A Phase II Study of Pazopanib With Oral Topotecan in Patients With Metastatic and Non-resectable Soft Tissue and Bone Sarcomas
Phase: PHASE2
Conditions: Adult Liposarcoma, Metastatic Liposarcoma, Metastatic Osteosarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Liposarcoma, Recurrent Osteosarcoma, Stage IV Adult Soft Tissue Sarcoma
Sponsor: Northwestern University

A Phase II Study of Pazopanib with Oral Topotecan in Patients 
with Metastatic and Non-resectable Soft Tissue and Bone 
Sarcomas
Principal Investigator:
Mary F Mulcahy, MD 
Northwestern University
Professor  of Hematology/Oncology
676 N. St. Clair, suite 850, Chicago, IL 60611
Phone: (312) 695-4440
Fax: (312) 695-6189
Email: Mary.Mulcahy@nm.org 
Sub-Investigator(s):
Valerie Nelson, M.D.
Northwestern University: 
Email: vnelson@nm.org
Sub-Investigators/Participating Sites in the Midwest Sarcoma Trials Partnership (MSTP)
Scott Okuno, MD 
Mayo Clinic
200 1st St. SW 
Rochester, MN 55905
Phone: (507) 284-4849 
okuno.scott@mayo.edu
Steven Attia, DO 
Mayo Clinic
4500 San Pablo Road S 
Jacksonville, FL 32225
Phone: (904) 953-2558 
attia.steven@mayo.edu
Kelly Curtis, MD 
Mayo Clinic
13400 East Shea Blvd
Scottsdale, AZ 85259
Phone: (480) 301-8335 
curtis.kelly1@mayo.edu
Mohammed Milhem, MD 
University of Iowa
200 Hawkins Dr. GH C32
Iowa City, IA 52246
Phone: (319) 356-2324 
mohammed-milhem@uiowa.edu
Brian Van Tine, MD, PhD 
Washington University
660 S. Euclid Ave, Box 8056
St. Louis, MO 63110
Phone: (314) 747-8475 
bvantine@dom.wustl.edu
Biostatistician:
Hui, Zhang, PhD 
Northwestern University 
hzhang@northwestern.edu
Study Intervention(s):
Pazopanib (Votrient) and Topotecan (Hycamtin)
IND Number:
EXEMPT
IND Holder:
IND-EXEMPT
Funding Source:
Novartis
Version Date:
June 26th 2020
Lead Site/ Coordinating Center:
Northwestern University
Robert H. Lurie Comprehensive Cancer Center
Clinical Research Office
676 N. St. Clair Street, Suite 1200, Chicago, IL 60611 
www.cancertrials.northwestern.edu
Amendment-13          Version Date: 06-26-2020 
i
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

TABLE OF CONTENTS
LIST OF ABBREVIATIONS............................................................................................................. 3
STUDY SCHEMA ............................................................................................................................ 4
1.0
Introduction – BACKGROUND & RATIONALE ................................................................ 7
2.0
OBJECTIVES & ENDPOINTS........................................................................................... 11
3.0
PATIENT ELIGIBILITY ...................................................................................................... 12
4.0
TREATMENT PLAN .......................................................................................................... 18
5.0
STUDY PROCEDURES..................................................................................................... 29
6.0
ENDPOINT ASSESSMENT ............................................................................................... 32
7.0
ADVERSE EVENTS .......................................................................................................... 36
8.0
DRUG INFORMATION ...................................................................................................... 40
9.0
CORRELATIVES/SPECIAL STUDIES.............................................................................. 46
10.0
STATISTICAL CONSIDERATIONS .................................................................................. 47
11.0
STUDY MANAGEMENT .................................................................................................... 49
REFERENCES............................................................................................................................... 52
APPENDICES ................................................................................................................................ 56
APPENDIX A1. GENERAL DRUGS TO BE AVOIDED WITH PAZOPANIB ............................... 56
APPENDIX A2. Table of Drugs known to be metabolized by CYP450 
isoenzymes 2D6 and 3A4 (to be avoided with pazopanib)…………………………….56
APPENDIX B. TABLE OF ORAL TOPOTECAN DRUG INTERACTIONS...................................59
Appendix C. New York Heart Association (NYHA) Functional Classification ........................60
APPENDIX D – DATA COLLECTION & SUBMISSION GUIDELINES ........................................ 61
APPENDIX E – DATA SAFETY MONITORING PLAN................................................................. 61
Appendix F- Patient Medication Diary ....................................................................................... 63
Appendix G – BLOOD PRESSURE LOG .................................................................................... 67
Appendix H- Protocol History of Changes ................................................................................ 68
Amendment-13
 Version Date: 06-26-2020                                                                                  ii
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
3
LIST OF ABBREVIATIONS
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CR
Complete Response
CTCAE
Common Terminology Criteria for Adverse Events
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration 
FGFR
Fibroblast Growth Factor Receptor 
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HFSR                   Hand-foot-skin reaction 
IB                         Investigator’s Brochure 
ICF                       Informed Consent Form
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
MAPK
Mitogen Activated Protein Kinase
OS
Overall Survival
PD
Progressive Disease
PDGFR-α
Platelet Derived Growth Factor Receptor-alpha 
PDGFR-β
Platelet Derived Growth Factor Receptor-beta 
PFR
Progression-free rate
PO
per oris, oral
PR
Partial Response
PS
Performance Status
PTT
Partial thromboplastin time
QD
quaque die, once daily
RAF
Rapidly Accelerated Fibrosarcoma
RAS
Rat sarcoma
RECIST
Response Evaluation Criteria for Solid Tumors
SAE
Serious Adverse Event
SD
Stable Disease
STS
Soft Tissue Sarcoma
TK
Tyrosine Kinase
TTP
Time to Progression
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
4
STUDY SCHEMA
Screening/Eligibility:
Patients with recurrent or metastatic and unresectable bone or soft tissue 
sarcoma who failed at least 1 prior therapy
Cohort 1: 
Soft Tissue 
Sarcoma (non 
Liposarcoma)
Cohort 2: 
Osteosarcoma
(up to 36 patients)
Cohort 3:
High-grade, de-differentiated, or
Myxoid Liposarcoma
(up to 20 patients)
Treatment (28 days per cycle):
Pazopanib 800mg po daily continous PLUS Topotecan 8mg 
po day 1,8,15
Disease Assessment:
Evaluation with CT or MRI at 6, 12, and 20 weeks and every
8 weeks thereafter
Continue treatment until:

