophosphatemia”
Revised to “Electrolyte 
supplementation for low 
electrolytes”
Correction
5.5.11 (Anti-viral 
Agents)
“Patients should be treated 
with prophylactic Valtrex 
(valacyclovir hydrochloride) 
500 mg daily”.
Revised to “It is 
recommended that patients 
be treated with prophylactic 
Valtrex (valacyclovir 
hydrochloride) 500 mg daily, 
however final decisions 
regarding this will be up to 
treating physician 
discretion.”
Clarification
5.7.2 (Treatment 
rules for toxicity for 
phase II)
Treatment rules for toxicity for 
phase II
Section name revised to 
“Treatment rules for toxicity 
for phase I AFTER the DLT 
period”
Clarification
5.7.3 (Patient dose 
level adjustments for 
toxicity)
“Discontinue”
Revised to “↓ 50 mg/m2 per 
day p.o”
Addition of reduced dose 
level adjustment for 
toxicity after DMC review 
of data
5.7.3 (Patient dose 
level adjustments for 
toxicity)
n/a
Added additional reduced 
dose level adjustment for 
toxicity for Temozolomide.  
“Level (-3) ↓50mg/m2 per 
day p.o., Dose Modification, 
Discontinue”
Addition of reduced dose 
level adjustment for 
toxicity after DMC review 
of data
5.7.4.2 (Table 7:  
Summary of 
Hematologic & Non-
Hematologic Dose 
Modifications for 
Pazopanib)
n/a
Revised to include “Diarrhea 
(despite optimal supportive 
care)”
Clarification
5.8 (Duration of 
Therapy)
n/a
Added “It is recommended 
that temozolomide treatment 
be discontinued after 1 year, 
due to risk of 
Myelodysplastic syndrome 
(MDS).  Patients can 
continue on Pazopanib.  If 
patient is receiving benefit 
from combination treatment 
after one year, it is up to the 
treating physician’s 
discretion whether or not the 
patient continues 
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Temozolomide..”
5.8.2 (Unacceptable 
toxicity)
“Thrombotic events, including 
cerebrovascular accident, 
myocardial 
infarction or thrombotic event 
requiring anticoagulation.   
Patients with superficial 
thrombophlebitis, superficial 
venous thrombosis, or portal 
venous thrombosis not 
requiring anticoagulation may 
remain on therapy at the 
discretion of the treating 
physician. “ 
Deleted
Anticoagulation allowed 
on study
5.9 (Follow-up)
After treatment 
discontinuation, patients will 
be followed every 3 months in 
clinic and/or via phone for 
survival follow-up
After treatment 
discontinuation, patients will 
be followed every 6 months 
for 1 year in clinic and/or 
via phone for survival 
follow-up.  
Clarification
9.4 (Replacement 
Policy)
“Patients will not be replaced 
if taken off study due to 
toxicity.”
Revised to “Patients will not 
be replaced if taken off study 
due to toxicity, however, if a 
patient is taken off study 
during their DLT period 
for a reason unrelated to 
study treatment, another 
patient may be added to 
that cohort.”
Amendment 6 – August 4, 2016
Section (s) 
Affected
Prior Version
Amendment 6 Changes
Rationale
Cover page
Section 3.1
Site PI for Fox Chase 
Center was 
Steven J.Cohen,MD
New Site PI for Fox 
Chase Center is 
Crystal Denlinger,MD
.Change in site PI
Throughout:
Synopsis;
Schema;
Section 1.5.4;
5.3.2; 8.2.5; 
12.1,8.1.5
N/A
Language inserted: 
Note: The MTD has been 
identified at dose level -2 
(75 mg/m2 per day p.o. 
days 1-7 and 15-21 of 
Temozolomide and 400 
mg per day p.o. days 1-
28 of Pazopanib. 
 As of 12.15.15 , all 
patients moving forward 
will be treated at this 
MTD has been established 
for this combination.
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dose
Section 1.4.2
Safety of 
pazopanib
Section 8.2.10
Side effects of 
pazopanib
Previous safety information
Language added:
 Note: please refer to 
updated IB version 14 
dated 01.07.16 for more 
information.
Per updated IB 
Section 1.5.6
Phase I 
summary
N/A
New Section added:
Phase I summary: 
language stating phase I 
treatment and 
establishment of MTD, 
which will serve as the 
dose for patients, moving 
forward.
Per study design and 
establishment of MTD
Throughout
Functional CT to be done
for all patients, in sites 
where it is feasible
The functional CT has 
been removed completely 
from the study. All 
descriptions and 
language pertaining to 
fCT has been removed in 
appropriate sections. 
