Clinical trial NCT01931098
Conditions: Glioblastoma Glioblastoma Multiforme Gliosarcoma Brain Neoplasms Central Nervous System Neoplasms
Keywords: Brain Tumors
Sponsor: National Cancer Institute (NCI)
Start date: 2015-12-10; Completion date: 2019-09-12
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

Glioblastoma is the most common and most aggressive type of malignant brain tumor. The drug pazopanib is used to treat people with a type of kidney cancer. Topotecan is used to treat lung cancer. Both topotecan and pazopanib have individually been used to treat patients with glioblastoma and some anti-tumor activity has been found. Researchers want to see if these two drugs together may be able to help people with glioblastoma.

Objectives:

To learn if pazopanib with topotecan can help control glioblastoma. Also, to study the safety of this drug combination.

Eligibility:

Adults at least 18 years old whose glioblastoma has returned after treatment.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Brain computed tomography (CT) or magnetic resonance imaging (MRI) For these, participants lay in a machine that takes pictures.

Chest CT scan or x-ray

Heart electrocardiogram (EKG)

A questionnaire about quality of life

Participants will be assigned to a study group.

Participants will take the study drugs for 28-day cycles for up to 1 year. They will take capsules of topotecan by mouth once every day. They will take tablets of pazopanib by mouth once every day.

Participants will write in a diary the times they take the study drugs.

Participants will have several study visits during each cycle. These may include

Blood pressure measurement

Blood and urine tests

EKG

Physical exam and/or neurological exam

Brain MRI or CT scan to check the status of the disease

A symptom questionnaire

At the end of treatment, participants will have a physical exam. They may have blood drawn.

Participants will have follow-up calls once every 3 months to check.

Detailed description:
Background

* Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment,consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor progression within one year of diagnosis despite treatment. At progression, treatment options are limited and mostly ineffective.
* Recently, bevacizumab was approved for recurrent GBM patients who fail bevacizumab indicate a short survival, on the order of 10 weeks, an approximate PFS 3 and 6 months of 0%.
* Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGFR), Platelet-derived growth factor receptors (PDGFR), and c-Kit, and was recently Food and Drug Administration (FDA) approved for advanced renal cell carcinoma.
* Topotecan is an orally bioavailable topoisomerase I and Hypoxia-inducible factor 1 (HIF-1) alpha inhibitor with reasonably high central nervous system (CNS)/cerebrospinal fluid (CSF) penetration
* Recent pre-clinical reports have begun to argue for the clinical testing of metronomic chemotherapy administration in various cancers. The theory of improved activity of Pazopanib + Topotecan administered metronomically is based on targeting tumor vasculature (both existing capillary endothelial cells and circulating bone marrow derived endothelial cell precursors), immune modulation, as well as tumor cell HIF-1 alpha inhibition, and the induction of Deoxyribonucleic acid (DNA) damage. Further support for the combination comes from recent data tying drug-induced VEGF inhibition to the induction of HIF-1 alpha activity in GBM suggesting possible synergy between Pazopanib and Topotecan
* The combination of Topotecan and Pazopanib has been directly demonstrated as active in

animal models

Objectives

* 6 month progression free survival rate for recurrent glioblastoma (rGBM) patients with no prior bevacizumab exposure treated with pazopanib and topotecan (Group A).
* 3 month progression free survival rate for rGBM patients with prior bevacizumab exposure treated with pazopanib and topotecan (Group B).

Eligibility

* Histologically proven intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS) with evidence of progression on MRI or CT scan.
* Patient must have failed prior chemoradiation with temozolomide and any other therapies except Bevacizumab (BEV) (group A), or must have failed primary chemoradiation and a BEVincorporating treatment (group B).
* Patients must be greater than 12 weeks following completion of chemoradiation.

  * Archived tumor tissue must be available for confirmation of the diagnosis
  * Patients must be \> 18 years old.
  * Patients must have a Karnofsky performance status of \> 60.
  * Patients must have adequate organ function.
  * No pregnancy or lactation.
  * Patients must not have any significant medical illnesses that in the investigators opinion cannot be adequately controlled with appropriate therapy or would compromise the patients ability to tolerate this therapy.
  * No history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are eligible.
  * No clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, or the absorption of the medications.
  * No prior major surgery or trauma within 28 days and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
  * No evidence of active bleeding or bleeding diathesis.
  * No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
  * No serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subjects safety, provision of informed consent, or compliance to study procedures.
  * No ongoing toxicity from prior anti-cancer therapy that is \> Grade 1 and/or that is progressing in severity, except alopecia.
  * No ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week washout has elapsed form last dose of EIAED.
  * No known hypersensitivity to pazopanib or topotecan or to their excipients.
  * No total daily dose of dexamethasone greater than 16 mg/day.
  * No prior therapy with topotecan, pazopanib, or related drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab). Prior treatment with Tyrosine kinase inhibitors (TKIs) that do not impact VEGFR -1, -2, or -3, Platelet Derived Growth Factor Receptor Alpha (PDGFRa) Platelet Derived Growth Factor Receptor Beta (-b) of cKIT could be allowed.

Design

This is a 2 arm phase II trial of the combination of topotecan and pazopanib in patients with recurrent GBM or GS. Patients will be enrolled into one of the following groups: (A) Glioblastoma or gliosarcoma with no prior bevacizumab exposure: (B) Glioblastoma or

gliosarcoma with prior bevacizumab exposure. Topotecan and pazopanib are administered orally daily. The primary efficacy endpoint is progression free survival (PFS) at six months from patient registration for bevacizumab na(SqrRoot) ve patients and progression free survival (PFS) at 3 months for patients with prior bevacizumab treatment.

Arms: arm 1: Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year. arm 2: Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
Interventions: intervention 1: topotecan intervention 2: pazopanib
Intervention descriptions: intervention 1: Taken .25 mg orally, daily continuous until progression up to one year. intervention 2: 600 mg orally, daily until progression, up to one year.

Protocol documents:
Prot_SAP_001.pdf: 
Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 1 of 96
BRAIN TUMOR TRIALS COLLABORATIVE (BTTC)
Abbreviated Title: Ph II Pazopanib Topotecan
NCI Protocol #: 16C0034
Version Date: 07/17/2025
BTTC Protocol #: BTTC12-01
NCT Number: NCT01931098
Title: A Phase II Trial of Oral Pazopanib plus Oral Topotecan Metronomic Antiangiogenic 
Therapy for Recurrent Glioblastoma Multiforme (A) without Prior Bevacizumab Exposure and 
(B) after Failing Prior Bevacizumab
Coordinating Center: NCI BTTC Coordinating Center, Center for Cancer Research
NCI Principal Investigator: 
Kevin Camphausen, MD 
Radiation Oncology Branch (ROB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Bldg. 10, Rm B2-3500
9000 Rockville Pike
Bethesda, MD 20892
Phone:  240-760-6205
Email: camphauk@mail.nih.gov 
Investigational Agents:
None
Commercial Agents: Pazopanib and Oral Topotecan


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A DISCLAIMER STATEMENT FOR BTTC PROTOCOLS
This is a research protocol of the Brain Tumor Trials Collaborative describing an experimental 
treatment procedure.  It is a privileged document and is not intended to be circulated or used for 
other purposes.  The Brain Tumor Trials Collaborative assumes no responsibility for its use 
outside of the constraints of this research protocol or by investigators other than those approved 
by the Consortium.


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


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PRÉCIS
Background
•
Glioblastoma (GBM) is the most common primary brain tumor.  With optimal treatment, 
consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant 
chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor 
progression within one year of diagnosis despite treatment.  At progression, treatment 
options are limited and mostly ineffective.
•
Recently, bevacizumab was approved for recurrent GBM patients who fail bevacizumab 
indicate a short survival, on the order of 10 weeks, an approximate PFS 3 and 6 months 
of 0%.
•
Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit, and 
was recently FDA approved for advanced renal cell carcinoma.
•
Topotecan is an orally bioavailable topoisomerase I and HIF-1 alpha inhibitor with 
reasonably high CNS/CSF penetration
•
Recent pre-clinical reports have begun to argue for the clinical testing of metronomic 
chemotherapy administration in various cancers. The theory of improved activity of 
Pazopanib + Topotecan administered metronomically is based on targeting tumor 
vasculature (both existing capillary endothelial cells and circulating bone marrow derived 
endothelial cell precursors), immune modulation, as well as tumor cell HIF-1 alpha 
inhibition, and the induction of DNA damage. Further support for the combination comes 
from recent data tying drug-induced VEGF inhibition to the induction of HIF-1 alpha 
activity in GBM suggesting possible synergy between Pazopanib and Topotecan
•
The combination of Topotecan and Pazopanib has been directly demonstrated as active in 
animal models 
Objectives
•
6 month progression free survival rate for recurrent glioblastoma (rGBM) patients with 
no prior bevacizumab exposure treated with pazopanib and topotecan (Group A).
•
3 month progression free survival rate for rGBM patients with prior bevacizumab 
exposure treated with pazopanib and topotecan (Group B).
Eligibility
•
Histologically proven intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS) 
with evidence of progression on MRI or CT scan. 
•
Patient must have failed prior chemoradiation with temozolomide and any other therapies 
except BEV (group A), or must have failed primary chemoradiation and a BEV-
incorporating treatment (group B).
•
Patients must be greater than 12 weeks following completion of chemoradiation. 
•
Archived tumor tissue must be available for confirmation of the diagnosis 
•
Patients must be > 18 years old.


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•
Patients must have a Karnofsky performance status of > 60.
•
Patients must have adequate organ function.
•
No pregnancy or lactation.
•
Patients must not have any significant medical illnesses that in the investigator’s opinion 
cannot be adequately controlled with appropriate therapy or would compromise the 
patient’s ability to tolerate this therapy.
•
No history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of 
the cervix), unless in complete remission and off of all therapy for that disease for a 
minimum of 3 years are eligible.
•
No clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding including, or the absorption of the medications.
•
No prior major surgery or trauma within 28 days and/or presence of any non-healing 
wound, fracture, or ulcer (procedures such as catheter placement not considered to be 
major).
•
No evidence of active bleeding or bleeding diathesis.  
•
No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
•
No serious and/or unstable pre-existing medical, psychiatric, or other condition that could 
interfere with subject’s safety, provision of informed consent, or compliance to study 
procedures. 
•
No ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is 
progressing in severity, except alopecia.
•
No ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week 
washout has elapsed form last dose of EIAED.
•
No known hypersensitivity to pazopanib or topotecan or to their excipients.
•
No total daily dose of dexamethasone greater than 16 mg/day. 
•
No prior therapy with topotecan, pazopanib, or related drugs such as tyrosine kinase 
inhibitors, VEGF inhibitors (except bevacizumab). Prior treatment with TKIs that do not 
impact VEGFR -1, -2, or -3, PDGFR –a, -b of cKIT could be allowed.
Design
This is a 2 arm phase II trial of the combination of topotecan and pazopanib in patients with 
recurrent GBM or GS. Patients will be enrolled into one of the following groups:  (A) 
Glioblastoma or gliosarcoma with no prior bevacizumab exposure: (B) Glioblastoma or 
gliosarcoma with prior bevacizumab exposure. Topotecan and pazopanib are administered orally 
daily. The primary efficacy endpoint is progression free survival (PFS) at six months from 
patient registration for bevacizumab naïve patients and PFS at 3 months for patients with prior 
bevacizumab treatment.


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TABLE OF CONTENTS
STATEMENT OF COMPLIANCE ................................................................................................3
PRÉCIS............................................................................................................................................4
TABLE OF CONTENTS ................................................................................................................6
1
INTRODUCTION ...................................................................................................................9
1.1
Objectives..........................................................................................................................9
1.2
Background .......................................................................................................................9
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................12
2.1
Eligibility Criteria ...........................................................................................................12
2.2
Pretreatment Evaluation..................................................................................................17
2.3
Registration Procedures ..................................................................................................18
2.4
Descriptive Factors .........................................................................................................20
3
STUDY IMPLEMENTATION .............................................................................................20
3.1
Study Design...................................................................................................................20
3.2
Drug Administration .......................................................................................................20
3.3
Dose Modifications:........................................................................................................20
3.4
On Study Evaluation .......................................................................................................26
3.5
Questionnaires.................................................................................................................27
3.6
Study Calendar................................................................................................................27
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................29
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................30
4.1
G-CSF Administration ....................................................................................................30
4.2
Corticosteroids ................................................................................................................30
4.3
Anti-seizure medications.................................................................................................30
4.4
Febrile neutropenia .........................................................................................................30
4.5
Anti-emetics....................................................................................................................31
4.6
Other Concomitant Medications .....................................................................................31
4.7
Other Anticancer or Experimental Therapies .................................................................31
4.8
Surgery............................................................................................................................31
5
BIOSPECIMEN COLLECTION...........................................................................................31
5.1
Pathology Review ...........................................................................................................31


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6
DATA COLLECTION AND EVALUATION .....................................................................32
6.1
Data Collection ...............................................................................................................32
6.2
Data Monitoring..............................................................................................................34
6.3
Data Sharing Plan............................................................................................................34
6.4
Response Criteria ............................................................................................................35
6.5
Toxicity Criteria..............................................................................................................37
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....37
7.1
Definitions.......................................................................................................................37
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................37
7.3
NIH Required Data and Safety Monitoring Plan............................................................38
8
SAFETY REPORTING TO BTTC .......................................................................................39
8.1
Definitions.......................................................................................................................39
8.2
Assessing Causality.........................................................................................................39
8.3
Protocol Specific Definitions..........................................................................................40
8.4
Guidelines & Procedures For Reporting Deviations And Unanticipated Problems .......40
8.5
Reporting to the Study Drug Manufacturer (Novartis)...................................................41
8.6
Guidelines for Reporting Serious Adverse Events to BTTC ..........................................41
9
STATISTICAL CONSIDERATIONS ..................................................................................42
10
COLLABORATIVE AGREEMENTS..................................................................................44
10.1
Agreement Type..............................................................................................................44
11
HUMAN SUBJECTS PROTECTIONS................................................................................44
11.1
Rationale for Subject Selection.......................................................................................44
11.2
Participation of Children.................................................................................................44
11.3
Evaluation of Benefits and Risks/Discomforts ...............................................................44
11.4
Risks/Benefits Analysis ..................................................................................................45
11.5
Consent and Assent Process and Documentation ...........................................................45
12
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................45
12.1
Quality Assurance and Quality Control..........................................................................45
12.2
Conflict of Interest Policy...............................................................................................46
12.3
Confidentiality and Privacy ............................................................................................46
13
PHARMACEUTICAL INFORMATION .............................................................................47
13.1
Drug Name: HYCAMTIN (Topotecan hydrochloride) ..................................................47


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13.2
Drug Name: Pazopanib ...................................................................................................59
14
REFERENCES ......................................................................................................................73
15
APPENDICES .......................................................................................................................75
15.1
Karnofsky Performance Status and Neurologic Function...............................................75
15.2
EIAEDs and Non-EIAEDs..............................................................................................76
15.3
Tumor Tissue Handling Instructions and Tissue Collection Shipping Form..................77
15.4
Drugs known to be metabolized by CYP450 isoenzymes 2D6 and 3A4........................80
15.5
MD Anderson Symptom Inventory for Brain Tumors (MDASI – BT)..........................83
15.6
Oral Topotecan Drug Interactions...................................................................................86
15.7
The New York Heart Association (NYHA) Functional Classification...........................87
15.8
Hepatitis Risk Factors .....................................................................................................88
15.9
CCR Problem Report Form.............................................................................................89
15.10 Pill Diary.........................................................................................................................91
15.11 Pill Count Documentation for Pazopanib .......................................................................93
15.12 Pill Count Documentation For Topotecan ......................................................................94
15.13 Technology Transfer Agreements...................................................................................96


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1
INTRODUCTION
1.1
OBJECTIVES
1.1.1
Primary endpoint:
•
6 month progression free survival rate for recurrent glioblastoma (rGBM) patients with 
no prior bevacizumab exposure treated with pazopanib and topotecan (Group A).
•
3 month progression free survival rate for rGBM patients with prior bevacizumab 
exposure treated with pazopanib and topotecan (Group B).
1.1.2
Secondary endpoint:
•
Overall survival for rGBMs (Group A and Group B) treated with pazopanib and 
topotecan measured from time of study enrollment.
•
Objective response rate for rGBM (Group A and Group B) treated with pazopanib and 
topotecan. 
•
Patient related outcome measures.
•
To evaluate the occurrence of symptoms and correlate to disease progression and 
tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module 
(MDASI-BT) self-reporting tool.  This will include:
o
To evaluate longitudinal changes in symptom measures and determine the impact 
of the therapy on these parameters.
o
To measure symptom burden over the course of therapy to evaluate differences 
between patients individual symptom severity, overall mean symptom severity, 
and difference in scores on the interference items between responders and non-
responders.
o
To describe the variability of symptom severity longitudinally over the treatment 
course and follow-up period. 
1.2
BACKGROUND
1.2.1
Glioblastoma (GBM) 
Glioblastoma (GBM) is the most common primary brain tumor.  With optimal treatment, 
consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant 
chemotherapy, median survival is 14.6 months (Stupp et al. 987-96;Stupp et al. 459-66;Stupp et 
al. 459-66;Stupp et al. 987-96).  Cure is exceptional and most patients have evidence of tumor 
progression within one year of diagnosis despite treatment.  At progression, treatment options are 
limited and mostly ineffective; most clinical trials demonstrate six month progression free 
survival rate of only 9-15% and median overall survival is less than 25 weeks from time of tumor 
progression (Lamborn et al. 162-70).  Recently, bevacizumab was approved for recurrent GBM 
based on data from Vredenburgh et al. and Kreisl et al. (Kreisl et al. 740-45;Vredenburgh et al. 
4722-29)  Data on patients who fail bevacizumab indicate a short survival, on the order of 10 
weeks, an approximate PFS 3 and 6 months of 0%.
Numerous molecular changes drive the growth and pro-angiogenic behavior of GBMs (Lim et al. 
158-64). Among the molecular features of GBM, Vascular Endothelial Growth Factor (VEGF) 


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overexpression is nearly universal and higher levels are correlated with higher tumor grade (Plate 
et al. 845-48;Chi et al. 621-36). Platelet Derived Growth Factor Receptor (PDGFR)-alpha is 
expressed in nearly all malignant gliomas and high levels of PDGFR-beta are seen on endothelial 
cells of capillaries adjacent to gliomas (Hermanson et al. 3213-19). Stem cell factor receptor (c-
Kit) pathway activation is less well defined in malignant glioma. Reports vary widely as to its 
expression from as high as 75% to as low as 4% (Morris and Abrey 193-200). C-Kit 
amplification may be associated with the presence of PDGFR-alpha expression, and may be seen 
more commonly in recurrent astrocytic tumors (Puputti et al. 927-34). Intriguingly, in a small 
number of patients with recurrent malignant glioma whose tumors possessed c-Kit polysomy or 
amplification, treatment with a c-Kit inhibitor resulted in a far longer freedom from progression, 
as compared to those patients whose tumors contained a normal c-Kit copy number (Reardon et 
al. 1995-2004).
Recent work has begun to subcategorize GBM into various subgroups based on the primary 
molecular pathways involved (Phillips et al. 157-73;Brennan et al. e7752). One study of 
particular relevance to this proposal, using proteomic analysis, identified three patterns of 
expression and activation of proteins in glioma signaling pathways, one of which was a PDGF-
pathway activation which was primarily ligand driven (Brennan et al. e7752). The other 
pathways were EGFR and NF1. GBM patients were evenly distributed among the three groups, 
suggesting up to 1/3 of GBM patients would possess the PDGF pathway activation pattern. 
There was a trend for tumors that had been previously treated to reside in the PDGF group 
(p=0.11). Interestingly, even though this group of tumors was defined by evidence of PDGF 
signaling at the protein level, none of the tumors in the class showed gene amplification of either 
PDGF receptors or ligands. The PDGF pathway analysis included a cluster of 17 proteins 
including PDGFB, phospho-PDGFRβ, and phospho-NFKB1 as well as others. This PDGF core 
was felt to most closely resemble the tumors recently described as “pro-neural” (Phillips et al. 
157-73). 
1.2.2
Pazopanib:
Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit, and was 
recently FDA approved for advanced renal cell carcinoma. Single-agent Pazopanib at 800 mg 
daily was tested in a phase 2 study in recurrent GBM and was well tolerated. However, 
Pazopanib demonstrated a 6-month progression free survival (PFS6) of only 3% (not meeting the 
efficacy target), a median PFS of 12 weeks, and a median overall survival of 35 weeks. 
However, Pazopanib did demonstrate biological activity, in that 11 patients (31%) had a PR or a 
<50% reduction in tumor, indicative of Pazopanib’s effect on tumor vasculature (Iwamoto et al. 
855-61). Pazopanib (in combination with lapatinib) in relapsed malignant glioma showed a 
clinical benefit rate (CR + PR + SD > 8 weeks) of 50-68%. 
1.2.3
Topotecan:
Topotecan is an orally bioavailable topoisomerase I and HIF-1 alpha inhibitor(Rapisarda et al. 
6845-48) with reasonably high CNS/CSF penetration (Baker et al. 195-202). A 1996 study of 
high dose IV topotecan in 31 adults with recurrent malignant gliomas demonstrated 1 CR in 
GBM and 1 PR in the anaplastic astrocytoma (AA) group (Macdonald et al. 205-07). More 
interestingly, the median time to progression was 19 weeks and the overall PFS6 was 23%, 
which is similar to the figure (21%) reported for temozolomide in recurrent GBM (Yung et al. 
588-93) (outcomes were similar for GBMs and AAs with respect to duration of stable disease). 