Disease Progression

Unacceptable toxicity

Patient preference

Physician recommendation
Follow Up:
Patients with progressive disease (PD) at end of treatment 
will be followed every 6 months for 2 years (or until death) for 
survival. Patients without PD at end of treatment will be 
followed every 6 months for 5 years (or until death) for 
survival and progression. Follow-up may occur over the 
phone
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
5
STUDY SUMMARY
Title
A Phase II Study of Pazopanib with Oral Topotecan in Unresectable or
Metastatic Soft Tissue and Bone Sarcomas
Short Title
Pazopanib and Oral Topotecan in Soft Tissue and Bone Sarcomas
Version
 06.26.20 Amendment 13
Study Design
Multicenter, phase II trial designed to estimate progression-free rate at
week 12 of combination pazopanib and topotecan in patients with soft 
tissue sarcoma (STS), as well as provide preliminary evidence of benefit 
for patients with osteosarcoma or liposarcoma.
This is a single arm two-stage Simon optimum Phase II study of 
pazopanib and topotecan with progression-free rate at 12 weeks as the 
primary outcome. The historic PD free rate at 12 weeks for single agent 
pazopanib is 55%. To detect a 20% improvement (an 11% absolute 
improvement) with the combination of pazopanib and topotecan in a 
single-arm two-stage optimum design and a one-tailed exact binomial p- 
value, a total of 92 evaluable patients is required to detect 55% vs 66% 
with 80% power and an alpha level of 10%. If 32 out of the first 55 
patients are alive and progression free at 12 weeks, the trial may enroll 
up to 108 patients in order to acquire a total of 92 evaluable patients. At 
that time, if 56 or more out of 92 are alive and progression-free at 12 
weeks, then the trial will conclude that the true 12 week PFS rate is at 
least 66%. There is a 63% probability of terminating the study after the 
first stage when the true rate is 55%.
Up to 36 patients with osteosarcoma and 20 patients with liposarcoma 
will be enrolled to obtain exploratory information for patients with these 
two histologies.
The DSMC reviewed the interim analysis data on 1/11/2017, and has 
approved cohort 1 to reopen to 96 total patients (to obtain 92 evaluable 
patients). In addition, based on the percentage of non-evaluable patients 
during the interim analysis, it was determined that a total of 108 patients 
would most likely need to be enrolled in order to obtain 92 evaluable 
patients.
The remaining slots have been equally divided in 5 ways among the 
sites, with an expiration date of May 12, 2017. Status of accrual will be 
reassessed at that time, and the remaining slots will be divided 
accordingly.
Study Center(s)
Lead Institution: Robert H. Lurie Comprehensive Cancer Center of
Northwestern University
Participating Sites: University of Wisconsin, Mayo Clinic (Rochester, 
MN), Mayo Clinic (Phoenix, AZ), Mayo Clinic (Jacksonville, FL), 
Washington University, University of Minnesota, University of Iowa
Objectives
Primary Objective:
Determine progression-free rate (PFR) at 12 weeks for patients with STS
treated with Pazopanib and Oral Topotecan
   Secondary Objectives:
1) Determine the overall response rate (CR + PR)
2) Determine the clinical benefit rate (CR + PR + SD)
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
6
4) Determine median PFR
5) Assess safety and tolerability
6) Estimate the PFR in patients with osteosarcoma
7) Estimate the PFR in patients with liposarcoma
Exploratory objectives: 
For Cohort 1 and 3
Quantify Cell-free circulating tumor DNA (ctDNA) at each time point, and 
correlate these results with demographic, diagnostic, treatment, and 
outcomes data.
For Cohort 2
Evaluate the correlation of PFR and OS to levels of sVEGFR2 and PIGF
Sample Size
A total of 164 patients may be enrolled including 108 patients with STS
(to acquire 92 evaluable patients), and up to 36 patients with 
osteosarcoma and 20 patients with liposarcoma.
The DMC reviewed the interim analysis data on 1/11/2017, and has 
approved cohort 1 to reopen to 96 total patients (to obtain 92 evaluable 
patients). In addition, based on the percentage of non-evaluable patients
during the interim analysis, it was determined that a total of 108 patients 
would most likely need to be enrolled in order to obtain 92 evaluable
patients.
Diagnosis & Key
Eligibility Criteria
Patients with histologically confirmed diagnosis of metastatic or locally
advanced unresectable:
a.
soft tissue sarcomas (non-liposarcoma)
b.
osteosarcoma 
c.
liposarcoma- high grade, de-differentiated, or myxoid
(exploratory)
Patients must have measurable disease within 4 weeks prior to 
registration by RECIST 1.1