Exploratory objective 
“Examine the 
relationship between 
tumor blood flow, as 
measured by perfusion 
functional computed 
tomography (fCT), and 
overall response “ has 
been removed
The fCT wasn’t required for 
Phase I. Some (3/4) affiliate 
sites stated they could not 
afford this component. 
Therefore, it would not be in 
best interest to only have 
this done at 1 participating 
site. Monetary resources 
saved  was used towards PK 
analysis
Section 3.1
Northwestern Memorial 
Hospital
Northwestern Medical 
group
Per new NU policy
Section 3.3.3
Patients with uncontrolled 
hyperlipidemia (total 
cholesterol >350 or 
This exclusion criteria 
removed
The study is not performing 
lipid profile tests at baseline.
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triglycerides>300) are NOT 
eligible for participation
Section4.0
Previous patient registration 
details
Updated with current 
language from NU 
template
Per current NU template
Section 5.7.3
Section heading: Patient 
dose level adjustments for 
toxicity
Section heading: Patient 
dose level adjustments 
for toxicity in Phase II
For clarity
Section 7.0 
Study 
procedures 
table
Only a +/-1 day window for 
assessments 
Appropriate windows 
have been inserted for 
treatment, assessments 
and imaging.
Footnote 7, 8 and 21 
modified to reflect this.
Treatment windows inserted 
for logistical convenience 
and to minimize protocol 
deviations
Section 6.1.2.2;
7.0,12.1,
PK sample collection time 
points listed without 
windows, for PK cohort. 
Two samples of 3 ml each 
were being drawn around 
the same time for Day 1 24 
hour post-dose and Day 2 ) 
sample pre-dose. 
Windows inserted for PK 
sample collection time 
points e.g 10mins(+/-5 
min)
Language inserted to 
state that these two 
samples may be clubbed 
into one 3ml sample 
provided that the study 
drug administration of 
Day 2 is done within an 
hour of drawing the 
sample. If it is delayed 
more than an hour then 
another 3 ml sample will 
have to be drawn.
Reference has been made 
to this wherever 
appropriate.
 Laboratory manual 
updated as well.
For logistical convenience 
and in order to minimize 
protocol deviations.
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Section 7.0
Study 
Procedures 
table
Has separate correlative 
studies section(PK cohort 
only)
Deleted “(PK cohort 
only)” Modified to cover 
both PK and Phase II 
Footnotes 14, 15 and 17 
updated.
For clarity
Section 7.1 
Schedule of 
Events Footnote 
7; section 6.2.1;
Imaging with CT or MRI 
(whichever test is used for a 
particular patient at baseline 
should be the same that is 
used throughout for disease 
assessment).  Response will 
be assessed 
every 2 cycles (8 weeks +/- 
7 days).
Added: After 1 year of 
protocol therapy, patients 
may switch to imaging 
every 12 weeks (+/-7 
days) per treating 
physician discretion.
This is for patients being 
treated beyond 1 year, so 
that Temozolomide safety 
can be monitored and at the 
same time radiation 
exposure will be decreased. 
Hence, it will be done per 
treating physician’s 
discretion.
Section 7.2.
Description of 
study 
procedures by 
visit
Each visit explained in 
detail 
Deleted this section. All 
necessary details are 
present in the Study 
procedures table(section 
7.0,Table 10) and 
accompanying footnotes.
All references to this 
section have been 
removed
This is to be in alignment 
with the current NU 
template.
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Section 8.2.9
Availability of 
pazopanib
Drug supply from GLAXO 
SMITHKINE(GSK): clinical 
supply
Drug supply from 
NOVARTIS: commercial 
supply with auxiliary 
label.
Other details added
Drug supply availability changed 
companies. 
Section 8.2.6
Preparation of 
pazopanib
Details about  
previous‘clinical 
supply’only 
Added details about 
‘commercial supply’ that 
is provided by Novartis
Added note: Sites will 
start using the 
commercial supply  when 
they finish the previous 
clinical supply).
Updated per information 
from Novartis 
Section 8.2.9
All requests for study drug 
should be submitted via 
email to Kamal Bhatt 
(kamalnaya.H.Bhatt@gsk.c
om) and Donna Scharff 
(Scharff@nccn.org) and 
should include the 
following information:
All requests for study 
drug should be 
submitted via email to 
Desiree Hiram 
(desiree.hiraman@nova
rtis.com), Lixian Jin 
(lixian.jin@novartis.co
m), and Donna Scharff 
(Scharff@nccn.org) 
and should include the 
following information:
Per Novartis
updated contact information
Section 8.2.10.3
Few uncommen side effects 
listed
Atrial fibrillation added
Per memo received from 
sponsor stating this was 
thought to be ‘possibly 
related’ to pazopanib. (This 
event occurred in a patient 
being treated with pazopanib, 
during the course of a clinical 
study [115210])
Section 10.2.1
Adverse Event
AE definition
Additional language 
added 
Per updated NU protocol 
template
Section 10.2.2
AE graded by NCT CTCAE 
version 4.0
Version updated to 4.03.