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Additionally, a recent phase 2 study of metronomically administered single-agent oral topotecan 
showed some efficacy in childhood brain tumors (Minturn et al. 39-44).
1.2.4
Rationale for combination therapy:
Recent pre-clinical reports have begun to argue for the clinical testing of metronomic 
chemotherapy administration in various cancers. The theory of improved activity of Pazopanib + 
Topotecan administered metronomically is based on targeting tumor vasculature (both existing 
capillary endothelial cells and circulating bone marrow derived endothelial cell precursors), 
immune modulation, as well as tumor cell HIF-1 alpha inhibition, and the induction of DNA 
damage. Further support for the combination comes from recent data tying drug-induced VEGF 
inhibition to the induction of HIF-1 alpha activity in GBM (Keunen et al. 3749-54) suggesting 
possible synergy between Pazopanib and Topotecan. 
The combination of Topotecan and Pazopanib has been directly demonstrated as active in animal 
models (Hashimoto et al. 996-1006;Merritt et al. 985-95). A mouse model of ovarian cancer 
showed substantially improved outcomes when both Pazopanib and Topotecan were 
administered in a metronomic fashion as compared to either agent alone, or when given in non-
metronomic schemes (Hashimoto et al. 996-1006). Further, the combination resulted in 
improvements in animal survival (and decreased tumor weight), decreased tumor microvessel 
density, decreased tumor cell VEGFR2 phosphorylation, decreased numbers of migrating tumor 
cells, decreased tumor cell proliferative activity, and increased percentages of tumor cells 
undergoing apoptosis (Merritt et al. 985-95). These pre-clinical findings led to a phase 1 clinical 
trial reported at the American Society of Clinical Oncology Meeting in 2012, abstract # 5014 
which showed the combination to be well tolerated, and with evidence of responses. 
The single-center, open-label phase I study included 25 extensively pretreated patients (pts) with 
gynecologic tumors (6 cervical, 7 endometrial, 8 ovarian, 4 other) were enrolled. Mean age was 
61 years; 19 Caucasian, 6 African American. This study comprised 28-day cycles of daily oral 
topotecan/pazopanib at dose levels of 0.50/400, 0.25/800, 0.25/600, and 0.25/400 mg. A standard 
3+3 dose escalation design was used. Dose limiting toxicity (DLT) was defined as ≥ grade 3 
adverse event (AE) occurring in cycle 1, noncompletion of cycle 1 at prescribed dose, or 
inability to start cycle 2 as scheduled due to toxicities. Imaging was conducted after every 2 
cycles for response assessment. Median number of cycles received was 4 (range 1-19). DLTs 
occurred ≥ 2 pts for A (2/6), B (2/7), C (3/7). For level D, 1/5 had a DLT, but one dose level C pt 
with a DLT received level D dosing due to unavailability of pazopanib. 9/25 pts had any serious 
adverse event (SAE), and respiratory SAEs were most common (4/16 SAEs). Nausea, fatigue, 
dysgeusia, diarrhea, and vomiting were the most common conditions reported as non-serious 
AEs. The best overall response was 28%. The conclusions were that DLTs in dose levels C and 
D were effectively managed with minor dose and schedule adjustments. 4 pts with DLTs at these 
doses remained on treatment for 4, 5, and 6 months, with one pt still on treatment at 9 months. 
The overall response rate (CR + PR + SD) was 36% and 42% in the higher dosed groups. 
Submitted abstract:
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&a
bstractID=93930


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Final Poster: 
http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentatio
ns_view&confID=114&sessionID=4842
Given the initial biologically favorable signal in this heavily pretreated group and low toxicity, 
the investigators recommended a randomized phase II trial to define efficacy using the 0.25/600 
regimen allowing for dose reduction if needed. 
Thus, several lines of reasoning argue for testing the oral combination of metronomic Topotecan 
and Pazopanib in recurrent GBM patients: A) There is prior clinical evidence of some, albeit 
limited, benefit of both Topotecan and Pazopanib, individually, in glioma patients (however, 
Topotecan has not been previously evaluated using metronomic dosing in GBM). B) The targets 
of Pazopanib and Topotecan, VEGFR, PDGFR, c-Kit, HIF-1 alpha, are all relevant in recurrent 
GBM. C) VEGF inhibition induces HIF-1 alpha activity in GBM, creating an environment for 
synergy. D) Recurrent GBM after standard therapy with chemoradiation or at the time of 
recurrence after bevacizumab (BEV) therapy are major problems, and unmet clinical needs. E) 
The oral administration of these agents will allow for rapid accrual and completion of this study 
and determination of an efficacy signal.
1.2.5
Rationale for patient outcomes measures:
This study seeks to establish effective therapies at recurrence and improve on current clinical 
results in patients with glioblastoma.  We hypothesize that using a combination of pazopanib and 
topotecan will result in improved survival.  It will be important to determine whether any 
determined survival benefit is associated with improvements in symptoms or does a worsening 
of symptoms offset the increase in survival. 
Precedence for measuring “non-therapeutic” endpoints exists in oncology research.  For 
example, Gemcitabine was approved by the FDA partially as a consequence of the decrease in 
pain reported in pancreatic patients who were treated, not on the basis of survival improvement 
which was modest, at best (Siu et al. 144-51).  There have been efforts in neuro-oncology to 
evaluate secondary endpoints using validated instruments as an additional indicator of benefit.  
The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) allows the self-
reporting of symptom severity and interference with daily activities.  The MDASI-BT has 
demonstrated reliability and validity in the adult primary brain tumor patient population 
(Armstrong et al. 27-35). This tool represents a modification of the widely used and validated 
MDASI, with particular attention to symptoms common in patients with brain tumors.   The 
availability of validated instruments provides an opportunity to prospectively assess the impact 
of treatment, both positive and negative, on patients.  This evaluation of symptom burden in this 
study will assist in finding the best possible treatment with the least toxicity.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
General Inclusion Criteria 
2.1.1.1
Patients with histologically proven intracranial glioblastoma multiforme 
(GBM) or gliosarcoma (GS). Patients will be eligible if the original 
histology was low-grade glioma and a subsequent histological diagnosis of a 
GBM or GS is made. Patients must have evidence of progression of the 


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GBM or GS on MRI or CT scan. Patient must have failed prior 
chemoradiation with temozolomide and any other therapies except BEV 
(group A), or must have failed primary chemoradiation and a BEV-
incorporating treatment (group B).
2.1.1.2
Patients may have had treatment for no more than 2 prior relapses.  Relapse 
is defined as progression following initial therapy (i.e. radiation+/- chemo if 
that was used as initial therapy).  The intent therefore is that patients had no 
more than 3 prior therapies (initial and treatment for 2 relapses). If the 
patient had a surgical resection for relapsed disease and no anti-cancer 
therapy was instituted for up to 12 weeks, and the patient undergoes another 
surgical resection, this is considered as 1 relapse.  For patients who had prior 
therapy for a low-grade glioma, the surgical diagnosis of a high-grade 
glioma will be considered the first relapse.
2.1.1.3
Patients must be greater than 12 weeks following completion of 
chemoradiation or any additional radiation to reduce the chance of 
pseudoprogression.
2.1.1.4
Measurable disease is required unless patient is post-operative and in that 
case patient can have no evidence of disease.
2.1.1.5
All patients must sign an informed consent indicating that they are aware of 
the investigational nature of this study.
2.1.1.6
Archived tumor tissue must be available for all subjects for confirmation of 
the diagnosis before or during treatment. Samples must be provided within 4 
weeks of enrollment.
2.1.1.7
Patients must be ≥ 18 years old.
2.1.1.8
Patients must have a Karnofsky performance status of ≥ 60.
2.1.1.9
At the time of registration:  Patients must have recovered from the toxic 
effects of prior therapy: > 28 days from any investigational agent, >28 days 
from prior cytotoxic therapy, >14 days from vincristine, >42 days from 
nitrosoureas, >21 days from procarbazine administration, >21 days from 
bevacizumab administration and >7 days for non-cytotoxic agents, e.g., 
interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer 
does not count).  Any questions related to the definition of non-cytotoxic 
agents should be directed to Academic PI.
2.1.1.10 Patients must have adequate organ function:
•
Bone marrow function (WBC > 3,000/µl, ANC > 1,500/mm3, platelet count of > 
100,000/mm3, and hemoglobin > 10 gm/dl). 
o
Eligibility level for hemoglobin may be reached by transfusion. 
•
Liver function (alanine amino transferase (ALT) and aspartate aminotransferase 
(AST) < 2.5 X ULN, and total bilirubin < 1.5 X ULN), prothrombin time (PT) or 
international normalized ratio (INR), and activated partial thromboplastin time 
(aPTT)  1.2 X ULN.


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o
Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit 
of normal) are not permitted.
o
Subjects receiving anticoagulant therapy are eligible if their INR is stable and 
within the recommended range for the desired level of anticoagulation.
•
Renal function (creatinine 1.5 mg/dL (133 µmol/L), or if > 1.5 mg/dL, calculated 
creatinine clearance ≥ 50 cc/min), and urine protein to creatinine ratio of < 1 prior to 
registration.
2.1.1.11 Patients must have shown unequivocal radiographic evidence for tumor 
progression by MRI or CT scan as defined by Section 6.4.1.4.5.  A scan 
should be performed within 14 days prior to registration and on a steroid 
dose that has been stable or decreasing for at least 5 days. If the steroid dose 
is increased between the date of imaging and registration a new baseline 
MR/CT is required. The same type of scan, i.e., MRI or CT must be used 
throughout the period of protocol treatment for tumor measurement.
2.1.1.12 Patients having undergone recent resection of recurrent or progressive tumor 
will be eligible as long as all of the following conditions apply:
•
They have recovered from the effects of surgery and be > 28 days from surgery. 
2.1.1.13 Residual disease following resection of recurrent GBM or GS is not 
mandated for eligibility into the study. To best assess the extent of residual 
disease post-operatively, a CT/ MRI should be done no later than 96 hours in 
the immediate post-operative period or at least 4 weeks post-operatively, 
within 14 days prior to registration.  If the 96-hour scan is more than 14 days 
before registration, the scan needs to be repeated.  If the steroid dose is 
increased between the date of imaging and registration, a new baseline 
MRI/CT is required on a stable steroid dosage for at least 5 days.
2.1.1.14 Patients must have failed prior radiation therapy and must have an interval of 
greater than or equal to 12 weeks from the completion of radiation therapy to 
study entry.
2.1.1.15 Patients with prior therapy that included interstitial brachytherapy or 
stereotactic radiosurgery must have confirmation of true progressive disease 
rather than radiation necrosis based upon either PET or Thallium scanning, 
MR spectroscopy or surgical/pathological documentation of disease.
2.1.1.16 A female is eligible to enter and participate in this study if she is of:
2.1.1.16.1 Non-childbearing potential (i.e., physiologically incapable of 
becoming pregnant), including any female who has had:
•
A hysterectomy
2.1.1.17 A bilateral oophorectomy (ovariectomy)
•
A bilateral tubal ligation
•
Is post-menopausal


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•
Subjects not using hormone replacement therapy (HRT) must have experienced 
total cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, 
in questionable cases, have a follicle stimulating hormone (FSH) value >40 
mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L). 
•
Subjects using HRT must have experienced total cessation of menses for >= 1 
year and be greater than 45 years of age OR have had documented evidence of 
menopause based on FSH and estradiol concentrations prior to initiation of 
HRT
2.1.1.17.1 Childbearing potential, including any female who has had a negative 
serum pregnancy test within 2 weeks prior to the first dose of study 
treatment, preferably as close to the first dose as possible, and agrees 
to use adequate contraception.  Novartis acceptable contraceptive 
methods, when used consistently and in accordance with both the 
product label and the instructions of the physician, are as follows:
•
Complete abstinence from sexual intercourse for 14 days before exposure to 
investigational product, through the dosing period, and for at least 21 days after 
the last dose of investigational product. Oral contraceptive, either combined or 
progestogen alone.
•
Injectable progestogen.
•
Implants of levonorgestrel.
•
Estrogenic vaginal ring.  
•
Percutaneous contraceptive patches. 
•
Intrauterine device (IUD) or intrauterine system (IUS) with a documented 
failure rate of less than 1% per year.
•
Male partner sterilization (vasectomy with documentation of azoospermia) 
prior to the female subject's entry into the study, and this male is the sole 
partner for that subject.  
•
Double barrier method: condom and an occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository).
•
Female subjects who are lactating should discontinue nursing prior to the first 
dose of study drug and should refrain from nursing throughout the treatment 
period and for 14 days following the last dose of study drug.
2.1.2
General Exclusion Criteria
2.1.2.1
Patients must not have any significant medical illnesses that in the 
investigator’s opinion cannot be adequately controlled with appropriate 
therapy or would compromise the patient’s ability to tolerate this therapy.
2.1.2.2
Patients with a history of any other cancer (except non-melanoma skin 
cancer or carcinoma in-situ of the cervix), unless in complete remission and 
off of all therapy for that disease for a minimum of 3 years are ineligible.


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2.1.2.3
Clinically significant gastrointestinal abnormalities that may increase the 
risk for gastrointestinal bleeding including, but not limited to:
•
Active peptic ulcer disease.
•
Known intraluminal metastatic lesion/s with risk of bleeding.
•
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other 
gastrointestinal conditions with increased risk of perforation.
•
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 28 days prior to beginning study treatment.
2.1.2.4
Clinically significant gastrointestinal abnormalities that may affect 
absorption of investigational product including, but not limited to:
•
Malabsorption syndrome 
•
Major resection of the stomach or small bowel.
•
Presence of uncontrolled infection.
•
Corrected QT interval (QTc) > 480 msecs using Bazett’s formula
Bazett’s Formula:  
2.1.2.5
History of any one or more of the following cardiovascular conditions within 
the past 6 months:
•
Cardiac angioplasty or stenting
•
Myocardial infarction
•
Unstable angina
•
Coronary artery bypass graft surgery
•
Symptomatic peripheral vascular disease
•
Class III or IV congestive heart failure, as defined by the New York Heart 
Association (NYHA), see appendix 15.7
•
Poorly controlled hypertension [defined as systolic blood pressure (SBP) of 
≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].
Note: Initiation or adjustment of antihypertensive medication(s) is permitted 
prior to study entry.  BP must be re-assessed on two occasions that are 
separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 
readings) SBP / DBP values from each BP assessment must be ≤ 140/90 
mmHg in order for a subject to be eligible for the study.
•
History of cerebrovascular accident including transient ischemic attack (TIA), 
pulmonary embolism or untreated deep venous thrombosis (DVT) within the 
past 6 months.
Note: Subjects with recent DVT who have been treated with therapeutic anti-
coagulating agents for at least 6 weeks are eligible.


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2.1.2.6
Prior major surgery or trauma within 28 days and/or presence of any non-
healing wound, fracture, or ulcer (procedures such as catheter placement not 
considered to be major).
2.1.2.7
Evidence of active bleeding or bleeding diathesis. 
2.1.2.8
Known endobronchial lesions and/or lesions infiltrating major pulmonary 
vessels
2.1.2.9
Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of 
first dose of study drug.
2.1.2.10 Any serious and/or unstable pre-existing medical, psychiatric, or other 
condition that could interfere with subject’s safety, provision of informed 
consent, or compliance to study procedures. 
2.1.2.11 Unable or unwilling to discontinue use of inducers and inhibitors of CYP450 
listed in Appendix 15.4 and BCRP and PgP inducers and inhibitors for at 
least 14 days or five half-lives of a drug (whichever is longer) prior to the 
first dose of study drug and for the duration of the study. (CYP3A4 
substrates can be administered, but investigators will need to be aware of 
possible increased or decreased effectiveness of the non-study drug and this 
should be recorded in concomitant medications.  Dexamethasone is 
acceptable although listed as a CYP3A4 inducers/inhibitors as long as the 
dose is 16 mg/day or lesser.  
2.1.2.12 Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or 
that is progressing in severity, except alopecia.
2.1.2.13 Ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 
week washout has elapsed form last dose of EIAED.
2.1.2.14 Patients must not have any significant medical illnesses that in the 
investigator’s opinion cannot be adequately controlled with appropriate 
therapy or would compromise the patient’s ability to tolerate this therapy.
2.1.2.15 Patients with a known hypersensitivity to pazopanib or topotecan or to their 
excipients.
2.1.2.16 Patients on total daily dose of dexamethasone greater than 16 mg/day. 
2.1.2.17 Patients must not have received prior therapy with topotecan, pazopanib, or 
related drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except 
bevacizumab). Prior treatment with TKIs that do not impact VEGFR -1, -2, 
or -3, PDGFR –a, -b of cKIT could be allowed.
2.1.2.18 Patients must not have any disease that will obscure toxicity or dangerously 
alter drug metabolism.
2.2
PRETREATMENT EVALUATION
A complete history and neurological examination (to include documentation of the patients 
Karnofsky Performance Status), as well as neuro-imaging confirming tumor progression shall be 
performed on all patients.  The scan done prior to study entry documenting progression will be 


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reviewed by the patient’s treating physician.  The baseline scan should be performed within 14 
days of registration. Patients should not be on a steroid dose higher than 16 mg/day.
Prestudy laboratory tests shall include ECG, and laboratory studies including CBC, differential, 
platelets, ALT, AST, bilirubin, PT, PTT, INR, TSH and T4, creatinine, urinalysis with urine 
protein creatine (UPC) ratio microanalysis, and serum pregnancy test for women of childbearing 
potential. Prestudy tests (except pregnancy test) must be obtained within 14 days of registration. 
UPC ratio < 1.0.  Pregnancy test must be obtained within 14 days prior to starting the study 
drugs.
All patients should be screened for hepatitis risk factors and any past illness of hepatitis B and 
hepatitis C (See appendix 15.8). If patient has positive (+) response to questionnaire the Hepatitis 
B and C screening test should be done and recorded in the patient’s chart. If liver tests are 
normal patient could still go on study, but the investigator would be paying close attention to the 
liver function test (LFT’s). 
2.2.1
Documentation of tumor diagnosis
Following registration, slides from the most recent pre-registration biopsy must be submitted for 
review15 Unstained Paraffin slides, or a paraffin tissue block, will be obtained in all study 
patients from original surgery or definitive surgery or the surgery closest to initiation of this 
clinical trial and in those patients who will be undergoing resection at time of treatment failure.  
These samples should be shipped overnight mail in an appropriate container to:
Ken Aldape, M.D. 
Toronto General Hospital
200 Elizabeth Street, 11th Floor
Toronto, Ontario M5G 2C4 Canada
kaldape@gmail.com
Patients will complete a baseline MD Anderson Symptom Inventory-Brain Tumor Module 
(MDASI-BT) (Appendix 15.5) within 14 days (+ 3 working days) after enrollment on the clinical 
trial. The MDASI-BT will be completed only by the patient, unless changes in vision or 
weakness make this difficult. If this occurs, then the caregiver or research assistant may read the 
questions to the patient or assist with marking the severity number or score as described by the 
patient. A patient caregiver may complete the questionnaires as a patient-preference proxy if the 
patient’s deficits preclude self-report.
2.3
REGISTRATION PROCEDURES
Patients who are candidates for the study will first be evaluated for eligibility by the local 
investigator. All patients must be registered both locally and centrally with BTTC.
BTTC patients will be registered with the BTTC Coordinating Center.  All eligibility 
requirements will be checked prior to registration.  The status of all regulatory documents will be 
checked prior to registration. No patient will be entered on protocol if they do not satisfy all 
regulatory document and eligibility requirements. 
2.3.1
Informed Consent/Authorization
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an 
Institutional Review Board (IRB) approved consent form.


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Registrations must be completed after the patient has signed the informed consent and has been 
determined to be eligible by the local investigator. 
At the time of registration, the following information will be requested by the BTTC 
Coordinating Center:
•
A copy of a completed and signed, protocol specific, Eligibility Checklist form 
•
One copy of the signed and dated Informed Consent/Authorization. 
•
Copies of all source documents to support protocol specific eligibility.  Please refer to 
the Operations Manual for specific source documents required. 
2.3.2
Registration at the NCI
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent for patients enrolling at the lead institution.  A registration 
Eligibility Checklist from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) 
must be completed and faxed to 301-480-0757.  After confirmation of eligibility at Central 
Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the patient 
on the protocol prior to the release of any investigational agents.  Verification of Registration 
will be forwarded electronically via e-mail to the research team. A recorder is available during 
non-working hours.
2.3.3
Participating Site Registration 
All patients must be registered through the NCI Central Registration Office (CRO). A protocol 
registration form and cover memo will be supplied by the Coordinating Center, NCI CCR and 
updates will be provided as needed. Subject eligibility and demographic information is required 
for registration. To initially register a subject, after the participant has signed consent, complete 
the top portion of the form and send to Coordinating Center’s Research Nurse, Melanie Herrin, 
RN; fax: 301-451-5429, Melanie.Herrin@nih.gov. Once eligibility is confirmed, send the 
completed eligibility checklist with the attached supporting source documents to Melanie Herrin, 
RN. If patient is not eligible, please notify Melanie Herrin, RN.  The CRO will notify you either 
by e-mail or fax that the protocol registration form has been received. Questions about eligibility 
should be directed to the Coordinating Center’s Research Nurse, Melanie Herrin, RN; 301-451-
5979;  fax: 301-451-5429,  Melanie.Herrin@nih.gov. 
2.3.3.1
Patient Number for Participating Institutions
Once eligibility has been confirmed by the Coordinating Center, the patient from the 
participating institution will be registered through the Central Registration Office. A Verification 
of Registration will be received from the Central Registration Office with the assigned patient ID 
number.  The patient ID number is unique to the patient and must be written on all data and 
correspondence for the patient and used to enter data into the C3D database.   The participating 
site will receive the Verification of Registration via fax or email within one working day of 
registration.


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2.3.4
Initiation of Therapy
Treatment may not be initiated until the participating institution receives a faxed or emailed copy 
of the patient’s Registration Verification Letter from the Central Registration Office. 
All Patients that are eligible to receive therapy must initiate treatment within 96 hours after 
the registration.  
The BTTC Coordinating Center must be notified in writing of any exceptions to this policy. 
2.3.5
Eligibility Exceptions
Eligibility Exceptions will not be granted.
2.4
DESCRIPTIVE FACTORS
Patients with recurrent GBM or GS will be enrolled into one of the following groups: (A) 
Glioblastoma or gliosarcoma with no prior bevacizumab exposure: (B) Glioblastoma or 
gliosarcoma with prior bevacizumab exposure. Accrual goals and endpoints for each group are 
determined separately as described in the statistical section.
There will be a total accrual of approximately 66 eligible patients to this 2-arm Phase II study 
(34 recurrent GBM/GS patients with no prior exposure to bevacizumab, and 32 GBM/GS 
patients with prior exposure to bevacizumab).
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a 2 arm phase II trial of the combination of topotecan and pazopanib in patients with 
recurrent GBM or GS. Patients will be enrolled into one of the following groups: (A) 
Glioblastoma or gliosarcoma with no prior bevacizumab exposure: (B) Glioblastoma or 
gliosarcoma with prior bevacizumab exposure. Topotecan and pazopanib are administered orally 
daily. The primary efficacy endpoint is progression free survival (PFS) at six months from 
patient registration for bevacizumab naïve patients and PFS at 3 months for patients with prior 
bevacizumab treatment.
3.2
DRUG ADMINISTRATION
Patients will be treated with the combination of topotecan and pazopanib at the following doses:
3.2.1.1
Pazopanib: Starting dose is 600 mg (3x200mg) per day to be taken orally, 
daily, continuous, without food at least one hour before or two hours after a 
meal.
Pazopanib should be taken whole with water and must not be broken or crushed.
If a dose of pazopanib is missed, it should not be taken if it is less than 12 hours until the next 
dose.
3.2.1.2
Topotecan:  Starting dose of topotecan is 0.25 mg orally, daily, continuous.
3.3
DOSE MODIFICATIONS:
3.3.1
For treatment or dose modification related questions, please contact the Academic PI or 
the BTTC Coordinating Center’s Research Nurse Melanie Herrin, RN; 301-451-5979; 


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fax: 301-451-5429, Melanie.Herrin@nih.gov. Topotecan length of treatment is until 
progression, up to one year. Drug may be held up to 3 weeks waiting from toxicities to 
resolve. Drug dose will not be reduced.
3.3.2
Pazopanib length of treatment is until progression, up to one year. Dose of Pazopanib 
may be held up to 3 weeks waiting from toxicities to resolve and reduced to 400 mg or to 
200 mg daily based on side effects. Patient may be maintained on the lower dose of 
pazopanib during protocol if deemed to be deriving benefit from the drug.
If a patient is felt to be deriving benefit for the agent(s) and is stable at the one year time point, 
based on discussion with the PI and sponsor it may be possible to continue treatment at that 
point. 
3.3.3
Patients with stable or responding disease may be retreated at the same dose (both 
Topotecan and Pazopanib) or at a reduced dose level (pazopanib only), depending upon 
the adverse events observed in the current cycle and any adverse events present on the 
first day of the next cycle. If multiple toxicities are seen, the dose administered in a 
subsequent cycle should be based on the most severe toxicity experienced in the current 
cycle. 
Dose modifications or delays should be made based upon whether toxicities occur within a 4-
week treatment cycle or at the expected start of the next treatment cycle. 
3.3.4
Within Treatment Cycles:
3.3.4.1
Topotecan:
For patients who experience Grade 3 or 4 diarrhea, or other non-hematologic toxicities, the 
topotecan dose can be held up to 3 weeks waiting for toxicity to resolve to < Grade 2. Drug may 
be resumed at that time at same dose. If toxicity does not resolve in 3 weeks, patient will be 
taken off study. Patients with Grade 2 diarrhea may need to follow the same dose modification 
guidelines. 
Topotecan should not be re-administered unless the neutrophil count is more than or equal to 1.5 
x 109/L, the platelet count is more than or equal to 75 x 109/L, and the hemoglobin level is more 
than or equal to 9 g/dL (after transfusion if necessary). 
Standard oncology practice for the management of neutropenia is either to administer topotecan 
with other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts. Please refer 
to section 4.1 for protocol guideline regarding G-CSF administration.
3.3.4.2
Pazopanib:
For Pazopanib, two dose reductions are permitted, from 600 to 400 or 200 mg daily or from 400 
to 200 mg daily. Further dose reduction is not allowed. Patients may be maintained on the lower 
dose of pazopanib during protocol if deemed to be deriving benefit from the drug. Doses that are 
reduced for pazopanib related toxicity will not be re-escalated, even if there is minimal or no 
toxicity with the reduced dose. Patients whose dose has been reduced for adverse events that are 
subsequently not felt to be related to pazopanib may have the dose re-escalated after completion 
of one cycle with toxicities less than or equal to grade 1.
3.3.5
Hematologic Toxicity:
Dose Modifications Based on ANC and Platelet Counts (topotecan):