Patients must have had a minimum of 0 and a maximum of 4 prior 
chemotherapy regimens for recurrent/metastatic disease deetermined by 
cohort assignment. It will be up to the investigator to determine what 
constitutes a “regimen” in each case. The last dose of systemic therapy 
must have been given at least 4 weeks prior to initiation of therapy. 
Patients receiving BCNU or mitomycin C must have received their last 
dose at least 6 weeks prior to initiation of therapy.
Treatment Plan
Patients will be treated with Pazopanib 800mg oral daily, plus Topotecan
8mg orally day 1, 8, 15 every 28 days until disease progression or 
unacceptable toxicity occurs, or until discontinuation per patient 
preference or physician recommendation.
Statistical Methodology
PFR and OS will be estimated using Kaplan-Meier methods for each
histologic group (STS, osteoscaroma, and liposarcoma). Response 
rates will be summarized by the observed proportion of patients with 
response, along with a 95% confidence interval.  Toxicities will be 
tabulated and summarized by the number of patients experiencing each 
toxicity. A formal hypothesis test for the median PFR of the STS patients 
is planned; no formal hypothesis test is planned for the other two 
histologic groups.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
7
1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1   Soft tissue and Bone Sarcoma- disease background and current treatment 
strategies
Soft Tissue Sarcomas (STS) are malignant tumors arising from mesenchymal tissue in 
the extremities, trunk, retroperitoneum, or head and neck. STS comprise a 
heterogeneous group of tumors, each with distinct histological, cytological, and 
molecular features.1 It is estimated that in the United States in 2014, there will be
12,020 new cases and 4,740 deaths from STS.2 Treatment of early stage disease 
consists of surgical resection with or without adjuvant radiation therapy for select 
patients.3-5 The data surrounding use of adjuvant chemotherapy is conflicting, as 
some studies suggest an improvement in disease free survival, with little or no
improvement in overall survival.6-8 Adjuvant therapy is often utilized in chemosensitive 
subtypes, such as rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma. Despite
a multimodality approach, development of distant metastases remains high, with 30-
60% of patients developing advanced disease.
For advanced disease, there is an established clinical benefit from chemotherapy yet 
prognosis remains poor and 5 year overall survival rates remain less than 20%.9 The 
median survival time for patients with metastatic disease is 12 months.10 Current 
chemotherapy options consist of single agent or combination doxorubicin, ifosfamide, 
dacarbazine, or gemcitabine. Therapy is often limited by substantial toxic effects and 
patients often relapse despite aggressive treatment. For most patients, the goal of 
therapy is palliative to reduce tumor size, tumor-related symptoms, and improve quality 
of life. A complete response to therapy is rare and the factors predicting response to 
chemotherapy are not the same as those that impact overall survival.10
Most patient develop progressive disease quickly and tumors become resistant to 
therapy within months. There are limited options available for subsequent treatment, 
therefore novel therapeutic strategies are needed in this area.
1.2   The Role of Angiogenesis in Soft Tissue sarcoma
Angiogenesis is an established mechanism for tumor growth, invasion and development 
of metastasis in several tumor types11 and has been recently recognized as an important 
factor in advanced STS. Although the exact mechanisms for invasion and hematologic 
spread of sarcomas are not entirely clear, metastatic potential has been associated with 
degree of vascularization.12 It has been long established that tumors require 
neovascularization to maintain growth beyond a certain size.13 Tumor angiogenesis is 
largely driven by endothelial formation of new blood vessels from existing vasculature. 
Regulation of angiogenesis is complex, involving an intricate interplay between 
endothelial cells, support cells, bone marrow derived stem cells,
and growth factors within the tumor and tumor microenvironment. Under normal 
circumstances, regulation of angiogenesis is maintained through balance of pro- 
angiogenic and anti-angiogenic factors. In malignancy driven angiogenesis, the 
balance is shifted in favor of more pro-angiogenic signaling, often referred to as the 
angiogenic switch.13-16
Tumor angiogenesis is largely regulated through vascular endothelial growth factor 
(VEGF).17-19 The VEGF pathway is made up of three receptors (VEGFR- 1, 2, 3) and 