Additional grading 
Per updated 
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Severity of 
AEs;
Section 5.7.4.2 
Table 7(dose 
modification for 
pazopanib)
information inserted in 
case CTCAE not 
available 
NU protocol template
Section 10.2.3
Serious 
Adverse Event
Previous standard SAE 
criteria
Updated with Novartis 
specifications/language
Per sponsor Novartis
Section 10.3.2
Previous NU template 
language
Note : SAE to be  reported 
to NU IRB within 10 
working days
Updated NU template 
language. 
Note : SAE to be  
reported to NU IRB 
within 5 working days
Per updated NU protocol 
template
Section 10.3.3;
10.3.4
Reporting to 
Novartis and 
NCCN
Information regarding 
Reporting to GSK and 
NCCN
Updated to :
Section 10.3.3: Reporting 
to Novartis
Section 10.3.4: Reporting 
to NCCN
Per new information from 
Novartis
Section 11.
Data 
submission
Previous NU template 
language
Replaced with current 
NU template language
Removed previous data 
submission guidelines 
from appendix  since it  
now available as stand-
alone document
Per current NU template 
requirements.
Section 12.1.3
Processing of 
PK sample
Transfer the plasma to 2 
polypropylene tubes 
(approximately 0.75 mL per 
tube).  
Transfer the plasma to 2 
polypropylene tubes (a 
primary and a back-up 
tube, approximately 0.75 
mL per tube).  
For clarity, based on 
information received from 
laboratory personnel.
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Section 12.1.4
Shipment of PK 
samples
Details about shipment.
Added: 
Please refer to 
laboratory manual for 
further details (available 
as stand-alone 
document)
As new laboratory manual 
has been developed
Appendices
Previous list of appendix
Numbering has been 
changed. Appendix with 
Data submission 
guidelines and Data 
safety Monitoring Plan 
and Slot reservation 
Procedure has been 
removed. These are now 
available as stand-alone 
documents.
Per changes made to the 
protocol and per new NU 
template requirements.
Throughout
Temozolomide spelling 
incorrect in some 
sections.Spelt as 
‘Temozolamide’
Spelling corrected 
throughout to 
Temozolomide
Correction of error
Amendment 7 – June 20, 2017
Section (s) 
Affected
Prior Version
Amendment 6 Changes
Rationale
Protocol title 
page and 
section 3.1
Dr.Halla Nimeri was the 
Principal Investigator
Dr.Nimeri is replaced by 
Dr.Sheetal M. Kircher as 
Principal Investigator
Dr.Nimeri leaving NU and 
handing over study to 
Dr.Kircher.
Section 9.5
Statement of 
feasibility 
Statement of feasibility with 
Dr.Nimeri’s details.
Added statement: 
“As of June 2017, she is 
being replaced by 
Dr.Sheetal Kircher as 
Principal Investigator of 
this study.”
Dr.Nimeri leaving NU and 
handing over study to 
Dr.Kircher.
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Amendment 8– January 24 , 2018
Section 7: 
Study 
procedures 
table
(Footnote 7)
Survival follow-up was 
stated as “every 3 months 
until death”
Updated to “every 6 
months for 1 year in 
clinic and/or via phone”
Correction of discrepancy.
(to be in alignment with 
information in section 5.9)
Section 7: 
Study 
procedures 
table
(Footnote 23)
All patients were required to 
do D15 labs till end of 
treatment, even if they 
discontinued  
Temozolamide after 1 year 
of treatment.
For patients who 
discontinue 
Temozolamide after 1 
year of treatmnet, for 
them the D15 laboratory 
tests (WBC, ANC, 
hemoglobin, platelet; 
Electrolytes & renal 
function tests [Na, K, Cl, 
CO2, BUN, Creatinine, 
Mg, Phos]; Liver 
function tests [AST, 
ALT, alk phos, total 
bilirubin])
 are not required. 
To save patients from 
undergoing additional 
testing that is not required 
from a safety standpoint.
Section 8.2.9
Pazopanib 
supply
One of the contact s for 
drug order was Lixian Jin
Update: Removed Lixian 
Jin and added  Quincy 
Chau 
(quincy.chau@novartis.c
om)
Lixian Jin is no longer part 
of the specific Votrient 
(Pazopanib) program.
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