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ANC (/mL) 
     Platelets (/mL)
% of Planned topotecan
> 1500            and      > 75,000
100%
< 750              or        < 50,000
hold*
*Topotecan should be held.  Upon recovery to ANC > 1,500/mL and platelets to >75,000/mL, 
the same dose level will be administered. 
3.3.6
Non-hematologic Toxicity:
Dose Modifications Based on topotecan- or pazopanib-Related Non-Hematologic Toxicities:
NCI Grade
% of Planned Dose
0-2+
100%+
3*
hold**
4
hold***
+For symptomatic Grade 2 toxicity, the suspect drug dose may be held at the discretion of the 
investigator until recovery to CTC Grade 0-1, then resume at same dose for topotecan or one 
dose lower for pazopanib.
*Except nausea/vomiting (unless patients are on optimal antiemetic therapy).
**Hold suspect drug until recovery to CTC Grade 0-1 (or to within 1 grade of starting values for 
pre-existing laboratory abnormalities), and then resume at same dose for topotecan or one dose 
level lower for pazopanib.  
***Hold suspect drug until recovery to CTC Grade 0-1 (or to within 1 grade of starting values 
for pre-existing laboratory abnormalities), and then resume at same dose for topotecan or two 
dose levels lower for pazopanib.
3.3.6.1
Management of other drug related complications:
3.3.6.1.1.1 Management of Hepatic effects:
Cases of hepatic failure (including fatalities) have been reported during the use of pazopanib. In 
clinical trials with pazopanib, increase in serum transaminases (ALT, AST) and bilirubin were 
observed. In the majority of the cases, isolated increases in ALT and AST have been reported, 
without concomitant elevations of alkaline phosphatase or bilirubin. The vast majority (92.5%) 
of all transaminase elevations of any grade occurred in the first 18 weeks. 
Monitor serum liver tests before initiation of treatment with pazopanib and at least once every 4 
weeks for at least the first 4 months of treatment, and as clinically indicated. Periodic monitoring 
should then continue after this time period.
The following guidelines are provided for patients with baseline values of total bilirubin ≤1.5 X 
ULN and AST and ALT ≤2 X ULN.
•
Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be 
continued on pazopanib with weekly monitoring of liver function until ALT return to 
Grade 1 (NCI CTCAE) or baseline.
•
Patients with ALT of >8 X ULN should have pazopanib interrupted until they return 
to Grade 1 (NCI CTCAE) or baseline. If the potential benefit for reinitiating 
pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then 
reintroduce pazopanib at a reduced dose of 400 mg once daily and measure serum 


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liver tests weekly for 8 weeks. Following reintroduction of pazopanib, if ALT 
elevations >3 X ULN recur, then pazopanib should be permanently discontinued. 
•
If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN 
pazopanib should be permanently discontinued. Patients should be monitored until 
return to Grade 1 (NCI CTCAE) or baseline. Pazopanib is a UGT1A1 inhibitor. Mild, 
indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s 
syndrome. Patients with only a mild indirect hyperbilirubinaemia, known or 
suspected Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed 
as per the recommendations outlined for isolated ALT elevations.
Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations and should 
be undertaken with caution and close monitoring. 
Beyond recommending that patients with mild hepatic impairment are treated with 800 mg 
pazopanib once daily (600 mg daily for this study) and reducing the initial starting dose to 200 
mg per day for patients with moderate impairment, no further dose modification guidelines based 
on results of serum liver tests during therapy have been established for patients with preexisting 
hepatic impairment.
3.3.6.2
Monitoring and management of hypertension
In clinical studies with pazopanib, events of hypertension including hypertensive crisis have 
occurred.  Hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 100 mm Hg) 
occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases 
occurred in the first 18 weeks).
Blood pressure should be well controlled prior to initiating pazopanib (see 2.1.2.5)  
3.3.6.2.1 BP MONITORING:
•
Check BP twice weekly for the first 2 months of therapy, then weekly for 2 months, 
and then once per month thereafter. On days that the patient is not scheduled for 
clinic visits, BP can be taken at home, local Pharmacy or local Physician’s office. 
•
BP should be taken preferably in the morning and after resting for at least 5 minutes.
•
If BP is ≥140/90, then it should be repeated twice (30 and 60 minutes after the first 
reading). The lowest of these 3 readings will be the one considered for grading and 
management purposes. 
•
If BP measured outside the clinic visits is ≥140/90, the result should be immediately 
reported to the Research Nurse and/or treating physician to take appropriate action as 
outlined below.  
BP MANAGEMENT BASED ON GRADE (CTCAE 4.02):
Hypertension- Adverse Event Grade
Management
Grade 1 (systolic 120-139, diastolic 80-
89)
•
no need to modify or add anti BP meds; if the patient 
is already taking BP meds, reinforce need for 
compliance.
•
continue pazopanib and topotecan at same doses.
Grade 2 (systolic BP 140-159 or 
•
add or increase dose of BP meds (at the discretion of 


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diastolic 90-99)*
the treating physician); 
•
continue topotecan; 
•
HOLD pazopanib at the discretion of the treating 
physician until AE recovers to grade 0-1, then restart 
same dose. 
Grade 3 (systolic ≥160 or diastolic ≥100)
•
add or increase dose of BP meds (at the discretion of 
the treating physician); 
•
continue topotecan; 
•
HOLD pazopanib until AE recovers to grade 0-1, 
then restart pazopanib reducing 1 dose level.
Grade 4 (malignant hypertension; 
transient or permanent neurologic 
deficit, hypertensive crisis)
•
DISCONTINUE pazopanib; 
•
patient finishes trial participation.
*Note: for elevated BP to be considered grade 2 or 3 the patient should be previously 
normotensive or should be taking BP medication/s regularly. 
3.3.6.2.2 IF THE PATIENT IS NOT COMPLIANT:
•
REINFORCE need for strict compliance with current BP medication/s, 
•
HOLD pazopanib AND CONTINUE BP monitoring at least once a day until BP 
returns to grade 0-1, 
•
Then resume pazopanib at same dose.
THIS ELEVATED BP WILL NOT BE CONSIDERED AN AE UNLESS THERE IS A 
SECOND OCCURRENCE WHILE TAKING BP MEDICATIONS REGULARLY.  
3.3.6.3
Management of QT Prolongation and Torsade de Pointes:
In clinical studies with pazopanib, events of QT prolongation or Torsade de Pointes have 
occurred. Pazopanib should be used with caution in patients with a history of QT interval 
prolongation, patients taking antiarrythmics or other medications that may potentially prolong 
QT interval, or those with relevant pre-existing cardiac disease. When using pazopanib, baseline 
and periodic monitoring of electrocardiograms and maintenance of electrolytes (calcium, 
magnesium, potassium) within normal range is recommended.
3.3.6.4
Management of Arterial Thrombotic Events: 
In clinical studies with pazopanib, myocardial infarctions, angina, ischemic stroke and transient 
ischemic attack were observed. Fatal events have been observed. Pazopanib should be used with 
caution in patients who are at increased risk of thrombotic events or who have had a history of 
thrombotic events. Pazopanib has not been studied in patients who have had an event within the 
previous 6 months. A treatment decision should be made based upon the assessment of 
individual patient’s benefit/risk.
3.3.6.5
Management of Hemorrhagic Events:
In clinical studies with pazopanib hemorrhagic events have been reported. Fatal hemorrhagic 
events have occurred. Pazopanib has not been studied in patients who had a history of 
hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. 
Pazopanib should be used with caution in patients with significant risk of hemorrhage.


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3.3.6.6
Management of Gastrointestinal Perforations and Fistula:
In clinical studies with pazopanib, events of gastrointestinal (GI) perforation or fistula have 
occurred. Fatal perforation events have occurred. Pazopanib should be used with caution in 
patients at risk for GI perforation or fistula.
3.3.6.7
Wound Healing issues: 
No formal studies on the effect of pazopanib on wound healing have been conducted. Since 
Vascular Endothelial Growth Factor (VEGF) inhibitors may impair wound healing, treatment 
with pazopanib should be stopped at least 7 days prior to scheduled surgery. The decision to 
resume pazopanib after surgery should be based on clinical judgment of adequate wound healing. 
Pazopanib should be discontinued in patients with wound dehiscence.
3.3.6.8
Hypothyroidism: 
In clinical studies with pazopanib, events of hypothyroidism have occurred. Proactive 
monitoring of thyroid function tests is recommended.
3.3.6.9
Proteinuria: 
In clinical studies with pazopanib, proteinuria has been reported. Baseline and periodic 
urinalyses during treatment are recommended and patients should be monitored for worsening of 
proteinuria. Pazopanib should be discontinued if the patient develops nephrotic syndrome.
3.3.6.10 Pregnancy: 
Pre-clinical studies in animals have shown reproductive toxicity. If the patient becomes pregnant 
while receiving pazopanib or topotecan, the potential hazard to the fetus should be explained to 
the patient. Women of childbearing potential should be advised to avoid becoming pregnant 
while receiving treatment with pazopanib or topotecan. Pazopanib or topotecan should not be 
used during pregnancy or lactation.
3.3.6.11 Topotecan-induced neutropenic colitis:
Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic 
colitis have been reported in clinical trials with topotecan. In patients presenting with fever, 
neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis 
should be considered.
3.3.6.12 Interstitial lung disease: 
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which 
have been fatal. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, 
thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors. 
Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, 
dyspnea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is 
confirmed.
3.3.6.13 Diarrhea
Diarrhea, including severe diarrhea requiring hospitalization, has been reported during treatment 
with oral topotecan. The incidence of diarrhea has been reported to be greater in patients 
receiving oral topotecan compared to those receiving topotecan i.v. Additionally, in patients with 
relapsing small cell lung cancer, greater than 65 years of age, there is substantially higher risk of 


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severe diarrhea and subsequent hospitalization than in patients less than 65 years of age. 
Communication with patients prior to drug administration regarding diarrhea and proactive 
management of all signs of diarrhea is important. Physicians are advised to follow guidelines that 
describe the aggressive management of this event. This includes use of anti-diarrheal agents, 
administration of fluids and electrolytes and interruption or discontinuation of therapy with oral 
topotecan. 
Diarrhea related to oral topotecan can occur at the same time as drug-related neutropenia and its 
sequelae.
3.3.6.14 At the Start of the Next Treatment Cycle:
A new course of treatment may begin when the ANC is at least 1500/mm3 and the platelet count 
is at least 75,000/mm3 and any other treatment-related toxicities are less than or equal to grade 1.  
If after a one-week delay, all treatment related toxicities are less than or equal to grade 1, then 
proceed with treatment at the dose level dictated by the modifications outlined above.  If 
treatment related toxicities have not resolved to less than or equal to grade 1 after a one-week 
delay, then treatment will be held again, and the patient will be evaluated weekly.  If treatment 
will be held for 2 weeks for treatment related toxicities, then reduce the pazopanib dose by one 
dose level beyond that indicated by whether or not the patient had DLT in the prior cycle.  If re-
treatment must be held for more than 2 weeks the investigator should be notified.  If a patient 
develops another DLT at the reduced dose or if they experience a life-threatening toxicity at any 
time, they will be removed from study.
3.4
ON STUDY EVALUATION
3.4.1
General Requirements
3.4.1.1
CBC with differential and platelets and serum chemistries and LFTs (ALT, 
AST and bilirubin) will be performed every two weeks X 2, (+/- 3 days) then 
every 4 weeks (+/- 3 days) prior to each cycle during treatment. UPC (+/- 3 
days) will be done monthly prior to each cycle.
3.4.1.2
A brain MRI/CT for group B will be done monthly until 3 months then every 
other month thereafter, for group A scan will be obtained every other month 
prior to initiation of odd numbered 28 days treatment cycles (+/- 3 days).
3.4.1.3
All relevant information regarding drug doses, concomitant medications, and 
doses, measurable lesions with measurements, tumor response, laboratory 
examinations, and treatment-related toxicities shall be documented in the 
patient’s medical record and flow sheets.
3.4.2
A complete Neurologic exam (to include documentation of the patients Karnofsky 
Performance Status) will be performed prior to every evaluation where an MRI is 
scheduled. The MDASI-BT (Appendix 15.5) will be completed at baseline and at the 
time of each evaluation that includes an imaging study. 
3.4.3
The patient will complete the MDASI-BT (see Appendix 15.5) at the time of clinical 
evaluation with MRI as long as the clinical therapy is being administered, unless clinical 
deterioration makes self-report not possible before that time.  The time when patients are 
unable to complete the self-report questionnaires will be used as part of the study 
analysis.  The MDASI-BT will be completed only by the patient, unless changes in vision 


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Page 27 of 96
or weakness make this difficult. If this occurs, then the caregiver or research assistant 
may read the questions to the patient or assist with marking the severity number or score 
as described by the patient. A patient caregiver may complete the questionnaires as a 
patient-preference proxy if the patient’s deficits preclude self-report.
3.4.3.1
A measurement of BP should be taken twice weekly for the first 2 months of 
therapy, then weekly for 2 months, and then once per month thereafter as 
detailed in 3.3.5.2. BP can be assessed by any method (i.e., at home or by 
another physician) as long as the treating physician is informed of the 
measurement, verifies any measurement that is not normal and takes 
appropriate action.
3.4.3.2
Thyroid function test (T4 and TSH) (+/- 3 days) are to be monitored every 8 
weeks (+/- 3 days)
3.4.3.3
EKG before treatment and week 4 and then every 8 weeks until end of 
treatment (+/- 3 days)
3.4.4
Follow-up
Patients will be evaluated for adverse events at the end of each cycle. In addition, all serious 
adverse events will be reported to the NCI BTTC as in section 8.6. 
All patients will be followed for overall survival, when possible.
Patients who discontinue treatment due to progression will be followed for survival every 3 
months.
Patients who come off therapy for reasons other than progression should be followed until 
progression or institution of new anti-tumor therapy.  They should then be followed for survival.
3.5
QUESTIONNAIRES
The MDASI-BT will be utilized for this portion of the study. Full instruments are provided in the 
Appendix 15.5  In addition, information regarding demographics and treatment history will be 
collected as part of the larger study and used in this analysis.   
The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 to 10) to indicate the 
presence and severity of the symptom, with 0 being “not present” and 10 being “as bad as you 
can imagine.” Each symptom is rated at its worst in the last 24 hours. Symptoms included on the 
instrument include those commonly associated with cancer therapies, those associated with 
increased intracranial pressure, and those related to focal deficits.  The questionnaire also 
includes ratings of how much symptoms interfered with different aspects of a patient’s life in the 
last 24 hours. These interference items include: general activity, mood, work (includes both work 
outside the home and housework), relations with other people, walking, and enjoyment of life. 
The interference items are also measured on 0 - 10 scales. The average time to complete these 
instruments is 5 minutes. The MDASI-BT has been translated into 18 languages [17, 20]
3.6
STUDY CALENDAR
Screening
Week 
One
Week 
Two
Every 4 
wks 
Every 8 
wks 
End of 
tx
F/Um
Informed Consent
X


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Screening
Week 
One
Week 
Two
Every 4 
wks 
Every 8 
wks 
End of 
tx
F/Um
History/Physical Exam
X
X
X
NeuroExamk
X
X
Concomitant 
Meds/Adverse Events
X
Vitals signs
X
Xa
Xa
X
X
Performance Status
X
X
X
Treatment Toxicity 
X
X
CBC g 
X
X
X
X
Chemistries, LFTsb
X
Xb
Xb
X
Pregnancy test j
X
X
UPC ratio
X
X
UA
X
Thyroid function test
X
Xc
Coagulation test
X
EKGd
X
Xd
MRI or CT brain
X
Xe
Xf
MDASI-BTl
X
X
X
Tumor tissue
Xi
Hepatitis Questionnaire
X
Hepatitis B and C
Xn
a Monitoring of BP only:  A measurement of BP should be taken twice weekly for the first 2 
months of therapy, then weekly for 2 months, and then once per month thereafter. BP can be 
assessed by any method (i.e., at home or by another physician) as long as the treating physician 
is informed of the measurement, verifies any measurement that is not normal and takes 
appropriate action.
b Monitoring of LFTs:   LFTs (AST, ALT, Bili) every 2 weeks X 2, (+/- 3 days) then every 4 
weeks prior to each cycle during treatment.  (+/- 3 days)
c Thyroid function test (T4 and TSH) are monitored every 8 weeks (+/- 3 days) 
d EKG:  Week 4 and then every 8 weeks until end of treatment (+/-3 days)
e MRI: Group B only: Every 4 weeks until 3 months, then every 8 weeks thereafter (+/- 3 days)
f MRI: Group A only: Scan will be obtained every other month prior to initiation of odd 
numbered 28 day treatment cycles (+/- 3 days)
g CBC: Performed every 2 weeks X 2 (+/- 3 days) then every 4 weeks (+/3 days) prior to each 
cycle. For patients experiencing significant drop in WBCs or platelets felt related to Topotecan, 
CBCs should be obtained more frequently (weekly or more frequently) to assess timing for 
retreatment or need for G-CSF or transfusion support.
i Tumor tissue blocks or 15 unstained paraffin slides to be obtained from institutions where 
surgery performed and provided to collaborating neuro-pathologist for confirmatory tumor 
diagnosis. Patient may be enrolled prior to acquisition of tumor tissue block. 
J Only for women of childbearing potential; must be tested within 14 days prior to starting study 
drugs


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k Complete Neurologic exam will be performed prior to every evaluation where an MRI is 
scheduled.
l MDASI-BT should be completed by patient at the time of clinical evaluation with MRI.
m Patient will be followed for overall survival when possible 
n  If positive (+) response to Hepatitis questionnaire Hepatitis B and C screening test should be 
done.
3.7
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
3.7.1
Criteria for Removal from Protocol Therapy
3.7.1.1
After administration of 12 28-day cycles of treatment, unless further 
treatment is felt to be in the best interest of the patient by the treating 
physician.
3.7.1.2
Progression of disease (as defined in Section 6.4.1).
Patients must be followed by the same type of brain scan, as was used for baseline tumor 
measurements, and will be removed from study if progression is documented after any cycle of 
treatment.  Patients with stable disease, partial or complete response will continue on therapy.
3.7.1.3
Unacceptable toxicity (see Section 3.3).
3.7.1.4
The patient may withdraw from the study at any time for any reason.
3.7.1.5
Medical or psychiatric illness which in the investigator's judgment renders 
the patient incapable of further therapy.
3.7.1.6
Treatment delay due to toxicity greater than 21 days measured from the start 
of the preceding cycle.
3.7.1.7
All reasons for discontinuation of treatment must be documented in the flow 
sheets
3.7.2
Off Study Criteria
All patients will be followed for overall survival, when possible.
Patients who discontinue treatment due to progression will be followed for survival every 3 
months.
Patients who come off therapy for reasons other than progression should be followed until 
progression or institution of new anti-tumor therapy.  They should then be followed for survival.
3.7.3
Off Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
faxed to 301-480-0757.
All subjects must be registered through the NCI Central Registration Office (CRO).  An off-
study form will be supplied by the Coordinating Center, NCI CCR. Send the completed off-study 
form to the Coordinating Center’s Research Nurse; Melanie Herrin, RN; fax: 301-451-5429, 
Melanie.Herrin@nih.gov.


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4
CONCOMITANT MEDICATIONS/MEASURES
4.1
G-CSF ADMINISTRATION
4.1.1.1
If neutrophil count < 1500/mm3 or platelet count < 75,000/mm3, hold 
topotecan until counts resolve to < grade 2 CTC grade toxicity. If neutrophil 
count remains < 1500/mm3 x 1 week or more, granulocyte colony 
stimulating factor may be used to support. If neutrophil count achieves level 
> 1500/mm3, patient may resume treatment with oral topotecan. If toxicities 
do not resolve to < CTC grade 2 after 3 weeks of drug hold, and with G-CSF 
support patient must be removed from study.  Platelet counts that do not 
resolve to < CTC grade 2 after 3 weeks require removal of patient from 
study. 
4.2
CORTICOSTEROIDS 
Corticosteroids should be used in the smallest dose to control symptoms of cerebral edema and 
mass effect, and discontinued if possible. Patients must not be on a dexamethasone dose of 
greater than 16 mg/day.
4.3
ANTI-SEIZURE MEDICATIONS
Anti-seizure medications should be used as indicated. If for unavoidable clinical reasons (severe 
allergies, toxicities, etc.) a patients AED is switched to the alternate AED group the following 
guidelines must be followed:
4.3.1.1
Patients are to be maintained on non-EIAEDS
4.3.1.1.1 Patients who were previously on an EIAED and need to change 
anticonvulsants, should first be started on a non-EIAED. Two weeks 
washout after this change are required before starting treatment on 
study.
4.3.1.1.2 Patients who were previously on a non- EIAED and were 
inadvertently and temporarily changed to an EIAED, should 
immediately be started on another non-EIAED. The patient may 
continue the current treatment dose while a non- EIAED is re-
started.
4.3.1.2
Patients who were previously on a non-EIAED and need to permanently 
change anticonvulsant, but who cannot change to another non-EIAED need 
to be removed from the study due to drug-drug interactions
4.3.1.3
Patients who were previously on a non-EIAED and need to change 
anticonvulsants, should be started on another non-EIAED if at all possible. 
No delays in treatment would be required.
4.4
FEBRILE NEUTROPENIA 
Febrile neutropenia may be managed according to the local institution's Infectious Disease 
Guidelines.  Measures may include appropriate laboratory testing, including blood and urine 
cultures and the institution of broad-spectrum antibiotics.  If a source for the fever is not 


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identified or the fever resolves when the neutrophil count recovers, antibiotics may be 
discontinued and the patient observed.
4.5
ANTI-EMETICS
The use of anti-emetics will be left to the investigators’ discretion.
4.6
OTHER CONCOMITANT MEDICATIONS
Therapies considered necessary for the well-being of the patient may be given at the discretion of 
the investigator. Other concomitant medications should be avoided except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life-threatening medical 
problems.  All concomitant medications must be recorded. For patients with known hypertension 
on BP medications, strict compliance with treatment should be reinforced.
4.7
OTHER ANTICANCER OR EXPERIMENTAL THERAPIES
No other anticancer therapy (including chemotherapy, radiation, hormonal treatment or 
immunotherapy) of any kind is permitted during the study period. No other drug under 
investigation may be used concomitantly with the study drug.
4.8
SURGERY
If neurosurgical management is required for reasons not due to tumor progression, these 
procedures must be documented, including the indications for surgery, the surgical operative 
note and pathology report. If possible defer surgery for 4 weeks from last dose of therapy.  
Patients who undergo resection for presumed tumor progression but are shown to only have 
treatment associated changes (treatment effect or necrosis) can resume treatment once they have 
recovered from the surgical procedure.  Pazopanib treatment can only resume > 28 days after 
surgery.
5
BIOSPECIMEN COLLECTION
5.1
PATHOLOGY REVIEW
Following registration, slides from the most recent pre-registration biopsy must be submitted for 
review.  The purpose of this review is to verify the histologic diagnosis.
The materials are to be submitted after registration step 1 to:
Ken Aldape, MD
Toronto General Hospital
200 Elizabeth Street, 11th Floor
Toronto, Ontario M5G 2C4 Canada
kaldape@gmail.com 
Pathology Materials Required for Review:
1. One to two representative H&E stained slides from a pre-registration biopsy 
demonstrating lesion.
2. A copy of the pathology report and the operative report.
3. The Tissue Collection Shipping Form (see 15.3).
4. The submitting institution is responsible for the costs of shipping and handling.