seven ligands (VEGF A, B, C, D, E, PIGF-1, 2). These ligands bind to their related 
receptors on endothelial cells resulting in downstream intra-cellular signaling that 
promotes endothelial growth, migration, and survival outside of the existing 
vasculature.20,21 VEGF-A is the key regulator of normal and tumor angiogenesis,22 
however evidence suggests that other pathways such as the platelet derived growth 
factor (PDGF) play a key role.23,24 PDGF receptors (PDGFRα and PDGFRβ), are 
expressed on pericytes and smooth muscle cells, and regulate pericyte differentiation,
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
8
recruitment and regulation of tumor stroma, and regulation of vessel stability and 
vascular survival.25,26 They can also function as growth factors, leading cells to 
progress through the cell-cycle and avoid apoptosis.27-29
VEGF is expressed in a number of STS30 and the expression of VEGF has been 
associated with higher tumor grade, increased ability to metastasize, and decreased 
overall survival in certain subtypes of sarcoma.31-34 For example, in leiomyosarcoma, 
higher VEGF serum levels were associated with worse prognosis and shorter overall 
survival.30,35 Platelet derived growth factor (PDGFR) also plays a role in STS 
angiogenesis and proliferation, and PDGFR- beta expression has been associated with 
higher grade tumors.36 Furthermore, hypoxia-inducible factor 1α (HIF-1), an upstream 
regulator of VEGF, was a predictor of metastatic potential in sarcomas.37
HIF-1 was found to be associated collagen modification promoting distant spread and 
decreased chemo-sensitivity and reduced apoptosis.38,39 Therefore agents that
disrupt tumor angiogenesis have become of interest in STS. Several phase II trials have 
been done to evaluate anti-angiogenic treatments.40-43 However, only one phase
III trial with Pazopanib has been completed to date.
1.3   Pazopanib in Sarcoma
Pazopanib, a synthetic indazolyl pyrimidine, is a multi-kinase inhibitor of VEGFR-
1/2/3, and to a lesser degree PDGFR-α/β, FGFR-1/2, and c-Kit.44-46 In vivo studies 
showed dose-dependent tumor growth inhibition in a variety of tumor xenografts by 
pazopanib (colon, melanoma, prostate, renal, breast, lung).47 Pazopanib is thought to 
inhibit angiogenesis through attenuation of VEGFR-2 signaling. Pharmacokinetic 
analysis revealed that the steady-state concentration (Ctrough) for tumor growth 
inhibition in vivo was almost equivalent to the concentration required for in vivo
inhibition of VEGFR-2 phosphorylation.47
Phase I studies determined Pazopanib 800mg daily as the recommended monotherapy 
dose.48 There is now plentiful evidence that single agent pazopanib has clinical benefit in 
advanced sarcomas. The phase II study (VEG20002) evaluated single agent pazopanib 
in patients with relapsed or refractory soft tissue sarcoma.43
Treatment response data are available for 138 patients who received pazopanib 800 mg 
once daily. Ninety-nine percent of patients had received prior chemotherapy: 35 patients 
(25%) had received therapy in a (neo)-adjuvant setting, 83 (59%) had received therapy 
in an advanced setting, and 22 (16%) had received both. The
primary endpoint was the progression-free rate, using Response Evaluation Criteria in 
Solid Tumors (RECIST) at 12 weeks after start of treatment. Patients with 
leiomyosarcoma, synovial sarcoma and “the other types of sarcoma” strata receiving 
pazopanib in VEG20002 experienced a 12 week progression free survival rate of ≥
40%, the pre-defined threshold indicating anti-tumor activity. The liposarcoma stratum did 
not meet its prespecified endpoint at the end of stage 1 and did not progress to stage 2.
Based on the results of the VEG20002, a Phase III randomized, double blind, placebo 
controlled study (VEG110727) of pazopanib versus placebo in patients with soft
tissue sarcoma (study excluded patients with GIST or liposarcoma) was initiated in
2008.49 372 patients were registered and 369 were randomly assigned to receive 
pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4.6 
months (95% CI 3.7–4.8) for pazopanib compared with 1.6 months (0.9–1.8) for 
placebo (hazard ratio [HR] 0.31, 95% CI 0.24–0.40; p<0.0001). Overall survival was
12.5 months (10.6–14.8) with pazopanib versus 10.7 months (8.7–12.8) with placebo (HR 
0.86, 0.67–1.11; p=0.25). The most common adverse events were fatigue (60 in the 
placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhea (20 [16%] vs
138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]),
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
9
and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for 