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6
DATA COLLECTION AND EVALUATION
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant..  Designated research staff from the 
registering institution will enter the data via remote electronic data entry. The protocol specific 
electronic forms are to be used by the participating sites.  All investigators will utilize these 
forms for Baseline, Treatment, Adverse Events, Tumor Evaluation, Off Treatment, Survival, and 
Off-study data.
All data will be kept secure. Personal identifiers will not be used when collecting and storing 
data. An enrollment log will be maintained in the regulatory binder/file which is the only 
location of personal identifiers with unique subject identification number.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.
6.1.1
Source Documentation Timeframes
The following information will be entered into C3D within the indicated timeframes. In addition, 
the source documents should be provided to the NCI BTTC coordinating center research nurse 
within the indicated timeframe.
Data Set / Source Documents
Schedule for Submission
Regulatory Documents
(as described in the BTTC Operations Manual)
Prior to Patient Registration
Eligibility Checklist 
Prior to Patient Registration 
Copy of signed & dated Informed Consent w/ 
HIPAA Authorization
Prior to Patient Registration 
Pathology Report (from the most recent pre-
registration diagnostic biopsy or surgery)
Prior to registration
Baseline Data
(To include prior disease/treatment history, and 
baseline clinical evaluation information)
Within 14 days after the registration date
Baseline MDASI – BT Questionnaire
Within 14 days after the registration date
Baseline Source Documents
Within 14 days after the registration date


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6.1.2
Database Entry Timeframes
The following data should be entered into C3D within the specified timeframes.  Source 
documentation will be kept at the participating site.
Treatment (Cycle) Data
(To include treatment, response, AE, and 
clinical evaluation information)
Within 40 days after the first day of 
each treatment cycle.
Off Treatment Data
Within 10 days after the last date of 
any modality of protocol treatment.
Follow-up (Survival) Data
Within 52 days after the last 
treatment date and then every 90 days 
until Off Study (unless otherwise 
specified by the protocol).
Non-Treatment Data
(May include Quality of Life questionnaires 
(MDASI-BT), Specimen Tracking 
information, Pathology Specimen 
Submission, etc.)
Within 10 days after each scheduled 
assessment, event, or activity.
Off Study Data
Within 10 days after the date the 
patient is removed from the study.
6.1.3
Confidentiality 
All documents, investigative reports, or information relating to the patient are strictly 
confidential. Any patient specific reports (i.e. Pathology Reports, MRI Reports, Operative 
Reports, etc.) submitted to the NCI BTTC Coordinating Center must have the patient’s full name 
& social security number “blacked out” and the assigned patient ID number and protocol number 
written in. Patient initials may be included or retained for cross verification of identification.
6.1.4
Safety Data 
All patients receiving study agents will be evaluated for safety.  The safety parameters include all 
laboratory tests and hematological abnormalities, CNS observations, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by patients.  All 
toxicities encountered during the study will be evaluated according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and recorded prior to each course 
of therapy.  Life-threatening toxicities that are unexpected and assessed to be possibly related to 
the study agent/s should be reported immediately as per section  7.2.
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the Adverse Event Case Report Form and followed as 
appropriate. An adverse event is any undesirable sign, symptom or medical condition occurring 
after starting study drug (or therapy) even if the event is not considered to be related to study 
drug.


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Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment (any procedures specified in the protocol). 
Adverse events occurring before starting study treatment but after signing the informed consent 
form are recorded on the Baseline Evaluations Case Report Form. Abnormal laboratory values or 
test results constitute adverse events only if they induce clinical signs or symptoms or require 
therapy, and are also recorded on the Adverse Events Case Report Form.
6.1.5
Data Sharing with Pharmaceutical Collaborator, Novartis
NCI may share data from this study with its pharmaceutical collaborator, Novartis, pursuant to 
the NCI CDA with Novartis.  Specifically, Novartis may access and review analytical results and 
primary quantitative and empirical data including identifiable private information in accordance 
with the terms of the CDA.
6.2
DATA MONITORING
All submitted data will be monitored by the BTTC Protocol Manager specifically assigned to this 
protocol.  Requests for correction of data deficiencies will be sent via mail to the Institutional 
Coordinator.  Any major deficiencies will be corrected by telephone communication.  All data 
will be monitored for completeness.  Key parameters such as drug dosages including attenuations 
and escalations, toxicity documentation and tumor measurements will be analyzed.  All data 
deficiencies will be corrected within two weeks.
6.3
DATA SHARING PLAN
6.3.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows (check all that 
apply):
X   Coded, Linked data in an NIH-funded or approved public repository.  
__  Coded, Linked data in another public repository.  
X   Identified data in BTRIS (automatic for activities in the Clinical Center)
X   Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
___ I will not share human data generated in this research for future research.  If checked, 
explain:
How and where will the data be shared? 
Data will be shared through (check all that apply):
X  An NIH-funded or approved public repository.  Insert name or names: clinicaltrials.gov
__  Another public repository.  Insert name or names: ____________________________.
X   BTRIS (automatic for activities in the Clinical Center)
X   Approved outside collaborators under appropriate individual agreements.


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X   Publication and/or public presentations.
When will the data be shared? (check all that apply)
X   Before publication.
X   At the time of publication or shortly thereafter.
6.4
RESPONSE CRITERIA
The primary efficacy endpoint is progression free survival (PFS) at six months from patient 
registration for bevacizumab naïve patients and PFS at 3 months for patients with prior 
bevacizumab treatment.  However, objective response status should be measured and recorded.
6.4.1
Definitions of Response
6.4.1.1
Measurable Disease: Bidimensionally measurable lesions with clearly 
defined margins by CT or MRI scan.
6.4.1.2
Evaluable Disease: Unidimensionally measurable lesions, masses with 
margins not clearly defined. 
6.4.1.3
Non-Evaluable Disease: Not Applicable for response evaluation
6.4.1.4
Objective Status, To Be Recorded at Each Evaluation: If there are too many 
measurable lesions to measure at each evaluation, choose the largest two to 
be followed before a patient is entered on study.  The remaining lesions will 
be considered evaluable for the purpose of objective status determination.  
Unless progression is observed, objective status can only be determined 
when ALL measurable and evaluable sites and lesions are assessed.
6.4.1.4.1 Complete Response (CR):  Complete disappearance of all 
measurable and evaluable disease.  No new lesions.  No evidence of 
non-evaluable disease.  All measurable, evaluable and non-evaluable 
lesions and sites must be assessed using the same techniques as 
baseline.  Patients must be on no steroids.
6.4.1.4.2 Partial Response (PR):  Greater than or equal to 50% decrease under 
baseline in the sum of products of perpendicular diameters of all 
measurable lesions.  No progression of evaluable disease.  No new 
lesions.  All measurable and evaluable lesions and sites must be 
assessed using the same techniques as baseline. The steroid dose at 
the time of the scan evaluation should be no greater than the 
maximum dose used in the first 8 weeks from initiation of therapy.
6.4.1.4.3 Partial Response, Non-Measurable (PRNM): Not applicable.
6.4.1.4.4 Stable/No Response: Does not qualify for CR, PR, or progression.  
All measurable and evaluable sites must be assessed using the same 
techniques as baseline.  The steroid dose at the time of the scan 


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evaluation should be no greater than the maximum dose used in the 
first 8 weeks from initiation of therapy.
6.4.1.4.5 Progression: 25% increase in the sum of products of all measurable 
lesions over smallest sum observed (over baseline if no decrease) 
using the same techniques as baseline, OR clear worsening of any 
evaluable disease, OR appearance of any new lesion/site, OR clear 
clinical worsening or failure to return for evaluation due to death or 
deteriorating condition (unless clearly unrelated to this cancer). 
Patients will also be considered to have progressive disease if there 
is significant increase in T2/FLAIR non-enhancing lesions AND 
clinical progression. (See section 6.4.1 and 6.3.7 for definitions). To 
be considered progressive disease, increase in T2/FLAIR should 
occur on stable or increasing doses of corticosteroids compared to 
baseline scan or best response following initiation of therapy, and 
should not be due to co-morbid events (e.g. radiation therapy, 
demyelination, ischemic injury, infection, seizures, post-operative 
changes, or other treatment effects).
6.4.1.4.6 Unknown: Progression has not been documented and one or more 
measurable or evaluable sites have not been assessed.
6.4.2
Best Response: This will be calculated from the sequence of objective statuses.
For patients with all disease sites assessed every evaluation period, the best response will be 
defined as the best objective status as measured according to Section 6.4.1.  If the response does 
not persist at the next regular scheduled MRI, the response will still be recorded based on the 
prior scan, but will be designated as a non-sustained response.  If the response is sustained, e. g. 
still present on the subsequent MRI, it will be recorded as a sustained response, lasting until the 
time of tumor progression.  Best response is unknown if the patient does not qualify for a best 
response or increasing disease and if all objective status determinations before progression are 
unknown.
6.4.3
Neurological Exam: Although not used for determining response, it is useful to evaluate 
improvement in the neurologic exam, (as compared to the baseline assessment), that 
should coincide with objective measurement of tumor size. 
+1
Better
  0
Unchanged
-1
Worse
B
Baseline


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6.4.4
Performance Status: Patients will be graded according to Karnofsky Performance Status 
(See Appendix 15.1). Clinical progression can be declared if there is a decrease in 100 or 
90 to 70 or less, at least 20 from 80 or less, or decline in KPS from any baseline to 50 or 
less, for at least 7 days and not attributable to comorbid events or change in steroid dose.
6.4.5
Time to Treatment Failure: From date of registration to the date of first observation of 
progressive disease (as defined in Section 6.4 .1.4.5), non-reversible neurologic 
progression or permanently increased steroid requirement (applies to stable disease only), 
death due to any cause, or early discontinuation of treatment. 
6.4.6
Time to Death: From date of registration to date of death due to any cause.
6.4.7
Documenting FLAIR: investigators will be asked to measure tumor related changes on 
FLAIR sequence as best as possible, as non-enhancing patterns of recurrence can 
occur.  If this occurs within the setting of clinical progression not caused by seizures or 
other identifiable cause, the patient will be considered to have progressive disease. Please 
see section 6.4.1 for definition of clinical progression.
Presumed non-enhancing tumor without clinical progression should be observed. The time of 
progression if eventual clinical deterioration occurs can be back dated to the time of the increase 
in non-enhancing tumor. Investigators will also be asked to document if recurrence of disease is 
multifocal.
6.5
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.


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7.2.3
Multi-Institutional Guidelines
7.2.3.1
IRB Approvals 
The Administrative PI will provide the NIH Intramural IRB with a copy of the participating 
institution’s approved yearly continuing review.  Registration will be halted at any participating 
institution in which a current continuing approval is not on file at the NIH Intramural IRB.
7.3
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.3.1
Principal Investigator/Research Team 
The clinical research team will have a teleconference every other week when patients are being 
actively treated on the trial to discuss each patient. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the Principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using eIRB system. 
The Principal Investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The Principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.3.2
NCI BTTC Coordinating Center Monitoring Plan
This trial will be monitored by personnel employed by Harris Technical Services on contract to 
the NCI, NIH. Monitors are qualified by training and experience to monitor the progress of 
clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial 
conduct.
At least 25% of enrolled patients will be randomly selected and monitored at least biannually or 
as needed, based on accrual rate. The patients selected will have 100% source document 
verification done. Additional monitoring activities will include: adherence to protocol specified 
study eligibility, treatment plans, data collection for safety and efficacy, reporting and time 
frames of adverse events to the NIH Intramural IRB and FDA, and informed consent 
requirements. Written reports will be generated in response to the monitoring activities and 
submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, 
NCI.
7.3.3
Safety Monitoring Committee (SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial 
review will occur as soon as possible after the annual NIH Intramural IRB continuing review 
date.   Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC.   For initial and subsequent 


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reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
SAFETY REPORTING TO BTTC
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
A congenital anomaly/birth defect.
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.
8.2
ASSESSING CAUSALITY
Investigators are required to assess whether there is a reasonable possibility that the study agent/s 
caused or contributed to an adverse event.  The following general guidance may be used.


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Yes:
If the temporal relationship of the clinical event to the study agent/s 
administration makes a causal relationship possible, and other drugs, therapeutic 
interventions or underlying conditions do not provide a sufficient explanation for the 
observed event.
No:
If the temporal relationship of the clinical event to the study agent/s 
administration makes a causal relationship unlikely, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the observed 
event.
8.3
PROTOCOL SPECIFIC DEFINITIONS
Events not considered to be serious adverse events are hospitalizations for the purposes of this 
protocol and include: 
•
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
•
treatment, which was elective or pre-planned, for a pre-existing condition that did 
not worsen
•
treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission.
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form and be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and the presence or absence of any birth defects or 
congenital abnormalities.
8.4
GUIDELINES & PROCEDURES FOR REPORTING DEVIATIONS AND UNANTICIPATED 
PROBLEMS
Neither the FDA nor the ICH GCP guidelines define the term “protocol deviation.”  The 
definition is often left to the Lead Institution IRB.  Accordingly, since NCI, Center for Cancer 
Research is the Coordinating Center and the Administrative PI must adhere to those policies set 
by the NIH Intramural IRB, the definitions for unanticipated problem and protocol deviation as 
described in Policy 801 will be applied for reporting purposes for all institutions participating in 
the NCI Center for Cancer Research Multi-center Project. 
Protocol Deviations or Unanticipated problems occurring at a participating institution will be 
submitted to that institution’s own IRB in accordance with local policies and procedures.   
However, the participating institution must submit a report to the BTTC Coordinating Center 
even in instances where the local IRB does not require a report. 
Deviations or Unanticipated problems must be submitted to the NCI BTTC Coordinating Center 
within 5 working days after becoming aware of the event (if not reportable to the local IRB). 
When Deviations or Unanticipated Problems are reported to BTTC, but, the local IRB does not 
require a report, the report that is submitted to the NCI BTTC Coordinating Center must be 
accompanied by a formal memo explaining the local policy and the rationale for not reporting 
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Deviation or Unanticipated problem Reports and any accompanying documentation (to include 
the local IRB acknowledgement of the event when applicable) are to be submitted to the NCI 
BTTC Coordinating Center using the problem report form in Appendix 15.9  via fax at: 301-451-
5429.
NCI Center for Cancer Research Coordinating Center:  Upon receipt of the 
deviation/unanticipated problem report from the participating institution, the NCI BTTC 
Coordinating Center will submit the report to the Academic PI for review. 
8.5
REPORTING TO THE STUDY DRUG MANUFACTURER (NOVARTIS)
The NCI BTTC Coordinating Center will forward all SAE reports to the lead IRB via the lead 
investigator, FDA (when applicable), and Novartis:
Novartis Pharmaceuticals Corporation
FAX:  888-299-4565
SAEs will be forwarded to Novartis via the NCI BTTC Coordinating Center in accordance 
with the following:
All serious adverse events should be reported to Novartis within 24 hours.  In the event of an 
SAE, the investigator should refer to the Pharmacovigilance section of the contract for reporting 
procedures.  In brief:
The Investigator/Sponsor may report serious adverse drug reactions 
(SADRs) using either: 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html  
OR
A MedWatch form available at http://www.fda.gov/medwatch/ 
Occasionally BTTC may contact the reporter for additional information, clarification, or current 
status of the subject for whom an adverse event was reported. 
8.6
GUIDELINES FOR REPORTING SERIOUS ADVERSE EVENTS TO BTTC
What to Report?
When to Report?
1. All Deaths, except that due to 
progressive disease, occurring from the 
time the consent is signed through 30 
days after the last day of active 
treatment
Within 1 working day (24 hours) from the 
time the research team becomes aware of 
event


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What to Report?
When to Report?
2. Other Serious Unexpected Suspected 
Adverse Reactions (that did not result in 
death) occurring from the time the 
consent is signed through 30 days after 
the last day of active treatment
Within 5 working days from the time the 
research team becomes aware of event
3. All protocol deviations, non-compliance 
and unanticipated problems
Within 5 working days from the time the 
research team becomes aware of event
4. Pregnancy, although not itself a serious 
adverse event, should also be reported 
on a serious adverse event form and be 
followed up to determine outcome, 
including spontaneous or voluntary 
termination, details of birth, and the 
presence or absence of any birth defects 
or congenital abnormalities.
Within 5 working days from the time the 
research team becomes aware of event
The CCR problem report form will be used to submit adverse events to BTTC.  See Appendix 
15.9. Participating centers must also submit the report to their IRB in accordance with their 
institutional policies. 
The BTTC Coordinating Center will maintain documentation of all Serious Adverse Events from 
each institution. The BTTC Coordinating Center will notify all investigators of any serious and 
unexpected adverse experiences that are possibly related to the study agent/s.  The investigators 
are to file a copy with their protocol file and send a copy to their IRB according to their local 
IRB’s policies and procedures. 
9
STATISTICAL CONSIDERATIONS
For this study, since there is experience with the drug combination a formal DSMB review will 
not be necessary. 
Time to progression and overall survival will be evaluated using the Kaplan-Meier product-limit 
survival curve methodology.  Six-month Progression Free Survival (PFS) will be estimated using 
Kaplan-Meier estimates and associated two-sided 95% confidence intervals.  
Recurrent glioblastoma with no prior exposure to bevacizumab cohort (Group A):  A 
maximum of 34 patients will be observed in a two-stage Simon optimum design.  In the first 
stage, 9 patients will be accrued.  If two or more patients are progression-free at 6 months 
(PFS6), an additional 25 patients will be accrued. We halt registering patients after 9 patients 
until we have at least 2 patients are progression free at six months.  If 9 or more out of 34 have 
PFS6, then the study will be declared promising. This study has a 5% chance of declaring 
promise if the PFS6 rate is at most 15%.  It has an 80% chance of declaring promise if the PFS 
rate is at least 35%. 
Recurrent glioblastoma with prior exposure to bevacizumab cohort (Group B):  In the 
group that failed bevacizumab, a maximum of 32 patients will be observed in a two-stage Simon 


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optimum design. In the first stage, 14 patients will be accrued.  If one or more patients is 
progression-free at 3 months (PFS3), an additional 18 patients will be accrued.  We will halt 
registration after 14 patients until at least 1 patient is progression free at 3-months.  If 2 or more 
out of 32 have PFS3, then the study will be declared promising.  This study has a 5% chance of 
declaring promise if the PFS3 rate is at most 1%.  It has an 80% chance of declaring promise if 
the PFS rate is at least 12%. 
In both patient cohorts, for patients who drop out for reasons other than PD or toxicity, we will 
replace them. We expect the dropout rate to be not more than 10%, therefore in general it is not 
an issue to implement the design. The patients who drop out due to toxicity will be counted as 
treatment failure when implementing the Simon’s two stage design and assessing the 6-month 
PFS rate in either cohort. 
The trial will be monitored by the Academic PI, Morris D. Groves, MD, and the study 
statistician, Yuan Ying, PhD.
We will monitor the toxicity based on the combined data from the above two cohorts with a total 
sample size of 66. All grade 3 or greater toxicities attributable to the study treatment will be 
counted. Accrual will be temporarily suspended for analysis after each of the following interim 
accrual goals. We will monitor the toxicity when the accrual is 5, 10, 20, 35, and 50 based on 
using the following stopping rule: if the posterior probability of toxicity greater than 0.3 is 
greater than 0.95 (i.e., Pr (toxicity>0.3|data) >0.95), we terminate the study for toxicity. 
Assuming the beta prior Beta (0.6, 1.4) for the toxicity, we have the following operating 
characteristics. 
Operating characteristics of the proposed stopping rule 
True toxicity probability
0.2
0.3
0.4
0.5
Stopping Probability
1.3%
12.4%
55.0%
92.7%
Average number of patients 
treated
65.3
60.3
43.9
24.2
We obtain the following stopping boundary: the study will be terminated if we observe >= 4/5, 
6/10, 10/20, 16/35, 21/50 (# of patients experienced DLTs/# of patients treated).  Note that our 
safety monitoring starts with a small cohort size of 5, and then gradually increases to 15. 
Therefore, if the treatment agents are overly toxic, the trial will stop before exposing many 
patients to toxicities.
Patient-reported outcomes:  The sample size for this trial was based on the primary endpoint of 
the study.
Received MDASI-BT forms will be checked versus the timing schedule and considered as valid 
if they fall within ten days of the scheduled assessment.  Compliance rates will be calculated as 
the number of received valid forms over the number of expected forms. Differences between 
groups in compliance will be tested by use of Fisher’s exact test at every time point.
We will use descriptive statistics to describe how patients rate symptom severity and interference 
with function at each time point.  Error bar graphs for each of the symptoms will be constructed 
at each time point.  The proportion of patients rating their symptoms to be 7 or greater (on a 0-10 
scale) will also be reported.  We will construct individual patient profiles for each of the selected 
symptoms to describe the individual patients’ patterns of change over time. We will calculate the 


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mean core symptom severity, mean severity of the MDASI-BT and mean symptom interference 
at the time of clinical evaluation. Estimates of differences in the mean symptom severity and 
mean symptom interference between responders and non-responders will be estimated in the 
intent to treat population.  All patients with at least one valid questionnaire will be included in 
the analyses.  Questionnaires completed at study registration will be considered baseline.  All 
questionnaire data received after randomization will be used in the primary analyses.
Differences of at least 2 points will be classified as the minimum clinically meaningful change in 
the symptom severity and symptom interference measures. For example, an increase of 2 points 
or more would mean a moderate improvement, whereas a decrease of 2 points or more would be 
interpreted as moderate worsening. For individual symptoms, a rise in a symptom score means 
deterioration, whereas a reduced score means improvement of the specific symptom.
10 COLLABORATIVE AGREEMENTS 
10.1 AGREEMENT TYPE
There is a BTTC consortia agreement in place between all of the participating institutions listed 
on the title page of this study.  In addition, there is a CDA (13618-17) in place with Novartis.  
Other agreements are found in Appendix 15.13, Technology Transfer Agreements. 
11 HUMAN SUBJECTS PROTECTIONS
11.1 RATIONALE FOR SUBJECT SELECTION
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  Males and females will be recruited with no preference to 
sex.  No exclusion to this study will be based on race.  Minorities will actively be recruited to 
participate.  High grade gliomas occur in patients of all races and although there is a slight 
predominance in men, this is a disease that is also common in women.  The molecular targets of 
pazopanib and topotecan within the tumor are not known to be different among patients based on 
sex or race; hence this study will be open to all adults.
11.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have glioblastoma, and because of unknown toxicities of the study agents in the 
pediatric patient.  Furthermore, the targets of the pazopanib and topotecan are not as prevalent in 
pediatric malignant gliomas and therefore, the efficacy of this regimen will be initially 
determined in the adult population before consideration of its use in pediatrics.
11.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The primary risk to patients participating in this research study is from the toxicity of pazopanib 
and topotecan, or both drugs.  Both are investigational agents in the treatment of gliomas, 
although bevacizumab is an FDA-approved drug for the treatment of colorectal carcinoma.  The 
protocol provides for detailed and careful monitoring of all patients to assess for toxicity.  
Toxicity data from the current dose level will be collected and reviewed to ensure that there were 
no severe toxicities that would preclude further patient enrollment.  Patients will be treated with 
therapeutic intent and response to the therapy will be closely monitored. 


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11.4 RISKS/BENEFITS ANALYSIS
11.4.1 Benefits
The potential benefit to a patient on this study is a reduction in the bulk of their tumor and 
improvement in cancer lesions, which may or may not have favorable impact on symptoms 
and/or survival.  
11.4.2 Risks
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document.  Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents.
11.4.3 Risks/Benefits Analysis
The potential benefits from this therapy are disease stabilization or shrinkage and a reduction in 
symptoms caused by the brain tumor such as neurological deficits and headache.  Given the 
efforts to minimize risk with the administration of this combination, this protocol involves 
greater than minimal risk, but presents the potential for direct benefit to individual subjects.
11.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
All patients who are being considered for this trial will undergo informed consent prior to being 
enrolled on the trial. The PI or associate investigator will perform the consenting process. 
Patients and family members when applicable will be asked to read the consent and will be 
encouraged to ask questions. It will be stated clearly that participation in the research study is 
voluntary and that participants can withdraw from the study without losing benefits they would 
otherwise be entitled to. Patients will be enrolled after the consent document has been signed. 
Separate consents will be obtained for any surgical procedures performed.  The informed consent 
process will be documented in the patient’s medical record and on the informed consent 
document. This process will be performed by the local Principal Investigator or designee.
If new safety information results in significant changes in the risk/ benefit assessment, the 
consent form will be reviewed and updated as necessary. All subjects (including those already 
being treated) will be informed of the new information, be given a copy of the revised form, and 
be asked give their consent to continue in the study.
12 REGULATORY AND OPERATIONAL CONSIDERATIONS 
12.1 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 


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Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
12.2 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the NCI has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.
12.3 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NCI CCR. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by NCI CCR research staff will be secured and 
password protected. At the end of the study, all study databases will be archived at the NCI CCR
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 


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local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
13 PHARMACEUTICAL INFORMATION 
There will be no IND obtained for the use of Topotecan or Pazopanib for this study. 
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling;
the drugs are already approved and marketed and the investigation is not intended to support a 
significant change in advertising; and the investigation does not involve a route of administration 
or dosage level in use in a patient population or other factor that significantly increases the risks 
(or decreases the acceptability of the risks) associated with the use of the drug product.
13.1 DRUG NAME: HYCAMTIN (TOPOTECAN HYDROCHLORIDE)
13.1.1 Chemical Name:(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-  
dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione 
monohydrochloride
13.1.2 Molecular Formula: C23H23N3O5 •HCl  
13.1.3 Molecular Weight: 457.9 g/mol
13.1.4 Appearance: Topotecan hard capsule, 0.25 mg: Opaque white to yellowish white, 
imprinted with HYCAMTIN 0.25 mg. Each hard capsule contains topotecan 
hydrochloride equivalent to 0.25 mg topotecan free base. 
13.1.5 Storage and Stability: Store refrigerated 2º to 8ºC (36º to 46ºF). Store the bottles 
protected from light in the original outer cartons.
13.1.6 Mechanism of Action: The anti-tumor activity of topotecan involves the inhibition of 
topoisomerase-I, an enzyme intimately involved in DNA replication as it relieves the 
torsional strain introduced ahead of the moving replication fork. Topotecan inhibits 
topoisomerase-I by stabilizing the covalent complex of enzyme and strand-cleaved DNA 
which is an intermediate of the catalytic mechanism. The cellular sequela of inhibition of 
topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand 
breaks.
13.1.7 Pharmacology 
The pharmacokinetics of topotecan after oral administration have been evaluated in cancer 
patients following doses of 1.2 to 3.1 mg/m2 and 4 mg/dose administered daily for 5 days.
13.1.7.1 Absorption
Topotecan is rapidly absorbed with peak plasma concentrations occurring between 1 to 2 hours 
following oral administration. Following co-administration of the ABCG2 (BCRP) and ABCB1 
(P-gp) inhibitor, elacridar (GF120918) at 100 to 1000 mg with oral topotecan, the AUC0-inf of 


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topotecan lactone and total topotecan increased approximately 2.5-fold. Administration of oral 
cyclosporin A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and ABCC1 (MRP-1) as 
well as the metabolizing enzyme CYP3A4, within 4 hours of oral topotecan increased the dose-
normalized AUC0-24h of topotecan lactone and total topotecan approximately 2.0- and 2.5-fold, 
respectively. Following a high-fat meal, the extent of exposure was similar in the fed and fasted 
state while tmax was delayed from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total 
topotecan). 
13.1.7.2 Distribution 
The binding of topotecan to plasma proteins was low (35%) and its distribution between blood 
cells and plasma was homogeneous.
13.1.7.3 Metabolism
A major route of inactivation of topotecan is a reversible pH-dependent ring opening to the 
inactive carboxylate form. Metabolism accounts for less than 10% of the elimination of 
topotecan. An N-desmethyl metabolite was found in urine, plasma, and feces. Following oral 
administration the mean metabolite: parent AUC ratio was less than 10% for both total topotecan 
and topotecan lactone. An O-glucuronide of topotecan and N-desmethyl topotecan has been 
identified in the urine. In vitro, topotecan did not inhibit human cytochrome P450 enzymes 
CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A nor did it 
inhibit the human cytosolic enzymes dihydropyrimidine dehydrogenase or xanthine oxidase.
13.1.7.4 Elimination 
Following oral administration, the plasma concentrations decline bi-exponentially. The 
pharmacokinetics of oral topotecan are approximately dose proportional. There is little or no 
accumulation of either formulation of topotecan with repeated daily dosing, and there is no 
evidence of a change in the pharmacokinetics with multiple dosing. The pharmacokinetics of 
topotecan after oral administration have been evaluated in cancer patients following doses of 1.2 
to 3.1 mg/m2 and 4 mg/dose administered daily for 5 days. Oral topotecan exhibits a mean 
terminal half-life of approximately 3.0 to 6.0 hours. Overall recovery of drug-related material 
following five daily doses of topotecan was 49% to 71% of the administered oral dose. 
Approximately 20% was excreted as total topotecan and 2% was excreted as N-desmethyl 
topotecan in the urine. Fecal elimination of total topotecan accounted for 33% while fecal 
elimination of N-desmethyl topotecan was 1.5%. Overall, the N-desmethyl metabolite 
contributed a mean of less than 6% (range 4–8%) of the total drug related material accounted for 
in the urine and feces.
13.1.8 Special Patient Populations 
A cross-study analysis in 217 patients with advanced solid tumors indicated that age and sex did 
not significantly affect the pharmacokinetics of oral topotecan.
13.1.8.1 Renal impairment 
Patients with small cell lung carcinoma who participated in oral topotecan clinical trials had a 
serum creatinine less than or equal to 1.5 mg/dL (133umol/L) or a creatinine clearance (CrCl) of 
greater than or equal to 60 mL/min. Dosing recommendations for patients receiving oral 
topotecan with CrCl less than 60 mL/min have not been established. 


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13.1.8.2 Hepatic impairment 
Pharmacokinetics of oral topotecan has not been specifically studied in patients with impaired 
hepatic function.
13.1.9 Pre-clinical Toxicology:
13.1.9.1 Carcinogenesis, mutagenesis
The carcinogenic potential of topotecan has not been studied. In common with a number of other 
cytotoxic agents, and resulting from its mechanism of action, topotecan is genotoxic to 
mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and mouse bone 
marrow cells in vivo.
13.1.9.2 Reproductive toxicology
As with other cytotoxics, topotecan was also shown to cause embryo-fetal toxicity when given to 
rats (0.59 mg/m2/day) and rabbits (1.25 mg/m2/day) at doses less than the clinical i.v. dose in 
humans (1.5 mg/m2/day). A dose of 0.59 mg/m2 was teratogenic in rats (predominantly effects of 
the eye, brain, skull and vertebrae).
13.1.10 Human Toxicity: 
13.1.10.1 Adverse Reactions
13.1.10.1.1 Infections and infestations
Very Common 
Infection
Common 
Sepsis
13.1.10.1.2 Blood and lymphatic system disorders
Very Common 
Anaemia, febrile neutropenia, leucopenia, 
neutropenia , thrombocytopenia
Common 
Pancytopenia
Not Known 
Severe bleeding (associated with thrombocytopenia)
13.1.10.1.3 Immune system disorders
Common 
Hypersensitivity, including rash
13.1.10.1.4 Metabolism and nutrition disorders
Very Common 
Anorexia (which may be severe)
13.1.10.1.5 Respiratory, thoracic and mediastinal disorders
Rare 
Interstitial lung disease
13.1.10.1.6 Gastrointestinal disorders
Very Common 
Diarrhea (see Warnings and Precautions), nausea 
and vomiting (all of which may be severe), 
abdominal pain*, constipation and stomatitis.
With oral topotecan, the overall incidence of drug-related diarrhea was 22%, including 4% with 
Grade 3 and 0.4% with Grade 4. With oral topotecan, drug-related diarrhea was more frequent in 
patients greater than or equal to 65 years of age (28%) compared to those less than 65 years of 


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age (19%). After i.v. topotecan, drug-related diarrhea in patients greater than 65 years of age was 
10%.
*Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a 
complication of topotecan-induced neutropenia.
13.1.10.1.7 Hepatobiliary disorders
Common 
Hyperbilirubinaemia
13.1.10.1.8 Skin and subcutaneous disorders
Very Common 
Alopecia
13.1.10.1.9 General disorders and administrative site conditions
Very Common 
Asthenia, fatigue, pyrexia
Common 
Malaise
Very Rare 
Extravasation (i.v. formulation only)
13.1.10.2 Integrated safety data
Safety data is presented on an integrated data set of 682 patients with relapsed lung cancer 
administered 2536 courses of oral topotecan monotherapy (275 patients with relapsed SCLC and 
407 with relapsed non-SCLC) (see Adverse Reactions).


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13.1.10.2.1 Hematological
13.1.10.2.1.1 Neutropenia: Severe neutropenia (Grade 4 - neutrophil count less than 0.5 x 
109/L) occurred in 32% of patients in 13% of courses. Median time to onset of 
severe neutropenia was Day 12 with a median duration of 7 days. In 34% of courses 
with severe neutropenia, the duration was greater than 7 days. In course 1 the 
incidence was 20%, by course 4 the incidence was 8%. Infection, sepsis and febrile 
neutropenia occurred in 17%, 2%, and 4% of patients respectively. Death due to 
sepsis occurred in 1% of patients. Growth factors were administered to 19% of 
patients in 8% of courses.
13.1.10.2.1.2 Thrombocytopenia: Severe thrombocytopenia (Grade 4 - platelets less than 10 x 
109/L (as defined by v2 of CTC criteria)) occurred in 6% of patients in 2% of 
courses. Median time to onset of severe thrombocytopenia was Day 15 with a 
median duration of 2.5 days. In 18% of courses with severe thrombocytopenia the 
duration was greater than 7 days. Moderate thrombocytopenia (Grade 3 - platelets 
between greater than or equal to 10 and less than 50 x 109/L) occurred in 29% of 
patients in 14% of courses. Platelet transfusions were given to 10% of patients in 4 
% of courses. Reports of significant sequelae associated with thrombocytopenia 
including fatalities due to tumor bleeds have been infrequent. 
13.1.10.2.1.3 Anemia: Moderate to severe anemia (Grade 3 and 4 - Hb less than 8.0 g/dl) 
occurred in 25% of patients (12% of courses). Median time to onset of moderate to 
severe anemia was Day 12 with a median duration of 7 days. In 46% of courses with 
moderate to severe anemia the duration was greater than 7 days. Red blood cell 
transfusions were given in 30% of patients (13% of courses). Erythropoietin was 
administered to 10% of patients in 8% of courses. 
13.1.10.2.2 Non-hematological 
The most frequently reported non-hematological adverse reactions, all cases irrespective of 
associated causality were nausea (37%), diarrhea (29%), fatigue (26%), vomiting (24%), 
alopecia (21%) and anorexia (18%). For severe cases (CTC grade 3/4) reported as 
related/possibly related to topotecan administration the incidence was diarrhea 5%, fatigue 4%, 
vomiting 3%, nausea 3% and anorexia 2%. 
The overall incidence of drug-related diarrhea was 22%, including 4% with Grade 3 and 0.4% 
with Grade 4. Drug-related diarrhea was more frequent in patients greater than or equal to 65 
years of age (28%) compared to those less than 65 years of age (19%). Loperamide was 
administered to 13% of patients in 5% of courses. The median time to onset of grade 2 or worse 
diarrhea was 9 days. 
Complete alopecia related/possibly related to topotecan administration was observed in 9% of 
patients and partial alopecia related/possibly related to topotecan administration in 11% of 
patients.
13.1.10.3 Special Warnings and Precautions for Use
Topotecan is approved for treatment of patients with ovarian, cervical cancers and small cell 
lung cancer.  There is less experience in treating primary brain tumor patient, thus there is always 
potential for unexpected adverse events.


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13.1.10.3.1 Pregnancy: Topotecan is contraindicated during pregnancy and 
during breast-feeding.
Women of childbearing potential must be apprised of the potential hazard to the fetus, which 
includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity).
Topotecan has been shown to be both embryotoxic and fetotoxic in preclinical studies. As with 
other cytotoxic drugs, topotecan may cause fetal harm when administered to pregnant women 
and therefore is contraindicated during pregnancy. Women should be advised to avoid becoming 
pregnant during therapy with topotecan and to inform the treating physician immediately should 
this occur.
Topotecan is contraindicated during breast-feeding. Topotecan should not be used during 
pregnancy. 


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13.1.10.3.2 Effects on ability to drive and use machines: Caution should be 
observed when driving or operating machinery if fatigue and 
asthenia persist.
13.1.10.3.3 Patients with Hepatic Impairment: Pharmacokinetics of oral 
topotecan have not been specifically studied in patients with 
impaired hepatic function.
13.1.10.3.4 Patients with Renal Impairment: Patients with small cell lung 
carcinoma who participated in oral topotecan clinical trials had a 
serum creatinine less than or equal to 1.5 mg/dL (133umol/L) or a 
creatinine clearance (CrCl) of greater than or equal to 60 mL/min. 
Dosing recommendations for patients receiving oral topotecan with 
CrCl less than 60 mL/min have not been established.
13.1.10.3.5 Carcinogenesis, Mutagenesis, Impairment of Fertility: The 
carcinogenic potential of topotecan has not been studied. In common 
with a number of other cytotoxic agents, and resulting from its 
mechanism of action, topotecan is genotoxic to mammalian cells 
(mouse lymphoma cells and human lymphocytes) in vitro and mouse 
bone marrow cells in vivo. As with other cytotoxics, topotecan was 
also shown to cause embryo-fetal toxicity when given to rats (0.59 
mg/m2/day) and rabbits (1.25 mg/m2/day) at doses less than the 
clinical i.v. dose in humans (1.5 mg/m2/day). A dose of 0.59 mg/m2 
was teratogenic in rats (predominantly effects of the eye, brain, skull 
and vertebrae).
13.1.10.3.6 Pediatric Use:  Use in children is not recommended as only 
limited data are available.
13.1.10.3.7 Geriatric Use:  No overall differences in effectiveness were 
observed between patients over 65 years and younger adult patients. 
However, it has been reported that patients older than 65 years old 
receiving topotecan experienced an increase in drug related diarrhea 
compared to those younger than 65 years of age.
13.1.10.3.8 Capsules:
Interaction with Other Medications: As with other myelosuppressive cytotoxic agents, greater 
myelosuppression is likely to be seen when topotecan is used in combination with other 
cytotoxic agents (e.g. paclitaxel or etoposide) thereby necessitating dose reduction. However, in 
combining with platinum agents (e.g. cisplatin or carboplatin), there is a distinct sequence-
dependent interaction depending on whether the platinum agent is given on day 1 or 5 of the 
topotecan dosing. If the platinum agent is given on day 1 of the topotecan dosing, lower doses of 
each agent must be given compared to the doses which can be given if the platinum agent is 
given on day 5 of the topotecan dosing. When topotecan (0.75 mg/m2/day for 5 consecutive 
days) and cisplatin (60 mg/m2/day on Day 1) were administered intravenously in 13 patients with 
ovarian cancer, mean topotecan plasma clearance on Day 5 was slightly reduced compared to 
values on Day 1. As a result, systemic exposure of total topotecan, as measured by AUC and 
Cmax, on Day 5 were increased by 12% (95% CI; 2%, 24%) and 23% (95% CI; —7%, 63%), 


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respectively. No pharmacokinetic data are available following topotecan (0.75 mg/m2/day for 3 
consecutive days) and cisplatin (50 mg/m2/day on Day 1) in patients with cervical cancer.
When oral topotecan was combined with cisplatin in a randomized Phase 3 study in 
chemotherapy-naïve, extensive disease, small cell lung cancer patients, the regimen of oral 
topotecan (1.7 mg/m2/d for 5 days) with i.v. cisplatin (60 mg/m2 on day 5) was selected.
Topotecan is a substrate for both ABCG2 (BCRP) and ABCB1 (P-glycoprotein). Inhibitors of 
ABCB1 and ABCG2 (eg. elacridar) administered with oral topotecan increased topotecan 
exposure. The effect of elacridar on the pharmacokinetics of intravenous topotecan was much 
less than the effect on oral topotecan Cyclosporin A (an inhibitor of ABCB1, ABCC1 [MRP-1], 
and CYP3A4) with oral topotecan increased topotecan AUC. 
Patients should be carefully monitored for adverse events when oral topotecan is administered 
with a drug known to inhibit ABCG2 or ABCB1.
The pharmacokinetics of topotecan after oral administration were generally unchanged when 
coadministered with ranitidine.
Table of oral topotecan drug interactions is below. This table is also included in Appendix 15.6
Breast Cancer Resistance Protein (ABCG2, BCRP, MXR) Inhibitors and 
Inducers 
Antiestrogens:    tamoxifen, toremifene
Antiretrovirals,  Protease inhibitors:    ritonavir, nelfinavir, saquinavir
Proton pump inhibitors:    pantoprazole, omeprazole
Others:   diethylstillbesterol, estrone, flavopiridol, novobiocin, reserpine, 
carbamazepine
P-glycoprotein (ABCB1, P-gp, MDR1) Inhibitors and Inducers
Antifungals:     Itraconazole, etraconazole, ketoconazole, clotrimazole
Antiretrovirals,  Protease inhibitors: amprenavir, indinavir, ritonavir, nelfinavir, 
saquinavir
Antibiotics:  erythromycin, rifampin
Calcium channel blockers:   diltiazem, nicardipine, verapamil
Anticonvulsants:   carbamazepine, phenobarbital
Analgesics:   meperidine, methadone, morphine, pentazocine
Immune modulators:  Valspodar
Others:  Atorvastatin,  bromocriptine, carvedilol, omeprazole, progesterone, 
quinine, dexamethasone (large doses), phenothiazine, retinoic acid, St. John’s 
wort
13.1.10.3.9 Pregnancy and Lactation
Pregnancy
Topotecan is contraindicated during pregnancy.
Lactation
Topotecan is contraindicated during breast-feeding.


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Topotecan has been shown to be both embryotoxic and fetotoxic in preclinical studies. As with 
other cytotoxic drugs, topotecan may cause fetal harm when administered to pregnant women 
and therefore is contraindicated during pregnancy. Women should be advised to avoid becoming 
pregnant during therapy with topotecan and to inform the treating physician immediately should 
this occur.
Topotecan is contraindicated during breast-feeding.
13.1.10.4 Frequency of adverse reactions to oral topotecan:
Likely adverse reactions (occurring in more than 20% of patients)
Diarrhea, Nausea, Vomiting, Fatigue, Anemia, Leukopenia, neutropenia, thrombocytopenia, 
pain, dyspnea, infection, alopecia
Common adverse reactions (occurring in 3 – 20% of Patients)
Anorexia, Stomatitis, asthenia, cough, fever, febrile neutropenia
Rare but Serious adverse reactions (occurring in fewer than 3% of patients)
Interstitial lung disease, sepsis
13.1.11 Clinical Pharmacokinetic Properties:
The pharmacokinetics of topotecan after oral administration have been evaluated in cancer 
patients following doses of 1.2 to 3.1 mg/m2 and 4 mg/dose administered daily for 5 days.
13.1.11.1 Absorption and Distribution
Absorption
Topotecan is rapidly absorbed with peak plasma concentrations occurring between 1 to 2 hours 
following oral administration. Following co-administration of the ABCG2 (BCRP) and ABCB1 
(P-gp) inhibitor, elacridar (GF120918) at 100 to 1000 mg with oral topotecan, the AUC (0-inf) of 
topotecan lactone and total topotecan increased approximately 2.5-fold. Administration of oral 
cyclosporin A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and ABCC1 (MRP-1) as 
well as the metabolising enzyme CYP3A4, within 4 hours of oral topotecan increased the dose-
normalized AUC (0-24h) of topotecan lactone and total topotecan approximately 2.0- and 2.5-
fold, respectively.
Following a high-fat meal, the extent of exposure was similar in the fed and fasted state while 
tmax was delayed from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total topotecan).
Distribution
The binding of topotecan to plasma proteins was low (35%) and its distribution between blood 
cells and plasma was homogeneous.
13.1.11.2 Metabolism and Elimination
Metabolism
A major route of inactivation of topotecan is a reversible pH-dependent ring opening to the 
inactive carboxylate form. Metabolism accounts for less than 10% of the elimination of 
topotecan. An N-desmethyl metabolite was found in urine, plasma, and feces. Following oral 
administration the mean metabolite: parent AUC ratio was less than 10% for both total topotecan 


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and topotecan lactone. An O-glucuronide of topotecan and N-desmethyl topotecan has been 
identified in the urine. In vitro, topotecan did not inhibit human cytochrome P450 enzymes 
CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A nor did it 
inhibit the human cytosolic enzymes dihydropyrimidine dehydrogenase or xanthine oxidase.
Elimination
Following oral administration, the plasma concentrations decline bi-exponentially. The 
pharmacokinetics of oral topotecan are approximately dose proportional. There is little or no 
accumulation of either formulation of topotecan with repeated daily dosing, and there is no 
evidence of a change in the pharmacokinetics with multiple dosing. The pharmacokinetics of 
topotecan after oral administration have been evaluated in cancer patients following doses of 1.2 
to 3.1 mg/m2 and 4 mg/dose administered daily for 5 days. Oral topotecan exhibits a mean 
terminal half-life of approximately 3.0 to 6.0 hours. Overall recovery of drug-related material 
following five daily doses of topotecan was 49% to 71% of the administered oral dose. 
Approximately 20% was excreted as total topotecan and 2% was excreted as N-desmethyl 
topotecan in the urine. Fecal elimination of total topotecan accounted for 33% while fecal 
elimination of N-desmethyl topotecan was 1.5%. Overall, the N-desmethyl metabolite 
contributed a mean of less than 6% (range 4–8%) of the total drug related material accounted for 
in the urine and feces.
13.1.11.3 Special Populations
A cross-study analysis in 217 patients with advanced solid tumors indicated that age and sex did 
not significantly affect the pharmacokinetics of oral topotecan.
13.1.11.3.1 Pediatric: Use in children is not recommended as only limited 
data are available.
13.1.11.3.2 Hepatic Impairment: Pharmacokinetics of oral topotecan has not 
been specifically studied in patients with impaired hepatic function.
13.1.11.3.3 Renal Impairment: Patients with small cell lung carcinoma who 
participated in oral topotecan clinical trials had a serum creatinine 
less than or equal to 1.5 mg/dL (133umol/L) or a creatinine 
clearance (CrCl) of greater than or equal to 60 mL/min. Dosing 
recommendations for patients receiving oral topotecan with CrCl 
less than 60 mL/min have not been established.
13.1.12 Administration:  0.25 mg (1 capsule) orally daily with or without food.
13.1.13 Supplier: Novartis
13.1.14 Ordering Study Agent/s: 
Study Agent/s may be requested by the Principal Investigator (or their authorized designees) at 
each participating institution. All regulatory document requirements (including a Pharmacy 
Initiation Worksheet), as described in the BTTC Operations Manual, must be current and up to 
date in the BTTC Coordinating Center. The participating institution must have received an 
Activation memo from the BTTC Coordinating Center prior to requesting study agents.  A study 
drug order form and Pharmacy Initiation Worksheet will be provided to the sites by BTTC 
Coordinating Center.