placebo and 96% for pazopanib. Despite improvement is progression-free survival, 
response rate was only 6% for patients receiving pazopanib.
1.4   Topotecan in Sarcoma
Camptothecin agents have been evaluated in sarcoma patients for the last decade. This 
class of agents is attractive because of commercial availability, modest single agent 
activity, and demonstrated tolerability. Camptothecins exert cytotoxicity by stabilizing the 
covalent complex between DNA and topoisomerase I, the enzyme which relieves 
torsional strain of DNA. This stabilization process prevents religation of DNA, and the 
ensuing collision of the stabilized complex with the advancing
replication fork results in double strand breaks and cell death. Topotecan is an orally 
available camptothecin analogue and has been shown to have activity against HIF1- α.50
Phase II studies of topotecan as salvage treatment for patients with soft tissue sarcoma 
have proven the drug to be well tolerated in anthracycline resistant patients with 
metastatic STS, and SD as best response has been documented in 38% of patients in 
one study and disease control rate was documented as 44% of patients in a second 
study.51,52 Objective responses were only seen in patients with uterine 
leiomyosarcoma.52
1.5   Rationale for Combination Therapy
Efforts have been made to potentiate the effect of chemotherapy without increasing 
toxicity. One strategy is to use ‘metronomic’ dosing which uses lower, more frequent 
doses of cytotoxic agents rather than the maximum tolerated dose (MTD).53,54
Continuous exposure to the drugs allows for similar tumor cell death as MTD however 
patients experience less daily and cumulative toxicity. Metronomic chemotherapy can 
also overcome drug resistance by shifting the therapeutic target from tumor cells to tumor 
vasculature as well.55 Metronomic therapy produces an antiangiogenic effect
through continued exposure on tumor endothelial cells,56,57 blocking mobilization of 
endothelial progenitor cells from the bone marrow, and restoration of anti-cancer
immune response.55,58 Simultaneously using anti-angiogenics with chemotherapy 
provides synergistic effects and improved clinical outcomes. There is now preclinical and 
clinical evidence that adding antiangiogenic agents to metronomic chemotherapy 
enhances anti-tumor and antiangiogenic effects.59-61 Therefore the combination of 
metronomic topotecan and pazopanib has become of interest. The theory for
improved activity of this combination is based on targeting both the existing
endothelial cells and bone marrow derived precursors, in addition to inhibition of HIF-
1 alpha and induction of DNA damage by topotecan.
1.6   Pre-clinical and Clinical Evidence for Topotecan and Pazopanib in Solid
Tumors
Support for this combination was demonstrated in mouse models of aggressive pediatric 
solid tumors.59 Results confirmed that metronomic administration of topotecan and 
pazopanib produced a statistically significant delay in tumor growth and was able to 
reduced tumor size in sarcoma models. Combination therapy yielded significant 
antitumor activity and significant improvement in survival compared to the single agents 
in all models. Furthermore, reduction in circulating endothelial cells and tumor 
microvessel density correlated with tumor response, confirming antiangiogenic activity of 
treatments. Pharmacokinetic studies did not reveal any drug–drug interactions between 
the two drugs.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
10
Based on this evidence, oral topotecan and pazopanib was evaluated in patients with 
advanced solid tumors as a phase I regimen. A two-stage, two-arm, phase I study of 
pazopanib and oral topotecan was performed in patients with advanced solid tumors to 
evaluate 2 different schedules of oral topotecan (weekly or daily x5 days) in combination 
with daily pazopanib.62 Part 1 of this study evaluated the effect of pazopanib on the 
bioavailability of topotecan and Part 2 determined the maximum tolerated dose (MTD) of 
combination regimens. Treatment consisted of daily pazopanib with either once weekly 
topotecan in Part 2A or daily topotecan for five consecutive days in Part 2B. The 
bioavailability and safety results of daily pazopanib combined with weekly oral topotecan 
(Part2A) were presented at the annual ASCO meeting in 2013.
Data is available for 28 patients that received at least one dose of therapy- 7 patients in 
Part1; 21 patients in Part 2 (4 STS, 2 colorectal cancer, 2 breast cancer, 1 renal cell 
carcinoma, 5 ovarian cancer, 2 osteosarcoma, and 5 classified as “other”). 
Pharmacokinetic analysis revealed that topotecan AUC0-∞ increased 1.58-fold (90%CI: 
1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with 
pazopanib compared to single administration (n=7). However, neither of these 
parameters were increased for pazopanib when given with topotecan.
During, the dose escalation phase (Part2A), Topotecan was increased from 4mg to
10mg (days 1, 8, 15) and Pazopanib was increased from 400mg to 800mg (q28 days). 
Three dose-limiting toxicities (DLTs) were experienced: grade 3 hand-foot- syndrome, 
diarrhea and neutropenia. Two of 6 patients had DLT with the combination of pazopanib 
800 mg/topotecan 10 mg thereby exceeding the MTD. The most frequent treatment-
related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue 
(2/28 each). There were cases of severe and fatal hepatic failure (n=1) and hemorrhage 
(n=1), requiring that these parameters be monitored closely. Response evaluation was 
possible in 23patients: 9% achieved a PR (2/23);
57% achieved SD (13/23) and 35% developed PD (8/23). The phase II recommended 
dose of weekly Topotecan is 8mg orally day 1, 8, 15 every 28 days with pazopanib
800mg daily.
1.7   Rationale for this study
There are several reasons to consider the combination of oral topotecan and pazopanib 
in recurrent STS. There is prior evidence that topotecan and pazopanib individually have 
clinical benefit in patients with STS (although oral topotecan has not been evaluated in 
STS). The targets of both agents are relevant in metastatic STS, including VEGF and 
HIF-1 alpha. Both agents produce anti-angiogenic effects depending on method and 
dose of administration. Pazopanib inhibits the VEGF and PDGFR pathways and 
topotecan affects endothelial cells, blocks bone marrow derived endothelial precursors, 
and inhibits HIF-1, an upstream regulator of VEGF expression. The utilization of 
pazopanib in combination with oral topotecan is anticipated to produce a synergistic anti-
tumor and worthwhile to explore in patients with STS. The desired effect of palliative 
chemotherapy is that tumor shrinkage or delay in progression will improve patients’ 
activity or wellbeing. With only a 6% response rate to single agent pazopanib, the 
addition of topotecan should potentiate the effect and improve response, thus providing 
increased palliation.
1.8   Exploratory Analysis
There is now data that anti-angiogenic therapy has some benefit in advanced 
osteosarcoma63 providing rationale for further exploring this group of therapies in this 
disease subtype. In patients with relapsed and unresectable high-grade osteosarcoma, 
sorafenib, an orally active multikinase inhibitor of MAPK, VEGFRs, PDGFRs and KIT, 
produced a PFR at 4 months of 46%. In a multicenter phase II trial,
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
11
35 patients received sorafenib 400mg twice a day. 46% of patients required a treatment 
interruption or reduction due to toxicity. Median PFR and OS were 4 (95% CI 2-5) and 7 
(95% CI 7-8) months, respectively. Six patients (17%) experienced PR/SD for ≥ 6 
months.
Data exists to help construct baseline event free survival outcomes that can be used as 
a comparison for future phase II trials for recurrent osteosarcoma (J Clin Oncol. 2016 
Sep 1;34(25):3031-8. doi: 10.1200/JCO.2015.65.5381. Epub 2016 Jul 11.) Using a 
single arm, 2 stage Phase II trial design: For stage I- If 4 or more of 19 patients have 
disease control of greater than 4 months then Stage 2 should be opened. The endpoint 
is that if 11 or more patients/ 36 have disease control at 4 months, then the agent is 
considered sufficiently efficacious for additional study.
While single agent pazopanib produced only modest responses in liposarcomas, the 
addition of oral topotecan to pazopanib is expected to yield higher response rates than 
pazopanib alone. The majority of patients evaluated in the phase II VEG20002 trial had 
tumors of low or intermediate grade (12/19 patients), which may have resulted in 
decreased efficacy in this group of patients. We will explore whether the combination of 
pazopanib and oral topotecan will result in clinical benefit when evaluated in patients 
with high grade, de-differentiated, or myxoid liposarcoma.
Therefore, we propose to conduct a phase II trial of combination pazopanib and oral 
topotecan in patients with unresectable or metastatic soft tissue sarcoma, as well as 
provide preliminary evidence of benefit for patients with osteosarcoma or liposarcoma to 
determine if further testing in these sarcoma subtypes is warranted. The target population 
for this study is appropriate given the toxicity and lack of efficacy of chemotherapy in 
patients with advanced disease.
2.0
OBJECTIVES & ENDPOINTS
2.1   Primary Objective & Endpoint