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Signed and Dated Drug requests should be emailed to:
Uintavision
Attn: Michelle DuBoise
Email: mdubois@uintavision.com
When a number of investigators are participating on a clinical study at the same institution, one 
investigator should be considered or designated the Principal or lead investigator under whom all 
investigational agents for that protocol should be ordered. 
13.1.15 Agent Storage and Accountability: 
The investigator is responsible for the proper and secure physical storage and record keeping of 
investigational agents received for BTTC protocols. Specifically, the investigator must:  
•
Maintain a careful record of the receipt, use and final disposition of all 
investigational agents received, using the NCI Agent Accountability Record 
Form (DARF), http://ctep.cancer.gov/forms/index.html.  
•
Store the agent in a secure location, accessible to only authorized personnel, 
preferably in the pharmacy.
•
 Maintain appropriate storage of the investigational agent to ensure the 
stability and integrity of the agent.
•
 Return or destroy any unused investigational agents at the completion of the 
study or upon notification that an agent is being withdrawn.
The intent of the agent accountability procedures described in this section is to assist the 
investigator in making certain that agents received from BTTC are used only for patients entered 
onto an approved protocol. The record keeping described in this section is required under FDA 
regulation. Investigators are responsible for the use of investigational agents shipped in their 
name. Even if a pharmacist or chemotherapy nurse has the actual task of handling these agents 
upon receipt, the investigator is the responsible individual and has agreed to accept this 
responsibility by signing the FDA 1572, 
http://www.fda.gov/opacom/morechoices/fdaforms/FDA-1572.doc.
13.1.16 BTTC Procedures for Agent Accountability and Storage 
•
Each investigational agent should be stored separately by protocol. If an agent 
is used for more than one protocol, there should be separate physical storage 
for each protocol. Remember that agents are provided and accounted for on a 
protocol-by-protocol basis.
•
Each agent should be accounted for separately by protocol. If an agent is used 
for more than one protocol, there should be a separate Drug Accountability 
Record Form (DARF) for each protocol, 
http://ctep.cancer.gov/forms/index.html. There should be a separate DARF for 
each agent in a multi-agent protocol.
•
Separate accountability forms should be maintained for each different strength 
or dosage form of a particular agent (e.g., an agent with a 1-mg vial and a 5-


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mg vial would require a different DARF for the 1-mg vial than for the 5-mg 
vial).
•
 The DARF has been designed for use at each location where agents are 
stored, e.g., main pharmacy, satellite pharmacy, physician's office, or other 
dispensing areas.
•
The DARF is also designed to accommodate both dispensing records and 
other agent transaction documentation (e.g., receipt of agent, returns, broken 
vials, etc.). A copy of the DARF may be found at 
http://ctep.cancer.gov/forms/index.html.
•
Unauthorized inter-institutional transfer of BTTC investigational agents from 
one participating institution to another is not permitted.  For some protocols 
the lead institution may enter into contractual agreements to forward agents to 
participating institutions (see BTTC Operations Manual).
•
BTTC Supplied agents must not be repackaged and forwarded to patients on a 
routine basis. Refer to the BTTC Operations Manual for BTTC polices on 
forwarding BTTC supplied agents under certain limited circumstances.
Verification of Compliance
Investigators are reminded that compliance with procedures to ensure proper agent usage will be 
reviewed during site visits conducted under the monitoring program. Specifically, site visitors 
will check that the agent accountability system is being maintained, and will spot-check the 
agent accountability records by comparing them with the patients' medical records to verify that 
the agents were administered to a patient entered in the recorded protocol
13.1.17 Returning or destroying unused and/or defective Agent: 
Investigators/Designees should make every effort to minimize the amount of agent ordered and 
returned or destroyed unused, (e.g. limit inventories to an 8 week supply or less). 
Investigators/Designees must return/or destroy unused supplied agent when: 
•
The agent is no longer required because the study is completed. 
•
Agent is outdated. 
•
The agent is damaged or unfit for use. 
General Guidelines 
•
Regulations require that all agents received be returned to the supplier for 
accountability and disposition or destroyed on-site in accordance with local 
procedures for agent destruction. On-site agent destruction must be 
documented in the protocol specific accountability records.
•
Return only unused vials/bottles. Do NOT return opened or partially used 
vials/bottles unless specifically requested otherwise in the protocol. 
•
Return only supplied agents. Do NOT ship agents received from other sources 
to the supplier. 
Procedure 


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Unused, expired or defective study drug should be destroyed by the site’s pharmacy in 
accordance with their drug disposal policy or standard operating procedure. The destruction of 
the study will be documented in the DARF. Submit copy of the destruction record (DARF) to 
Novartis only if study is closing. 
13.1.18 Handling of study medication: Store refrigerated 2º to 8ºC (36º to 46ºF). Store the 
bottles protected from light in the original outer cartons. Topotecan capsules must not be 
opened or crushed. If the capsules are punctured or leaking, you should immediately 
wash your hands thoroughly with soap and water. If you get it in your eyes, wash them 
immediately with gently flowing water for at least 15 minutes. Consult your 
doctor/healthcare provider after eye contact or if you experience a skin reaction. 
Pharmacists should use appropriate precautions in handling and disposal of hazardous 
agents.
13.2 DRUG NAME: PAZOPANIB
13.2.1 Chemical Name: 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-
pyrimidinyl]amino]-2-methylbenzolsulfonamide monohydrochloride.
13.2.2 Molecular formula: C21H23N7O2S • HCl
13.2.3 Molecular Weight: 473.99 g/mol (monohydrochloride salt) 
437.53 g/mol (free base)
13.2.4 Appearance: White to slightly colored solid. The 50 mg and 100 mg tablets are round, 
the 200 mg and 400 mg tablets are oval shaped or capsule-shaped, and the 500 mg tablets 
are capsule shaped. The 50 mg, 100 mg, and 500 mg tablets are white to slightly colored, 
while the oval-shaped 200 mg and 400 mg tablets are white. Additionally, the capsule-
shaped 200 mg tablets can be gray or pink and may be debossed, and the capsule-shaped 
400 mg tablets can be white or yellow and may be debossed
13.2.5 How Supplied: GW786034B Tablets are supplied as 50 mg, 100 mg, 200 mg, 400 mg 
and 500 mg (as free base) tablets for oral administration to support oncology indications. 
Tablets are packaged in white high density polyethylene (HDPE) bottles with white 
plastic, induction seal, child-resistant caps.
13.2.6 Formulation: Pazopanib is supplied as tablets for oral administration containing 
pazopanib together with magnesium stearate, microcrystralline cellulose, povidone 
sodium starch glycolate, magnesium stearate and a film coat containing: hypromellose, 
macrogol/polyethylene glycol 400, polysorbate 80, titanium dioxide and may contain Iron 
Oxide Yellow, Red, or Black depending on tablet color, all as inactive ingredients.
13.2.7 Storage and Stability: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 
86°F).
13.2.8 Mechanism of Action: Pazopanib is an orally administered, potent multi-target tyrosine 
kinase inhibitor (TKI) of Vascular Endothelial Growth Factor Receptors (VEGFR)-1, -2, 
and -3, platelet-derived growth factor (PDGFR)-α and –β, and stem cell factor receptor 
(c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively. In preclinical 
experiments, pazopanib dose dependently inhibited ligand-induced auto-phosphorylation 
of VEGFR-2, c-Kit and PDGFR-β receptors in cells. In vivo, pazopanib inhibited VEGF-


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induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal 
models, and the growth of multiple human tumor xenografts in mice.
13.2.9 Pharmacology
DRUG INTERACTIONS
In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes   
is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. 
Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.
Agents that may Increase pazopanib Blood Concentrations
CYP3A4 Inhibitors: Co-administration of pazopanib with strong inhibitors of the CYP3A4 
family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase pazopanib 
concentrations. Grapefruit juice may also increase plasma concentrations of pazopanib. 
Administration of 1500 mg lapatinib a substrate and weak inhibitor of CYP3A4, Pgp and BCRP 
with 800 mg pazopanib resulted in an approximately 50 % to 60 % increase in mean pazopanib 
AUC(0-24) and Cmax compared to administration of 800 mg pazopanib alone. Co-administration 
of pazopanib with a CYP3A4, Pgp, and BCRP inhibitor, such as lapatinib, will result in an 
increase in plasma pazopanib concentrations. Combination with strong CYP3A4 inhibitors 
should therefore be avoided, or selection of an alternate concomitant medication with no or 
minimal potential to inhibit CYP3A4 is recommended. A dose reduction of pazopanib should be 
considered when it must be co-administered with strong CYP3A4 inhibitors (see Dosage and 
Administration).
Agents that may Decrease pazopanib Blood Concentrations 
CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib 
concentrations. Selection of an alternate concomitant medication with no or minimal enzyme 
induction potential is recommended.
Effects of Pazopanib on CYP Substrates
In vitro studies with human liver microsomes showed that pazopanib inhibited CYP enzymes 
1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was 
demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 
800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect 
on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe 
substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in 
an increase of approximately 30 % in the mean AUC and Cmax of midazolam (CYP3A4 probe 
substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan 
concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe 
substrate). Co-administration of pazopanib 800 mg once daily and paclitaxel 80 mg/m2 
(CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26 % and 31 % in 
paclitaxel AUC and Cmax, respectively.
Effects of Pazopanib on Other Enzymes and Transporters 


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In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1 with 
IC50 of 1.2 and 0.79 μM respectively. Pazopanib may increase concentrations of drugs primarily 
eliminated through UGT1A1 and OATP1B1.
Effect of concomitant use of Pazopanib and Simvastatin
Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. 
Across monotherapy studies with pazopanib, ALT > 3x ULN was reported in 126/895 (14%) of 
patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant 
use of simvastatin (p= 0.038). If a patient receiving concomitant simvastatin develops ALT 
elevations, follow guidelines for pazopanib posology and discontinue simvastatin. Insufficient 
data are available to assess the risk of concomitant administration of alternative statins and 
pazopanib.
Effect of Food on Pazopanib
Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold 
increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 
2 hours after a meal.
13.2.10 Pre-clinical Toxicology
The toxicity profile of pazopanib has been defined in single dose studies in the rat and dog and 
repeat dose toxicity studies of up to 13 weeks in mice, 26 weeks in rats and 52 weeks in 
monkeys. The genetic toxicity has been assessed in vitro and in vivo. Embryo fetal development 
has been assessed in rats and rabbits, and effects on fertility have been assessed in male and 
female rats. Juvenile toxicity studies are in progress. Dermal and ocular irritation, in vitro 
phototoxicity and mouse local lymph node assays have also been conducted. Definitive studies 
were conducted with the monohydrochloride salt which is used in the clinic and with batches 
having a similar impurity profile. The toxicokinetic profile of pazopanib was evaluated in all 
definitive repeat dose studies, and comparison of systemic exposure to pazopanib achieved in 
key toxicology studies is presented in Table 4 in the investigator’s Brochure. Exposure margins 
are presented based upon comparison of the animal systemic exposure with that reported for 
cancer patients receiving an oral therapeutic dose of 800 mg/day pazopanib (AUC of 1037 
μg.h/mL and a Cmax of 58.1 μg/mL). 
The principal nonclinical toxicology findings associated with pazopanib treatment are believed 
to be directly associated with VEGFR-2 inhibition, or secondary consequences to this inhibition, 
and in rodents reflect the responsive nature of these species to inhibition of VEGF receptors 
(Patyna et al. 905-16). These include effects on bone, bone marrow, incisor teeth, ovary, kidney, 
pancreas, nails, testes, adrenal, pituitary, trachea, hematological tissues, salivary glands and 
developing embryo/fetus. Some effects occurred at doses of 3 mg/kg/day. Other effects have 
been noted in liver, small intestine and mesenteric lymph nodes (mice, rats, monkey). Toxicities 
observed in rodents in teeth, bone, pancreas, nails, bone marrow, kidney and liver were assessed 
clinically and/or via serum chemistries in the clinic, or in the case of other pre-clinical targets 
such as adrenal, pituitary, trachea and spleen, were of minimal severity and unlikely to result in 
adverse clinical events.
13.2.11 Human Toxicity
WARNINGS AND PRECAUTIONS


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13.2.11.1 Hepatic Effects:
Cases of hepatic failure (including fatalities) have been reported during the use of pazopanib. In 
clinical trials with pazopanib, increase in serum transaminases (ALT, AST) and bilirubin were 
observed. In the majority of the cases, isolated increases in ALT and AST have been reported, 
without concomitant elevations of alkaline phosphatase or bilirubin. The vast majority (92.5%) 
of all transaminase elevations of any grade occurred in the first 18 weeks. Grades are based on 
the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI 
CTCAE). 
Monitor serum liver tests before initiation of treatment with pazopanib and at least once every 4 
weeks for at least the first 4 months of treatment, and as clinically indicated. Periodic monitoring 
should then continue after this time period. 
The following guidelines are provided for patients with baseline values of total bilirubin ≤1.5 X 
ULN and AST and ALT ≤2 X ULN.
•
Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be 
continued on pazopanib with weekly monitoring of liver function until ALT return to 
Grade 1 (NCI CTCAE) or baseline.
•
Patients with ALT of >8 X ULN should have pazopanib interrupted until they return 
to Grade 1 (NCI CTCAE) or baseline. If the potential benefit for reinitiating 
pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then 
reintroduce pazopanib at a reduced dose of 400 mg once daily and measure serum 
liver tests weekly for 8 weeks. Following reintroduction of pazopanib, if ALT 
elevations >3 X ULN recur, then pazopanib should be permanently discontinued.
•
If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN 
pazopanib should be permanently discontinued. Patients should be monitored until 
return to Grade 1 (NCI CTCAE) or baseline. Pazopanib is a UGT1A1 inhibitor. Mild, 
indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s 
syndrome. Patients with only a mild indirect hyperbilirubinaemia, known or 
suspected Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed 
as per the recommendations outlined for isolated ALT elevations. 
Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations and should 
be undertaken with caution and close monitoring. Beyond recommending that patients with mild 
hepatic impairment are treated with 800 mg pazopanib once daily and reducing the initial starting 
dose to 200 mg per day for patients with moderate impairment, no further dose modification 
guidelines based on results of serum liver tests during therapy have been established for patients 
with preexisting hepatic impairment.
13.2.11.2 Hypertension:
In clinical studies with pazopanib, events of hypertension including hypertensive crisis have 
occurred. Blood pressure should be well controlled prior to initiating pazopanib. Patients should 
be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. 
Hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 100 mm Hg) occurs 
early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in 
the first 18 weeks). In the case of persistent hypertension despite anti-hypertensive therapy, the 


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pazopanib dose may be reduced. Pazopanib should be discontinued if there is evidence of 
hypertensive crisis or if hypertension is severe and persists despite anti-hypertensive therapy and 
pazopanib dose reduction (see specific guidelines for BP monitoring and management in Section 
3.3.6.2)
13.2.11.3 QT Prolongation and Torsade de Pointes:
In clinical studies with pazopanib, events of QT prolongation or Torsade de Pointes have 
occurred. Pazopanib should be used with caution in patients with a history of QT interval 
prolongation, patients taking antiarrythmics or other medications that may potentially prolong 
QT interval, or those with relevant pre-existing cardiac disease. When using pazopanib, baseline 
and periodic monitoring of electrocardiograms and maintenance of electrolytes (calcium, 
magnesium, potassium) within normal range is recommended. 
13.2.11.4 Arterial Thrombotic Events: 
In clinical studies with pazopanib, myocardial infarctions, angina, ischemic stroke and transient 
ischemic attack were observed. Fatal events have been observed. Pazopanib should be used with 
caution in patients who are at increased risk of thrombotic events or who have had a history of 
thrombotic events. Pazopanib has not been studied in patients who have had an event within the 
previous 6 months. A treatment decision should be made based upon the assessment of 
individual patient’s benefit/risk.
13.2.11.5 Hemorrhagic Events: 
In clinical studies with pazopanib hemorrhagic events have been reported. Fatal hemorrhagic 
events have occurred. Pazopanib has not been studied in patients who had a history of 
hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. 
Pazopanib should be used with caution in patients with significant risk of hemorrhage.
13.2.11.6 Gastrointestinal Perforations and Fistula: 
In clinical studies with pazopanib, events of gastrointestinal (GI) perforation or fistula have 
occurred. Fatal perforation events have occurred. Pazopanib should be used with caution in 
patients at risk for GI perforation or fistula.
13.2.11.7 Wound Healing: 
No formal studies on the effect of pazopanib on wound healing have been conducted. Since 
Vascular Endothelial Growth Factor (VEGF) inhibitors may impair wound healing, treatment 
with pazopanib should be stopped at least 7 days prior to scheduled surgery. The decision to 
resume pazopanib after surgery should be based on clinical judgment of adequate wound healing. 
Pazopanib should be discontinued in patients with wound dehiscence.
13.2.11.8 Hypothyroidism: 
In clinical studies with pazopanib, events of hypothyroidism have occurred. Proactive 
monitoring of thyroid function tests is recommended.
13.2.11.9 Proteinuria: 
In clinical studies with pazopanib, proteinuria has been reported. Baseline and periodic 
urinalyses during treatment are recommended and patients should be monitored for worsening of 
proteinuria. Pazopanib should be discontinued if the patient develops nephrotic syndrome.


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13.2.11.10 Pregnancy: 
Pre-clinical studies in animals have shown reproductive toxicity. If pazopanib is used during 
pregnancy, or if the patient becomes pregnant while receiving pazopanib, the potential hazard to 
the fetus should be explained to the patient. Women of childbearing potential should be advised 
to avoid becoming pregnant while receiving treatment with pazopanib.
13.2.12 Interactions
13.2.12.1.1 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes
In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes 
is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. 
Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.
13.2.12.1.1.1 CYP3A4 Inhibitors: Concurrent administration of a single dose pazopanib eye 
drops with the strong CYP3A4 inhibitor, ketoconazole, in healthy volunteers resulted 
in 220 % and 150 % increase in mean AUC(0-t) and Cmax values, respectively. Co-
administration of pazopanib with strong inhibitors of the CYP3A4 family (e.g., 
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase 
pazopanib concentrations. Grapefruit juice may also increase plasma concentrations 
of pazopanib. Administration of 1500 mg lapatinib a substrate and weak inhibitor of 
CYP3A4, Pgp and BCRP with 800 mg pazopanib resulted in an approximately 50 % 
to 60 % increase in mean pazopanib AUC(0-24) and Cmax compared to 
administration of 800 mg pazopanib alone.
Co-administration of pazopanib with a CYP3A4, Pgp, and BCRP inhibitor, such as lapatinib, 
will result in an increase in plasma pazopanib concentrations. 
Combination with strong CYP3A4 inhibitors should therefore be avoided, or selection of an 
alternate concomitant medication with no or minimal potential to inhibit CYP3A4 is 
recommended. A dose reduction of pazopanib should be considered when it must be 
coadministered with strong CYP3A4 inhibitors.
13.2.12.1.1.2 CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma 
pazopanib concentrations. Selection of an alternate concomitant medication with no 
or minimal enzyme induction potential is recommended.
13.2.12.2 Effects of Pazopanib on CYP Substrates
In vitro studies with human liver microsomes showed that pazopanib inhibited CYP enzymes 
1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was 
demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 
800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect 
on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe 
substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in 
an increase of approximately 30 % in the mean AUC and Cmax of midazolam (CYP3A4 probe 
substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan 
concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe 
substrate). Co-administration of pazopanib 800 mg once daily and paclitaxel 80 mg/m2 


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(CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26 % and 31 % in 
paclitaxel AUC and Cmax, respectively.
13.2.12.3 Effects of Pazopanib on Other Enzymes and Transporters
In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1 with 
IC50 of 1.2 and 0.79 μM respectively. Pazopanib may increase concentrations of drugs primarily 
eliminated through UGT1A1 and OATP1B1.
13.2.12.4 Effect of concomitant use of Pazopanib and Simvastatin
Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. 
Across monotherapy studies with pazopanib, ALT > 3x ULN was reported in 126/895 (14%) of 
patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant 
use of simvastatin (p= 0.038). If a patient receiving concomitant simvastatin develops ALT 
elevations, follow guidelines for pazopanib posology and discontinue simvastatin. Insufficient 
data are available to assess the risk of concomitant administration of alternative statins and 
pazopanib. 
13.2.12.5 Effect of Food on Pazopanib
Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold 
increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 
2 hours after a meal.
13.2.12.5.1 Medication that raise gastric pH
Concomitant use of pazopanib with esomeprazole decreases the bioavailability of pazopanib by 
approximately 40% (AUC and Cmax), and co-administration of pazopanib with medicines that 
increase gastric pH should be avoided.
13.2.13 Pregnancy and Lactation
13.2.13.1 Fertility
Pazopanib may impair fertility in human males and females. In female reproductive toxicity 
studies in rats, reduced female fertility has been observed.
13.2.13.2 Pregnancy
There are no adequate data from the use of pazopanib in pregnant women. Studies in animals 
have shown reproductive toxicity. The potential risk for humans is unknown. Pazopanib should 
not be used during pregnancy unless the clinical condition of the woman requires treatment with 
pazopanib. If pazopanib is used during pregnancy, or if the patient becomes pregnant while 
receiving pazopanib, the potential hazard to the fetus should be explained to the patient. Women 
of childbearing potential should be advised to use adequate contraception and avoid becoming 
pregnant while receiving treatment with pazopanib.
13.2.13.3 Lactation
The safe use of pazopanib during lactation has not been established. It is not known whether 
pazopanib is excreted in human milk. Breast feeding should be discontinued during treatment 
with pazopanib.


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13.2.14 Ability to perform tasks that require judgment, motor or cognitive skills
There have been no studies to investigate the effect of pazopanib on driving performance or the 
ability to operate machinery. A detrimental effect on such activities would not be anticipated 
from the pharmacology of pazopanib. The clinical status of the patient and the adverse event 
profile of pazopanib should be borne in mind when considering the patient’s ability to perform 
task that require judgment, motor and cognitive skills.
13.2.15Adverse Reactions
The safety and efficacy of pazopanib in renal cell carcinoma (RCC) were evaluated in a 
randomized, double-blind, placebo-controlled multi-centre study. Patients with locally advanced 
and/or metastatic RCC were randomized to receive pazopanib 800 mg once daily (N=290) or 
placebo (N=145). The median duration of treatment was 7.4 months for the pazopanib arm and 
3.8 months for the placebo arm.
Adverse reactions are listed below by MedDRA body system organ class.
The following convention has been utilized for the classification of frequency:
Very common ≥ 1 in 10
Common ≥ 1 in 100 and < 1 in 10
Uncommon ≥ 1 in 1,000 and < 1 in 100
Categories have been assigned based on absolute frequencies in the clinical trial 
data. Note: Updated to about 6000 patients as of February 9, 2012.
13.2.15.1 Blood and lymphatic system disorders
Common  
Thrombocytopenia
Neutropenia
13.2.15.2 Endocrine disorders
Very common
Changes in blood sugar
Common 
Hypothyroidism*
13.2.15.3 Metabolism and nutrition disorders
Very common 
Anorexia, weight loss
13.2.15.4 Nervous system disorders
Very common 
Headache, dysgeusia
Common 
Transient ischaemic attack*
Uncommon
 Ischaemic stroke*
13.2.15.5 Cardiac disorders
Very common
slow heart beat (<60 beats per minute)
Common 
Myocardial ischaemia* QT prolongation* Cardiac 
dysfunction (such as a decrease in ejection
 fraction and 
congestive heart failure), Myocardial infarction*
Uncommon 
Torsade de Pointes* 


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13.2.15.6 Vascular disorders
Very common 
Hypertension*
13.2.15.7 Hemorrhages*
Common 
Epistaxis, Haematuria, blood clots, Pulmonary 
haemorrhage
Uncommon 
Gastrointestinal haemorrhage, Cerebral haemorrhage
13.2.15.8 Gastrointestinal disorders
Very common 
Diarrhea, Nausea, Vomiting, Abdominal pain
Common 
Dyspepsia, Lipase elevations, abdominal gas
Uncommon
Gastrointestinal perforation*, Gastrointestinal fistula*
13.2.15.9 Hepatobiliary disorders*
Very common 
Alanine aminotransferase increased, Aspartate 
aminotransferase increased
Common 
Hepatic function abnormal, Hyperbilirubinaemia
13.2.15.10 Skin and subcutaneous tissue disorders
Very common 
Hair depigmentation, hair loss, exfoliative rash, Palmar-
plantar erythrodysaesthesia syndrome, lightening of skin 
color
Common 
Rash, dry skin, nail disorder
13.2.15.11 Renal and urinary disorders
Common 
Proteinuria*
13.2.15.12 General disorders and administration site conditions
Very common 
Fatigue, Asthenia, dyspnea, cough, peripheral edema, 
dizziness, mouth sores, muscle pain or cramps, chest pain*
Common 
Chills
*See Warnings and Precautions in Investigator’s Brochure for additional information.
13.2.15.13 Overdosage
Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Grade 3 fatigue (dose 
limiting toxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 
mg and 1,000 mg daily, respectively.
13.2.15.14 Symptoms and Signs
There is currently limited experience with overdosage in pazopanib.
13.2.15.15 Treatment
Further management should be as clinically indicated or as recommended by the national poisons 
centre, where available. Haemodialysis is not expected to enhance the elimination of pazopanib 
because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.