The primary endpoint is to determine progression free rate at week 12 for patients with 
soft tissue sarcoma (STS) treated with pazopanib plus oral topotecan. The endpoint will 
be the time from enrollment to progression, with progression defined as changes in 
RECIST 1.1 defined imaging, progression in non-target lesions as defined by RECIST 
1.1, unequivocal clinical deterioration, or death from any cause.
2.2   Secondary Objectives & Endpoints
2.2.1
The objective is to determine the overall response rate for patients with STS 
treated with combination pazopanib and topotecan. The endpoint is the 
presence of response (ORR- CR+PR) per RECIST version 1.1 in cohort 1.
2.2.2
The objective is to determine the clinical benefit rate (CR+ PR + SD) for 
patients with STS treated with combination pazopanib and topotecan. The 
endpoint is the presence of clinical benefit (CR+ PR + SD) per RECIST 
version 1.1 in cohort 1
2.2.3
The objective is to determine median PFR for patients with STS treated with 
combination pazopanib and topotecan. The endpoint is the time from the first 
dose of the study treatment until death from any cause, up to a maximum 
follow-up of two years
2.2.4
The objective is to evaluate overall survival (OS) for patients with STS treated 
with combination pazopanib and topotecan. The endpoint is to determine OS 
for patients with STS treated with combination pazopanib and topotecan.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
12
2.2.5
The objective is to assess safety and tolerability for patients treated with 
combination pazopanib and topotecan. The endpoint is the presence of all 
toxicities outlined in NCI CTCAE version 4.03 from time of first treatment.
2.2.6
The objective is to estimate the PFR for patients with osteosarcoma treated 
with combination pazopanib and topotecan. The endpoint for patients with
osteosarcoma, time from treatment to progression, based upon changes in 
RECIST 1.1 defined imaging, progression in non-target lesions as defined by 
RECIST 1.1, uniequivocal clinical deterioration, or death from any cause.
2.2.7
The objective is to estimate the PFR for patients with liposarcoma treated 
with combination pazopanib and topotecan. The endpoint for patients with 
liposarcoma, time from treatment to progression based upon changes in 
RECIST 1.1 defined imaging, progression in non-target lesions as defined by 
RECIST 1.1, uniequivocal clinical deterioration, or death from any cause.
2.3   Exploratory Objective & Endpoint
For cohort 1 and 3:   Quantify Cell-free circulating tumor DNA (ctDNA) at each time point, 
and correlate these results with demographic, diagnostic, treatment, and outcomes data. 
For cohort 2:
The objective is to estimate the correlation of PFR and OS to levels of sVEGFR2 and 
PIGF. To meet this endpoint we will collect samples at baseline, 4 weeks, 8 weeks, and 
12 weeks to both verify the results of Sleijfer et al and to determine if there is an even 
earlier correlation that can be detected between levels of these cytokines and PFR as 
well as OS which may allow us to better predict treatment response early on in therapy.
3.0
PATIENT ELIGIBILITY
The target population for this phase II study is patients with recurrent or metastatic and non- 
resectable soft tissue and bone sarcomas who have failed at least one prior therapy. This will 
be a multicenter trial conducted at Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University. Northwestern University will serve as the lead site and coordinating 
center for this study. Participating sites will include the University of Iowa, Mayo Clinic 
(Rochester, Jacksonville, and Scottsdale), Washington University, University of Wisconsin, 
and University of Minnesota.
A total of 164 patients may be enrolled including 108 patients with STS (to acquire 92 
evaluable patients), and up to 36 patients with osteosarcoma and 20 patients with 
liposarcoma. Potential patients may be referred to the Principal Investigator (PI) at 
Northwestern University, or to the local PI at each participating site.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and none of the exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is 
registered. Please refer to Section 11 for complete instructions regarding registration 
procedures.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
13
3.1   Inclusion Criteria
3.1.1
Patients must provide written informed consent prior to performance of study- 
specific procedures or assessments and must be willing to comply with 
treatment and follow-up.
3.1.2
Patients must be age ≥ 18 years.
3.1.3
Patients must have a histologically confirmed diagnosis of metastatic or 
locally advanced, unresectable :
 