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13.2.16Frequency of adverse reactions to pazopanib:
13.2.16.1 Likely (occurring in more than 20% of patients)
Diarrhea, hypertension, hair color changes, hair loss, painful blisters and/or rash on palms and 
soles, nausea, anorexia, vomiting, fatigue, weight loss, tumor pain, dysgeusia, headache, 
gastrointestinal pain, musculoskeletal pain, myalgia, decreased albumin, hypomagnesemia, 
hypophosphatemia, increased glucose level, leucopenia, neutropenia, thrombocytopenia, ALT 
increased, AST increased, bilirubin increased, tumor pain
13.2.16.2 Common (occurring in 3 – 20% of Patients)
Asthenia, abdominal pain, exfoliative rash, cough, constipation, peripheral edema, abnormal ear 
nose and throat examination, skin disorder or hypopigmentation, dizziness, stomatitis, chest pain, 
pyrexia, dyspnea, hypertensive crisis,  hypothyroidism, lymphopenia, slow heart beat, chills, dry 
skin, nail disorder
13.2.16.3 Rare but Serious (occurring in fewer than 3% of patients)
Hepatotoxicity, congestive heart failure, myocardial infarction, prolonged QT interval, Torsades 
de pointes, bleeding from anus, bleeding from mouth, gastroinstinal fistula, pancreatitis, rectal 
hemorrhage, venous thromboembolism, stroke, reversible posterior leukoencephalopathy 
syndrome, transient ischemic attack, pneumothorax, pulmonary embolism, pulmonary 
hemorrhage
13.2.17Clinical Pharmacokinetic Properties
13.2.17.1 Absorption
Pazopanib is absorbed orally with median time to achieve peak concentrations of 2.0 to 4.0 hours 
after the dose. Daily dosing results in 1.23- to 4-fold increase in AUC. There was no consistent 
increase in AUC and Cmax when the pazopanib dose increased above 800 mg. 
Systemic exposure to pazopanib is increased when administered with food. Administration of 
pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC 
and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a 
meal.
Administration of a single pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% and 
Cmax by approximately 2 fold and decreased tmax by approximately 1.5 hours compared to 
administration of the whole tablet. These results indicate that the bioavailability and the rate of 
pazopanib oral absorption are increased after administration of the crushed tablet relative to 
administration of the whole tablet. Therefore, due to this potential for increased exposure, tablets 
should not be crushed.
13.2.17.2 Distribution
Binding of pazopanib to human plasma protein in vivo was greater than 99 % with no 
concentration dependence over the range of 10-100 μg/ml. In vitro studies suggest that 
pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).
13.2.17.3 Metabolism
Results from in vitro studies demonstrated that the metabolism of pazopanib is mediated 
primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8.


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13.2.17.4 Elimination
Pazopanib is eliminated slowly with mean half-life of 30.9 hours after administration of the 
recommended dose of 800 mg. Elimination is primarily via feces with renal elimination 
accounting for < 4 % of the administered dose.
13.2.18Special Populations
13.2.18.1 Renal Impairment
In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine 
clearance (30-150 ml/min) did not influence clearance of pazopanib. Renal impairment is not 
expected to influence pazopanib exposure, and dose adjustment is not necessary in patients with 
creatinine clearance ≥ 30 ml/min.
13.2.18.2 Hepatic Impairment
The median steady-state pazopanib Cmax and AUC(0-24) in patients with mild hepatic 
impairment (defined as either normal bilirubin and any degree of ALT elevations or as an 
elevation of bilirubin up to 1.5 x ULN regardless of the ALT value) after a once daily dose of 
800 mg/day (30.9 μg/ml, range 12.5-47.3 and 841.8 μg.hr/ml, range 600.4-1078) are similar to 
the median in patients with no hepatic impairment (49.4 μg/ml, range 17.1-85.7 and 888.2 
μg.hr/ml, range 345.5-1482).
The maximally tolerated pazopanib dose (MTD) in patients with moderate hepatic impairment 
(defined as an elevation of bilirubin > 1.5 x to 3 x ULN regardless of the ALT values) was 200 
mg once daily. The median steady-state values of Cmax (22.4 μg/ml, range 6.4-32.9) and AUC(0-
24) (350.0 μg.hr/ml, range 131.8-487.7) after administration of 200 mg pazopanib once daily in 
subjects with moderate hepatic impairment were approximately 45% and 39%, respectively, that 
of the corresponding median values after administration of 800 mg once daily in subjects with 
normal hepatic function. There are insufficient data in patients with severe hepatic impairment 
(total bilirubin >3x ULN regardless of any level of ALT); therefore, use of pazopanib is not 
recommended in these patients.
13.2.19 
Administration
Pazopanib (GW786034) is an orally administered multi-targeted tyrosine kinase inhibitor (TKI) 
currently under development by Novartis for the treatment of a variety of human cancers in 
adults. Currently, pazopanib is administered orally at 800 mg daily in Phase II and Phase III 
monotherapy studies.
13.2.19.1 Combination therapy
Doses ranged from 200 to 800 mg daily in a Phase I combination dose-ranging study 
(VEG10006) in which pazopanib was administered in combination with the Novartis compound 
lapatinib (GW572016). Pazopanib 200 to 800 mg daily is being investigated in combination with 
multiple cytotoxic chemotherapy regimens.
13.2.19.2 Dosing information from recent studies combining Pazopanib and oral 
topotecan
Recent investigations of the combination, relevant to this study found safe and effective dosing 
of pazopanib using a starting dose of 600 mg (3x200mg) Pazopanib per day taken orally without 
food at least one hour before or two hours after a meal. The dose of Pazopanib may be held up to 


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3 weeks and reduced to 400 mg or to 200 mg daily based on side effects. Patient may be 
maintained on the lower dose of pazopanib during protocol if deemed to be deriving benefit from 
the drug. Length of treatment will be until progression, up to one year.
13.2.20 Supplier: Novartis
13.2.20.1 Ordering Study Agent/s: 
Study Agent/s may be requested by the Principal investigator (or their authorized designees) at 
each participating institution. All regulatory document requirements (including a Pharmacy 
Initiation Worksheet), as described in the BTTC Operations Manual, must be current and up to 
date in the BTTC Coordinating Center. The participating institution must have received an 
Activation memo from the BTTC Coordinating Center prior to requesting study agents.  A study 
drug order form will be provided to the sites by BTTC Coordinating Center.
Signed and Dated Drug requests should be emailed to:
Uintavision
Attn: Michelle Dubois
Email: mdubois@uintavision.com
When a number of investigators are participating on a clinical study at the same institution, one 
investigator should be considered or designated the Principal or lead investigator under whom all 
investigational agents for that protocol should be ordered. 
13.2.20.2 Agent Storage and Accountability
The investigator is responsible for the proper and secure physical storage and record keeping of 
investigational agents received for BTTC protocols. Specifically, the investigator must:  
•
Maintain a careful record of the receipt, use and final disposition of all 
investigational agents received, using the NCI Agent Accountability Record 
Form (DARF), http://ctep.cancer.gov/forms/index.html.  
•
Store the agent in a secure location, accessible to only authorized personnel, 
preferably in the pharmacy.
•
 Maintain appropriate storage of the investigational agent to ensure the 
stability and integrity of the agent.
•
 Return or destroy any unused investigational agents at the completion of the 
study or upon notification that an agent is being withdrawn.
The intent of the agent accountability procedures described in this section is to assist the 
investigator in making certain that agents received from BTTC are used only for patients entered 
onto an approved protocol. The record keeping described in this section is required under FDA 
regulation. Investigators are responsible for the use of investigational agents shipped in their 
name. Even if a pharmacist or chemotherapy nurse has the actual task of handling these agents 
upon receipt, the investigator is the responsible individual and has agreed to accept this 
responsibility 
by 
signing 
the 
FDA 
1572, 
http://www.fda.gov/opacom/morechoices/fdaforms/FDA-1572.doc.


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13.2.21BTTC Procedures for Agent Accountability and Storage 
•
Each investigational agent should be stored separately by protocol. If an agent 
is used for more than one protocol, there should be separate physical storage 
for each protocol. Remember that agents are provided and accounted for on a 
protocol-by-protocol basis.
•
Each agent should be accounted for separately by protocol. If an agent is used 
for more than one protocol, there should be a separate Drug Accountability 
Record 
Form 
(DARF) 
for 
each 
protocol, 
http://ctep.cancer.gov/forms/index.html. There should be a separate DARF for 
each agent in a multi-agent protocol.
•
Separate accountability forms should be maintained for each different strength 
or dosage form of a particular agent (e.g., an agent with a 1-mg vial and a 5-
mg vial would require a different DARF for the 1-mg vial than for the 5-mg 
vial).
•
 The DARF has been designed for use at each location where agents are 
stored, e.g., main pharmacy, satellite pharmacy, physician's office, or other 
dispensing areas.
•
The DARF is also designed to accommodate both dispensing records and 
other agent transaction documentation (e.g., receipt of agent, returns, broken 
vials, 
etc.). 
A 
copy 
of 
the 
DARF 
may 
be 
found 
at 
http://ctep.cancer.gov/forms/index.html.
•
Unauthorized inter-institutional transfer of BTTC investigational agents from 
one participating institution to another is not permitted.  For some protocols 
the lead institution may enter into contractual agreements to forward agents to 
participating institutions (see BTTC Operations Manual).
•
BTTC Supplied agents must not be repackaged and forwarded to patients on a 
routine basis. Refer to the BTTC Operations Manual for BTTC polices on 
forwarding BTTC supplied agents under certain limited circumstances.
Verification of Compliance
Investigators are reminded that compliance with procedures to ensure proper agent usage will be 
reviewed during site visits conducted under the monitoring program. Specifically, site visitors 
will check that the agent accountability system is being maintained, and will spot-check the 
agent accountability records by comparing them with the patients' medical records to verify that 
the agents were administered to a patient entered in the recorded protocol.
13.2.22 Returning or Destroying unused or defective Agent
Investigators/Designees should make every effort to minimize the amount of agent ordered and 
returned or destroyed unused, (e.g. limit inventories to an 8 week supply or less). 
Investigators/Designees must return/or destroy unused supplied agent when: 
•
The agent is no longer required because the study is completed. 
•
Agent is outdated.


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•
The agent is damaged or unfit for use. 
General Guidelines 
•
Regulations require that all agents received be returned to the supplier for 
accountability and disposition or destroyed on-site in accordance with local 
procedures for agent destruction. On-site agent destruction must be 
documented in the protocol specific accountability records.
•
Return only unused vials/bottles. Do NOT return opened or partially used 
vials/bottles unless specifically requested otherwise in the protocol. 
•
Return only supplied agents. Do NOT ship agents received from other sources 
to the supplier.
Procedure 
Unused or defective drug will be destroyed. Novartis should be notified of this action.
13.2.23 Handling of Study medication: Pharmacists should use appropriate precautions in 
handling and disposal of hazardous agents. Store at 25°C (77°F); excursions permitted to 
15° to 30°C (59° to 86°F) 


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14 REFERENCES
Armstrong, T. S., et al. "Validation of the M.D. Anderson Symptom Inventory Brain Tumor 
Module (MDASI-BT)." J.Neurooncol. 80.1 (2006): 27-35.
Baker, S. D., et al. "Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion 
topotecan in children with central nervous system tumors." Cancer 
Chemother.Pharmacol. 37.3 (1996): 195-202.
Brennan, C., et al. "Glioblastoma subclasses can be defined by activity among signal 
transduction pathways and associated genomic alterations." PLoS.One. 4.11 (2009): 
e7752.
Carmichael, J., et al. "Phase II study of gemcitabine in patients with advanced pancreatic 
cancer." Br.J.Cancer 73.1 (1996): 101-05.
Chi, A. S., et al. "Angiogenesis as a therapeutic target in malignant gliomas." Oncologist. 14.6 
(2009): 621-36.
Hashimoto, K., et al. "Potent preclinical impact of metronomic low-dose oral topotecan 
combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer." 
Mol.Cancer Ther. 9.4 (2010): 996-1006.
Hermanson, M., et al. "Platelet-derived growth factor and its receptors in human glioma tissue: 
expression of messenger RNA and protein suggests the presence of autocrine and 
paracrine loops." Cancer Res. 52.11 (1992): 3213-19.
Iwamoto, F. M., et al. "Phase II trial of pazopanib (GW786034), an oral multi-targeted 
angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain 
Tumor Consortium Study 06-02)." Neuro Oncol. 12.8 (2010): 855-61.
Keunen, O., et al. "Anti-VEGF treatment reduces blood supply and increases tumor cell invasion 
in glioblastoma." Proc.Natl.Acad.Sci.U.S.A. 108.9 (2011): 3749-54.
Kreisl, T. N., et al. "Phase II trial of single-agent bevacizumab followed by bevacizumab plus 
irinotecan at tumor progression in recurrent glioblastoma." J.Clin.Oncol. 27.5 (2009): 
740-45.
Lamborn, K. R., et al. "Progression-free survival: an important end point in evaluating therapy 
for recurrent high-grade gliomas." Neuro Oncol. 10.2 (2008): 162-70.
Lim, S. K., et al. "Glioblastoma multiforme: a perspective on recent findings in human cancer 
and mouse models." BMB.Rep. 44.3 (2011): 158-64.
Macdonald, D., et al. "Phase II study of topotecan in patients with recurrent malignant glioma. 
National Clinical Institute of Canada Clinical Trials Group." Ann.Oncol. 7.2 (1996): 205-
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Merritt, W. M., et al. "Bridging the gap between cytotoxic and biologic therapy with metronomic 
topotecan and pazopanib in ovarian cancer." Mol.Cancer Ther. 9.4 (2010): 985-95.
Minturn, J. E., et al. "A phase II study of metronomic oral topotecan for recurrent childhood 
brain tumors." Pediatr.Blood Cancer. 56.1 (2011): 39-44.
Morris, P. G. and L. E. Abrey. "Novel targeted agents for platelet-derived growth factor receptor 
and c-KIT in malignant gliomas." Target Oncol. 5.3 (2010): 193-200.
Patyna, S., et al. "Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, 
KIT, FLT3, and RET receptors." Toxicol.Pathol. 36.7 (2008): 905-16.
Phillips, H. S., et al. "Molecular subclasses of high-grade glioma predict prognosis, delineate a 
pattern of disease progression, and resemble stages in neurogenesis." Cancer Cell 9.3 
(2006): 157-73.
Plate, K. H., et al. "Vascular endothelial growth factor is a potential tumour angiogenesis factor 
in human gliomas in vivo." Nature. 359.6398 (1992): 845-48.
Puputti, M., et al. "Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas." 
Mol.Cancer Res. 4.12 (2006): 927-34.
Rapisarda, A., et al. "Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein 
accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma 
xenografts." Cancer Res. 64.19 (2004): 6845-48.
Reardon, D. A., et al. "Multicentre phase II studies evaluating imatinib plus hydroxyurea in 
patients with progressive glioblastoma." Br.J.Cancer. 101.12 (2009): 1995-2004.
Siu, L. L., et al. "Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an 
expanded cohort in advanced pancreatic cancer." Clin.Cancer Res. 12.1 (2006): 144-51.
Stupp, R., et al. "Effects of radiotherapy with concomitant and adjuvant temozolomide versus 
radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year 
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Stupp, R., et al. "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma." 
N.Engl.J.Med. 352.10 (2005): 987-96.
Vredenburgh, J. J., et al. "Bevacizumab plus irinotecan in recurrent glioblastoma multiforme." 
J.Clin.Oncol. %20;25.30 (2007): 4722-29.
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15 APPENDICES
15.1 KARNOFSKY PERFORMANCE STATUS AND NEUROLOGIC FUNCTION 
Karnofsky Performance Status
Patient's performance status and Neurologic Functions will be graded according to the following 
scales:
KPS 100Normal; no complaints; no evidence of disease
KPS   90Able to carry on normal activity; minor signs or symptoms of disease
KPS   80Normal activity with effort; some sign or symptoms of disease
KPS   70Cares for self; unable to carry on normal activity or do active work
KPS   60Requires occasional assistance, but is able to care for most personal needs
KPS   50Requires considerable assistance and frequent medical care
KPS   40Disabled; requires special care and assistance
KPS   30Severely disabled; hospitalization is indicated, although death no imminent
KPS   20Very sick; hospitalization necessary; active support treatment is necessary
KPS   10Moribund; fatal processes progressing rapidly
KPS     0Dead
Neurologic Function
+1
Better
 0
Unchanged
-1
Worse
 B
Baseline


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15.2 EIAEDS AND NON-EIAEDS
EIAEDs:
Carbamazipine (Tegretol, Tegretol XR, Carbatrol)
Oxcarbazepine(Trileptal)
Phenytoin
(Dilantin, Phenytek)
Fosphenytoin (Cerebyx)
Phenobarbital
Primidone
(Mysoline)
Non-EIAEDs:
Valproic acid (Depakote, Depakene)
Gabapentin 
(Neurontin)
Lamotrigine
(Lamictil)
Topriamate
(Topamax)
Tiagabine 
(Gabatril)
Zonisamide
(Zonegran)
Levatriacetam (Keppra)
Clonazepam (Klonopin)
Clonozam
(Frisium)


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15.3 TUMOR TISSUE HANDLING INSTRUCTIONS AND TISSUE COLLECTION SHIPPING FORM
General Information: Tissue evaluation is highly recommended for this study. The 
evaluation will consist of confirmation that the histologic features meet WHO criteria for 
GBM or GS. All blocks for review will be sent directly to Dr. Aldape.
Rationale
The purpose of analyzing the tissue samples is to confirm the diagnosis of GBM 
Specimen Collection: Tissue specimens should be taken from pre-study diagnostic open biopsy 
or surgical resection.       
To be eligible for this study, the patient must have a GBM, or GS, WHO grade IV.  Features of a 
high-grade astrocytic neoplasm with tumor necrosis and/or microvascular proliferation must be 
present.
The following materials will be required for tissue evaluation:
Representative tissue blocks or 15 unstained paraffin slides that contain diagnostic tumor. A 
block that, when sectioned, yields at least 1 square centimeter of viable tumor must be 
present on the H&E slide. Blocks obtained via the CUSA methodology are not adequate for 
tissue analysis. Do not send blocks with tissue obtained by this method. 
An accompanying H&E is encouraged for rapid diagnosis but not required. If an H&E is 
included, Dr. Aldape will use this for the review. If not included, Dr. Aldape will cut a section 
from the paraffin block, stain this with H&E, and use that slide for the review.
A Pathology Report documenting that the submitted material contains tumor; the report must 
include the protocol number, patient case number, and the patient’s initials. The patient’s name 
and/or other identifying information should be removed from the report. The surgical pathology 
numbers and information must NOT be removed from the report.
A Tissue Collection Shipping Form (below) listing pathology materials being submitted for 
Tissue Evaluation completed by the local pathologist must be included in the pathology 
submission. These forms must include the protocol number, patient case number, and the 
patient’s initials.
Tissue evaluation is highly recommended for every case. Send pathology material by overnight 
mail directly to:
Ken Aldape, M.D. 
Toronto General Hospital
200 Elizabeth Street, 11th Floor
Toronto, Ontario M5G 2C4 Canada
kaldape@gmail.com
•
Include on the form the name, telephone number, and fax number of the 
person to notify with the results of the tissue evaluation.
•
Shipments must be made Monday through Thursday.
•
Notify Dr. Aldape by email on or before the day of submission: (1) that a case 
is being submitted for review; (2) the name of the contact person; (3) when to 
expect the sample; and (4) the overnight shipping carrier and tracking number.


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•
Dr. Aldape will email the appropriate contact person from the submitting 
institution with the results and will fax a copy of the completed form to the 
institution.
When Dr. Aldape has completed testing of the tumor tissue, the remaining tissue will be sent 
back to the submitting institution.
Submission of frozen tissue is strongly encouraged in order to maximize the information gained 
from this trial. When available, frozen tissue should be sent in dry ice to Dr. Aldape at the above 
address. 
Upon receipt, the specimen is labeled with the protocol number and the patient’s case number 
only. 
The specimens will be stored for an indefinite period of time. If at any time the patient 
withdraws consent to store and use the specimens, the material will be returned to the institution 
that submitted it. 


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Tissue Collection Shipping Form
**PLEASE USE ONE FORM PER PATIENT**
BTTC12‐01: PHASE II Trial of Oral Pazopanib plus Oral Topotecan Metronomic Antiangiogenic 
Therapy for Recurrent Glioblastoma Multiforme (A) without Prior Bevacizumab Exposure and 
(B) after Failing prior Bevacizumab
DATE SHIPPED:   
SITE NAME:  
INVESTIGATOR’S NAME:   
PATIENT’S INITIALS:  
PATIENT’S ID NUMBER:  
Tissue sample:
Collection Date:  
Number of paraffin blocks:  
Number of unstained slides (15 slides preferred if block is not available):  
Please remember all samples for a patient must be shipped within 28 days of collection and to 
label samples as instructed in the protocol. See section 5.1 of the protocol for shipment and 
labeling instructions.
Name of person completing this form:  
Telephone number:  
Signature:  
Date:  
SHIP TO:
Ken Aldape, M.D. 
Toronto General Hospital
200 Elizabeth Street, 11th Floor
Toronto, Ontario M5G 2C4 Canada
kaldape@gmail.com
**Note: Prior to shipping the samples, please contact Dr. Aldape by email on or before the day of 
to ensure appropriate tracking and receipt of the sample. Shipment must be made Mondays 
through Thursdays by overnight shipment to ensure timely arrival of samples during working 
days. s


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15.4 DRUGS KNOWN TO BE METABOLIZED BY CYP450 ISOENZYMES 2D6 AND 3A4
CYP3A3/4
Substrates
Acetaminophen
Aifentanil
Alosetron
Alprazolam
Amiodarone
Amitriptyline (minor)
Amlodipine
Anastrozole
Androsterone
Antipyrine
Astemizole
Atorvastatin
Benzphetamine
Bepridil
Bexarotene
Bromazepam
Bromocriptine
Budesonide
Bupropion (minor)
Buspirone
Busutfan
Caffeine
Cannabinoids
Carbamazepine
Cevimeline
Cerivastatin
Digitoxin
Diltiazem
Disopyramide
Docetaxel
Dolasetron
Donepezil
Doxorubicin
Doxycycline
Dronabinol
Enalapril
Erythromycin
Estradiol
Ethinyl estradiol
Ethosuximide
Chlorpromazine
Cimetidine
Cisapride
Citałopram
Clarithromycin
Clindamycin
Clomipramine
Clonazepam
Clozapine
Cocaine
Codeine (demethylation)
Cortisol
Cortisone
Cyclobenzaprine (demethylation)
Cyclophosphamide
Cyclosporine
Dapsone
Dehydroepiandrostendione
Delavirdine
Desmethyldiazepam
Dexamethasone
Dextromethorphan (minor, N-
demethylation) 
Diazepam (minor; hydroxylation, N-
demethylation)
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Niludipine
Nimodipine
Nisoldipine
Nitrendipine
Omeprazole (sulfonation)
Ondansetron
Oral contraceptives
Orphenadrine
Paclitaxel
Pantoprazole


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Etoposide
Exemestene
Dofetilide (minor)
Felodipine
Fentanyl
Fexotenadine
Finaxteride
Fluoxetine
Flutamide
Glyburide
Granisetron
Halofantrine
Hydrocortixone
Hydroxyarginine
lfosfamide
lmipramine
lndinavir
lsradipine
ltraconazole
Ketoconazole
Lansoprazole (minor)
Letrozole
Levobupivicaine
Lidocaine
Loratadine
Losartan
Lovastatin
Methadone
Mibefradil
Miconazole
Midazolam
Mifepristone
Mirtazapine (N-demethylation)
Montelukast
Navelbine
Toremifene
Trazodone
Tretinoin
Triazolam
Troglitazone
Troleandomycin
Venlafaxine (N-demethylation)
Verapamil
Vinblastine
Pimozide
Pioglitazone
Pravastatin
Prednisone
Progesterone
Proguanil
Propafenone
Quercetin
Quetiapine
Quinidine
Quinine
Repaglinide
Retinoic acid
Rifampin
Risperidone
Ritonavir
Salmeterol
Saquinavir
Sertindole
Sertraline
Sibutramine
Sildenafil citrate
Simvastatin
Sirolimus
Sufentanil
Tacrolimus
Tamoxifen
Temazepam
Teniposide
Terfenadine
Testosterone
Tetrahydrocannabinol
Theophylline
Tiagabine
Tolterodine
Vincristine
Warfarin (R-warfarin)
Yohimbine
Zaleplon (minor pathway)
Zatoestron
Zileuton
Ziprasidone
Zolpidem
Zonisamide
Inducers


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Carbamazepine
Dexamethasone
Ethosuximide
Glucocorticoids
Griseofulvin
Nafcillin
Nelfinavir
Nevirapine
Oxcarbazepine
Phenobarbital
Phenylbutazone
Phenytoin
Primidone
Progesterone
Rifabutin
Rifampin
Rofecoxib (mild)
St John’s wort
Sulfadimidine
Sulfinpyrazone
Troglitazone
Inhibitors
Amiodarone
Anastrozole
Atazanavir
Azithromycin
Cannabinoids
Cimetidine
Clarithromycin
Clotrimazole
Cyclosporine
Danazol
Delavirdine
Dexamethasone
Diethyldithiocarbamate
Diltiazem
Dirithromycin
Disulfiram
Entacapone (high dose)
Erythromycin
Ethinyl estradiol
Fluconazole (weak)
Fluoxetine
Fluvoxamine
Gestodene
Grapefruit juice
lndinavir
lsoniazid
ltraconazole 
Ketoconazole
Metronidazole
Mibefradil
Miconazole (moderate)
Nefazodone
Nelfinavir
Nevirapine
Norfloxacin
Norfluoxetine
Omeprazole (weak)
Oxiconazole
Paroxetine (weak)
Propoxyphene
Quinidine
Quinine
Quinupristin and dalfopristin
Ranitidine
Ritonavir
Saquinavir
Sertindole
Sertraline
Telithromycin
Troglitazone
Troleandomycin
Valproic acid (weak)
Verapamil
Voriconazole
Zafirlukast
Zileuton
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL, 
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 
2000: 1364-1371)


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 83 of 96
15.5 MD ANDERSON SYMPTOM INVENTORY FOR BRAIN TUMORS (MDASI – BT)


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Version Date:  07/17/2025
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Abbreviated Title: Ph II Pazopanib Topotecan
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Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
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15.6 ORAL TOPOTECAN DRUG INTERACTIONS
Breast Cancer Resistance Protein (ABCG2, BCRP, MXR) Inhibitors and 
Inducers 
Antiestrogens:    tamoxifen, toremifene
Antiretrovirals,  Protease inhibitors:    ritonavir, nelfinavir, saquinavir
Proton pump inhibitors:    pantoprazole, omeprazole
Others:   diethylstillbesterol, estrone, flavopiridol, novobiocin, reserpine, 
carbamazepine
P-glycoprotein (ABCB1, P-gp, MDR1) Inhibitors and Inducers
Antifungals:     Itraconazole, etraconazole, ketoconazole, clotrimazole
Antiretrovirals,  Protease inhibitors: amprenavir, indinavir, ritonavir, nelfinavir, 
saquinavir
Antibiotics:  erythromycin, rifampin
Calcium channel blockers:   diltiazem, nicardipine, verapamil
Anticonvulsants:   carbamazepine, phenobarbital
Analgesics:   meperidine, methadone, morphine, pentazocine
Immune modulators:  Valspodar
Others:  Atorvastatin,  bromocriptine, carvedilol, omeprazole, progesterone, 
quinine, dexamethasone (large doses), phenothiazine, retinoic acid, St. John’s 
wort


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 87 of 96
15.7 THE NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION 
The New York Heart Association (NYHA) Functional Classification provides a simple way of 
classifying the extent of heart failure. It places patients in one of four categories based on how 
much they are limited during physical activity; the limitations/symptoms are in regards to normal 
breathing and varying degrees in shortness of breath and or angina pain:
Functional Capacity
Objective Assessment
Class I. Patients with cardiac disease but without 
resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, 
palpitation, dyspnea or anginal pain.
No objective evidence 
of cardiovascular 
disease
Class II. Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain.
Objective evidence of 
minimal 
cardiovascular disease
Class III. Patients with cardiac disease resulting in 
marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease
Class IV. Patients with cardiac disease resulting in 
inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort increases.
Objective evidence of 
severe cardiovascular 
disease


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 88 of 96
15.8 HEPATITIS RISK FACTORS
Note: The site cannot use the form attached in the protocol (Appendix 13.8). The site will need 
to copy the form with their own site letterhead.  The form need to be signed and dated by the 
research staff after discussion with the patient.
Hepatitis A Risk factors
1.
Travel or work in regions with high rates of hepatitis A
2.
Are a man who has sexual contact with other men
3.
Are HIV positive
4.
Use injected or noninjected illicit drugs
5.
Live with another person who has hepatitis A
6.
Receive clotting-factor concentrates for hemophilia or another medical 
condition
Hepatitis B risk factors 
1.
A history of having unprotected sex with more than one partner
2.
If you have had unprotected sex with someone who's infected with HBV
3.
If you have a sexually transmitted infection such as gonorrhea or 
chlamydia
4.
If you are a man who has sexual contact with other men
5.
If you share needles during intravenous (IV) drug use
6.
If you share a household with someone who has a chronic HBV infection
7.
If you have a job that exposes you to human blood
Hepatitis C Risk factors
1.
Health care worker who has been exposed to infected blood
2.
Have ever injected illicit drugs
3.
Are HIV positive
4.
Received a piercing or tattoo in an unclean environment using unsterile 
equipment
5.
Received a blood transfusion or organ transplant before 1992
6.
Received clotting factor concentrates before 1987
7.
Received hemodialysis treatments for a long period of time
8.
Were born to a woman with a hepatitis C infection


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 89 of 96
15.9 CCR PROBLEM REPORT FORM
CCR PROBLEM REPORT FORM
NCI Protocol #: 
Protocol Title: 
Report version: (select one)
____Initial Report 
____Revised Report
____Follow-up 
Site Principal Investigator:
 
Date of problem:    
Location of problem: (e.g.,  patient’s home, 
doctor’s office )
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, 
etc…)
Brief Description of Subject (if 
applicable) 
(Do NOT include personal 
identifiers) 
Sex:  ___ Male  ___ Female Age:  
 ___ Not applicable (more than subject is involved)
Diagnosis under study:  
Name the problem: (select all that apply)  
[  ] Adverse drug reaction  
[  ] Abnormal lab value  
[  ] Death  
[  ] Cardiac Arrest/ code 
[  ] Anaphylaxis 
[  ] Sepsis/Infection  
[  ] Blood product reaction
[  ] Unanticipated surgery/procedure  
[  ] Change in status (e.g. increased level of care required)   
[  ] Allergy (non-medication) 
[  ] Fall 
[  ] Injury/Accident (not fall) 
[  ] Specimen collection issue  
[  ] Informed consent issue  
[  ] Ineligible for enrollment  
[  ] Breach of PII 
[  ] Tests/procedures not performed on schedule 
[  ]  Other, brief  1-2 word description: _________________________
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history):


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 90 of 96
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  
Please explain:
 *Is this problem related or possibly related to participation in the research?  __YES __NO  
Please explain:
*Does the problem suggest the research places subjects or others at a greater risk of harm 
than was previously known or recognized?    __YES __NO      Please explain:
Is this problem? (select all that apply)
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious 
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious
[  ] Non-compliance
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP.
Is the problem also (select one)  [  ] AE  [  ] Non-AE
Have similar problems occurred on this protocol at your site? __YES __NO      
If “Yes”, how many? ____      Please describe:
Describe what steps you have already taken as a result of this problem:
In addition to the NCI IRB, this problem is also being reported to: (select all that apply)
[  ] Local IRB
[  ] Study Sponsor
[  ] Manufacturer : ____________________ 
[  ] Institutional Biosafety Committee 
[  ] Data Safety Monitoring Board
[  ] Other: ____________________________________ 
[  ] None of the above, not applicable
INVESTIGATOR’S SIGNATURE: 
DATE:  


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 91 of 96
15.10 PILL DIARY


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 92 of 96


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 93 of 96
15.11 PILL COUNT DOCUMENTATION FOR PAZOPANIB
TO BE COMPLETED BY CLINICAL RESEARCH STAFF
PATIENT INITIALS:  
BTTC ID #:  
CYCLE#:  
DOSE OF PAZOPANIB PRESCRIBED:
mg PO Daily for 28 days EVERY cycle
(Pazopanib is supplied in Tablet strength(s) mg
DATE DISPENSED:   
(mm/dd/yyyy)
QUANTITY OF BOTTLES DISPENSED:   
QUANTITY OF
MG TABLETS DISPENSED:   
NUMBER OF MG TABLETS PER DAY REQUIRED TO ACHIEVE PRESCRIBED DOSE:    
**********DO NOT RETURN UNUSED TABLETS TO THE PATIENT*************
RETURN PILL COUNT DATE:  
(mm/dd/yyyy)
Has the patient taken the dose scheduled for this date?
YES
NO
QUANTITY OF BOTTLES RETURNED:  
QUANTITY OF TABLETS RETURNED:  
QUANTITY OF TABLETS DESTROYED:  
SIGNATURE OF PHARMACY OR RESEARCH STAFF:
DATE:
 
SITE: _____________________________________
PHONE #  
 


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 94 of 96
15.12 PILL COUNT DOCUMENTATION FOR TOPOTECAN
PATIENT INITIALS:  
BTTC ID #:  
CYCLE#:  


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 95 of 96
DOSE OF TOPOTECAN PRESCRIBED:
mg PO Daily for 28 days EVERY cycle
(Topotecan is supplied in Capsule strength(s)
mg
DATE DISPENSED:   
(mm/dd/yyyy)
QUANTITY OF BOTTLES DISPENSED:   
QUANTITY OF
MG TABLETS DISPENSED:   
NUMBER OF
MG TABLETS PER DAY REQUIRED TO ACHIEVE PRESCRIBED 
DOSE:    
**********DO NOT RETURN UNUSED TABLETS TO THE PATIENT*************
RETURN PILL COUNT DATE:  
mm/dd/yyyy)
Has the patient taken the dose scheduled for this date?
YES
NO
QUANTITY OF BOTTLES RETURNED:  
QUANTITY OF TABLETS RETURNED:  
QUANTITY OF TABLETS DESTROYED:  
SIGNATURE OF PHARMACY OR RESEARCH STAFF:
DATE:
 
SITE: _____________________________________
PHONE #  


Abbreviated Title: Ph II Pazopanib Topotecan
Version Date:  07/17/2025
Page 96 of 96
15.13 TECHNOLOGY TRANSFER AGREEMENTS
Agreement
Party
Number
Date Executed
DTA Amendment 1
Baylor
13855-18
5/7/2018
CDA
Baylor
13855-18
11/7/2017
DTA  
Cleveland Clinic
14084-18
7/11/2018
DTA 
Henry Ford
13837-18
10/30/2017
DTA Amendment 1
Henry Ford
13837-18
5/21/2018
DTA 
MDACC 
14085-18
4/13/2018
DTA
NorthShore
14167
4/30/2018
DTA
Northwestern
14168-18
6/18/2018
CDA
Texas Oncology
13754-17
10/24/2017
CDA Amendment 1
Texas Oncology
13754-17
6/22/2018
DTA
UTSW
14169-18
6/6/2018
DTA
Utah
14083-18
5/28/2018
CDA
MDACC 
13471-17
7/3/2017
DTA
Texas Oncology
14403-18
8/8/2018
CDA
Novartis
13618-17
9/6/2017

ICF_002.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
16-C-0034 
PRINCIPAL INVESTIGATOR: 
Mark Gilbert, M.D. 
STUDY TITLE:  
A Phase II Trial of Oral Pazopanib plus Oral Topotecan Metronomic Antiangiogenic 
Therapy for Recurrent Glioblastoma Multiforme (A) without Prior Bevacizumab 
Exposure and (B) after Failing Prior Bevacizumab 
Continuing Review Approved by the IRB on 11/07/16 
Amendment Approved by the IRB on 01/08/16 (A) 
                   Date posted to web:  12/01/16 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 2 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Why is this study being done?  
The goal of this clinical research study is to learn if pazopanib when given in combination with 
topotecan can help to control glioblastoma.  The safety of this drug combination will also be 
studied. 
This is an investigational study.  Pazopanib is FDA approved and commercially available for the 
treatment of renal cell cancer.  Topotecan is FDA approved and commercially available for the 
treatment of lung cancer.  In this study, the combination of pazopanib and topotecan being used 
to treat brain tumors is investigational.  At this time, this combination is only being used in 
research. 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have glioblastoma (brain tumor) that 
is recurrent (has returned after treatment). 
How many people will take part in this study?  
Up to 66 participants will be enrolled in this multicenter study.  Up to 6 will take part at NCI. 
Description of Research Study 
Before you begin the study 
You will have screening tests to help the doctor decide if you are eligible to take part in this 
study. If some of these tests have been performed within the past 14 days, they may not need to 
be repeated. These tests include medical history, physical exam, routine blood and urine tests, 
CT scan or MRI of your brain, CT scan or x-ray of your chest, an EKG and you will also 
complete a questionnaire about your quality of life. 
During the study 
If you are found to be eligible to take part in this study, you will be assigned to a study group 
based on if you have received a drug called bevacizumab in the past. 
You will be in Group A if you have not received bevacizumab in the past. 
You will be in Group B if you have received bevacizumab in the past.   
Both groups will receive pazopanib and topotecan at the same dose level and on the same 
schedule.   Up to 34 participants will be enrolled in Group 1 and up to 32 participants will be 
enrolled in Group 2.   
Study Drug Administration 
Each cycle is 28 days. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 3 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
You will take capsules of topotecan by mouth 1 time every day at about the same time each day.  
You should swallow the capsules whole with at least 1 cup (8 ounces) of water, with or without 
food. 
You will take tablets of pazopanib by mouth 1 time every day at about the same time each day.  
They should be taken on an empty stomach (at least 1 hour before and 2 hour after eating) with 
about 1 cup (8 ounces) of water.  
Pazopanib should be taken whole with water and must not be broken or crushed. 
If a dose of pazopanib is missed, it should not be taken if it is less than 12 hours until the next 
dose. 
If you vomit after taking the study drugs, you should not take a replacement dose on that day.  
You should resume taking the study drugs at the next scheduled dose on the following day.  If 
vomiting continues, you should tell your doctor. 
You will be given a study drug diary to record the times that you take the study drugs and if you 
vomit.  You should bring the diary to each study visit. 
Study Visits 
At Week 1, your blood pressure will be measured. 
At Week 2, your blood pressure will be measured and blood (about 1 teaspoon) will be drawn for 
routine tests. 
At Week 4, you will have an EKG. 
Every 4 weeks: 
• You will have a physical exam. 
• Blood (about 2 teaspoons) will be drawn for routine and biomarker testing. 
• Urine will be collected to check your kidney function. 
Every 8 weeks:  
• You will have a neurological exam. 
• Blood (about 1 teaspoon) will be drawn to check thyroid function. 
• You will have an EKG. 
• If you are in Group A, you will have a brain MRI or CT scan at Week 4 of Cycle 2, and 
then every other cycle after that (Cycles 4, 6, 8 and so on) to check the status of the 
disease.  You will also complete the symptom questionnaire at these visits.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 4 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• If you are in Group B, you will have a brain MRI or CT scan at Week 4 of Cycles 1, 2, 3, 
and then every other cycle after that (Cycles 5, 7, 9 and so on)  to check the status of  the 
disease.  You will also complete the symptom questionnaire at these visits.  
At any time during the study, extra tests may be performed if the doctor thinks they are needed 
for your safety.  The study doctor will tell you more about any extra tests. 
End-of-Treatment Visit 
Within 14 days after your last dose of the study drugs, you will have an end-of-treatment visit.  
The following tests and procedures will be performed: 
• You will have a physical exam. 
• Blood (about 2 teaspoons) will be drawn for routine and biomarker testing.  This blood 
draw will also include a pregnancy test if you can become pregnant.  
Length of Treatment 
You may take the study drugs for up to 1 year.  You will no longer be able to take the study 
drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow 
study directions. 
Your participation on the study will be over after the long-term follow-up phone calls. 
Long-Term Follow-Up Calls 
After you have stopped taking the study drugs and completed your end-of-treatment visit, the 
study staff will call you 1 time every 3 months from then on to check on how you are doing.  
Each phone call should last about 5 minutes. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 6 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• condoms with spermicide 
• diaphragm with spermicide 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 5 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Alternative Approaches or Treatments 
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Risks or Discomforts of Participation 
While on this study, you are at risk for side effects.  These side effects will vary from person to 
person. The more commonly occurring side effects are listed in this form, as are rare but serious 
side effects.  You should discuss these with the study doctor. You may also want to ask about 
uncommon side effects that have been observed in small numbers of patients but are not listed in 
this form.  Many side effects go away shortly after treatment is stopped, but in some cases, side 
effects may be serious, long-lasting or permanent, and may even cause death. 
Tell the study staff about any side effects you may have, even if you do not think they are related 
to the study drugs. 
Topotecan and pazopanib each may cause low blood cell counts (red blood cells, platelets, and/or 
white blood cells): 
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You 
may need a blood transfusion. 
• A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding). You may need a platelet transfusion. 
• A low white blood cell count increases your risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing. 
Topotecan Side Effects 
Common (occurring in more than 20% of patients) 
• fatigue 
• weakness 
• fever 
• hair loss (partial or total)  
• nausea 
• vomiting 
• diarrhea 
• constipation 
• pain 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 6 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• abdominal pain 
• low blood cell counts 
(red, platelets, white) 
• difficulty breathing 
failure, and/or heart 
failure) 
Occasional (occurring in 3-20% of patients) 
• headache 
• skin rash 
• abnormal sensation (such as 
pins and needles) 
• intestinal blockage 
• loss of appetite 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• abnormal liver tests 
(possible liver damage 
or yellowing of the skin 
and/or eyes) 
• cough 
Rare but serious (occurring in fewer than 3% of patients) 
• tissue swelling 
• lung inflammation 
(possible difficulty 
breathing) 
• allergic reaction 
(possibly life-
threatening, such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure)  
Pazopanib Side Effects 
Common (occurring in more than 20% of patients)  
• high blood pressure 
• fatigue  
• headache 
• change in hair color 
• abnormal salts, minerals, 
and/or acids in the blood 
(possible weakness, swelling, 
fatigue, low blood pressure, 
organ failure, heart problems, 
changes in mental status, 
and/or seizure) 
• high blood sugar 
(possible diabetes) 
• overactive thyroid gland 
(possible weight loss, 
heart rate changes, and/or 
sweating) 
• diarrhea  
• nausea  
• abnormal digestive blood 
test (possible 
inflammation of the 
pancreas) 
• weight loss  
• loss of appetite  
• vomiting  
• abnormal taste 
• abdominal pain 
• low blood cell counts 
(white/platelets) 
• abnormal liver tests 
(possible liver damage 
and yellowing of the skin 
and/or eyes)  
• pain (muscle/bone/tumor) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 7 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Occasional (occurring in 3-20% of patients) 
• swelling (arm/leg) 
• chest pain  
• severe heart problems 
• blood clots in a vein 
(possible pain, swelling, 
and/or redness) 
• dizziness  
• difficulty sleeping 
• voice changes 
• chills 
• hand-foot syndrome (palms 
of hands/soles of feet having 
pain, swelling, and 
blistering) 
• skin rash  
• hair loss (partial or total) 
• lightening of skin  
• dry skin  
• nail changes 
• low blood sugar 
• underactive thyroid 
gland (possible weight 
gain, heart failure, 
and/or constipation) 
• upset stomach  
• bleeding in the mouth 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• weakness 
• blurry vision 
• blood in the urine  
• abnormal kidney test 
(possible kidney 
damage) 
• difficulty breathing 
• cough  
• collapsed lung (possibly 
difficulty breathing) 
• nosebleed 
Rare but serious (occurring in fewer than 3% of patients)   
• irregular heartbeat 
• heart attack/failure 
• decreased blood supply to 
the heart  
• severe increase in blood 
pressure (possible stroke) 
• swelling (face) 
• temporary stroke symptoms 
• brain damage that may be 
reversible (possible 
• uncontrolled movements 
• stroke 
• bleeding in/around the 
brain 
• multiple blood clots 
(possible organ 
dysfunction and/or 
failure) 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• bleeding or blood in the 
stool  
• abnormal connections or 
passageways between 
different  parts of the 
digestive system 
• liver damage 
• decreased kidney 
function (possible 
kidney failure) 
• coughing up blood 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 8 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
headache, confusion, 
seizures, and/or vision loss)  
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen)  
• blood clots in the lung 
(possible failure to 
breathe) 
• bleeding in or from the 
tumor  
Frequency Unknown 
Pazopanib may cause fatal liver damage.   
Other Risks 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or develop an 
infection with redness and irritation of the vein at the site where blood is drawn.  Frequent blood 
collection may cause anemia (low red blood cell count), which may create a need for blood 
transfusions. 
Questionnaires may contain questions that are sensitive in nature.  You may refuse to answer any 
question that makes you feel uncomfortable.  Collection of this information is authorized under 
42 USC 285.  If you have concerns about completing the questionnaire, you are encouraged to 
contact your doctor or the Principal Investigator. 
This study may involve unpredictable risks to the participants. 
Potential Benefits of Participation 
Are there benefits to taking part in this study? 
The aim of this study is to determine a safe dose and to see if this experimental treatment will 
cause your tumors to shrink.   We do not know if you will receive personal medical benefit from 
taking part in this study.  These potential benefits could include shrinking of your tumor or 
lessening of your symptoms, such as pain, that are caused by the cancer.  Because there is not 
much information about the drug’s effect on your cancer, we do not know if you will benefit 
from taking part in this study, although the knowledge gained from this study may help others in 
the future who have cancer.   
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 9 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• The study Sponsor, Brain Tumor Trials Collaborative (BTTC) or their agent(s)  
• Qualified representatives from Novartis, the pharmaceutical company who produces 
pazopanib. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if your disease comes back during treatment 
• if you become pregnant while on study therapy 
• if you have side effects from the treatment that your doctor thinks are too severe 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0034 
CONTINUATION: page 10 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Brain Tumor Trials 
Collaborative (BTTC), Novartis or designated representatives. If you withdraw your consent and 
leave the trial, any samples of yours that have been obtained for the study and stored at the 
NCI can be destroyed upon request. However, any samples and data generated from the samples 
that have already been distributed to other researchers or placed in the research databases cannot 
be recalled and destroyed. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using drugs developed 
by Novartis through a joint study with your researchers and the company.   The company also 
provides financial support for this study.  


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 16-C-0034 
 
CONTINUATION: page 11 of 12 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Mark Gilbert, M.D.,  Building 82, Room 235A, Telephone:  301- 
402.6383. You may also call the Clinical Center Patient Representative at 301-496-2626.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 16-C-0034 
 
CONTINUATION: page 12 of 12 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby consent to take part in this study. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby give permission for my child to take 
part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian 
Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM NOVEMBER 07, 2016 THROUGH NOVEMBER 6, 2017.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name