soft tissue sarcomas (non-liposarcoma)
 
osteosarcoma
 
liposarcoma- high grade, de-differentiated, or myxoid
NOTE: Pathology is not required to be reviewed at the treating institution. A
copy of the pathology report is sufficient for eligibility purposes
3.1.4
Patients must exhibit an Eastern Cooperative Oncology Group (ECOG)
performance status of 0-1
3.1.5
Patients must have measurable disease within 4 weeks prior to registration 
by RECIST 1.1, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10mm with spiral CT scan.
3.1.6
Cohort 1: Patients must have had a minimum of 1 and a maximum of 4 prior 
chemotherapy regimens for recurrent/metastatic or locally 
advanced/unresectable disease. It will be up to the investigator to determine 
what constitutes a “regimen” in each case.
Cohort 2: Patients may have had any number of prior therapies for
recurrent/metastatic or locally advanced/unresectable disease. There are no 
restrictions.
Cohort 3: Patients must have had a minimum of 1 and maximum of any
number of prior chemotherapy regimens for recurrent/metastatic or locally 
advanced/unresectable disease.
All cohorts: The last dose of systemic therapy must have been given at least
28 days prior to initiation of therapy. Patients receiving BCNU or mitomycin C 
must have received their last dose at least 6 weeks prior to initiation of 
therapy.
3.1.7
Patients with brain metastasis are eligible for participation ONLY if they have 
been treated with definitive surgery or radiation (surgery ± radiotherapy, 
radiosurgery, or gamma knife) and meet both of the following criteria: a) are 
asymptomatic and b) have no requirement for steroids or enzyme-inducing 
anticonvulsants in prior 12 week interval.
3.1.8
Patients must have adequate organ function within 14 days prior to 
registration, as defined below:
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
14
System
Laboratory Values
Hematology
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobina
9 g/dL (5.6 
mmol/L)
Plateletsa
100 X 109/L
Prothrombin time (PT) or international normalized ratio (INR)b
1.2 X ULN
Activated partial thromboplastin time (aPTT)
1.2 X ULN
Hepatic
Total bilirubin
1.5 X ULN
Alanine amino transferase (ALT) and Aspartate aminotransferase (AST)c
2.5 X ULN
Renal
Serum creatinine
1.5 mg/dL (133
µmol/L)
OR, if >1.5 mg/dL: Calculated creatinine clearance (ClCR)
50 mL/min
Urine Protein to Creatinine Ratio (UPC;)d
<1
, 24-hour urine protein, if requiredd
<1g
a. Subjects may not have had a transfusion within 7 days of screening assessment.
b. Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the 
recommended range for the desired level of anticoagulation.
c. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are 
not permitted.
d. If UPC 1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour 
urine protein value <1 g to be eligible. Use of urine dipstick for renal function assessment is 
not acceptable.
3.1.9
Females of child-bearing potential (FOCBP) and males must agree to use 
adequate contraception (see Section 4.3.12) prior to study entry, for the 
duration of study participation, and for 30 days following completion of 
therapy. Should a female patient become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating 
physician immediately.
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:
 
Has not undergone a hysterectomy or bilateral oophorectomy
 
Has had menses at any time in the preceding 12 consecutive months
(and therefore has not been naturally postmenopausal for > 12 months)
3.1.10  FOCBP must have a negative pregnancy test within 7 days prior to 
registration on study.
NOTE: Female patients who are lactating should discontinue nursing prior to 
the first dose of study drug and should refrain from nursing throughout
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
15
the treatment period and for 14 days following the last dose of study 
drug
3.1.11  Are able to swallow and retain oral tablets.
3.2   Exclusion Criteria
3.2.1
Patients with any of the following sarcoma histologic subtypes will not be 
eligible for participation:
 
Alveolar soft-part sarcoma
 
Chondrosarcoma
 
Dermatofibrosarcoma
 
Ewing sarcoma
 
GIST
 
Kaposi sarcoma (non-HIV and HIV related disease)
 
Mixed mesodermal tumor/carcinosarcoma
 
Low grade (grade 1) sarcomas
 
Rhabdomyosarcoma (embryonal, alveolar)
 
Interdigitating dendritic sarcoma
 
Giant cell tumor of the bone
3.2.2
Patients must not have received prior treatment with pazopanib or topotecan.
3.2.3
Patients must not have an active secondary malignancy.
3.2.4
Prior malignancy, unless they have been disease-free for 3 years, or have a 
history of completely resected non-melanomatous skin carcinoma or 
successfully treated in situ carcinoma
3.2.5
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
3.2.6
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
3.2.7
Corrected QT interval (QTc) > 480 msecs using Bazett’s formula (QTc= 
QT/√RR). EKG for screening must be within 28 days prior to registration.
3.2.8
History of any one or more of the following cardiovascular conditions within 
the past 12 months:
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
16
 
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) (Appendix C)
3.2.9
Left ventricular ejection fraction < 45% in patients with prior anthracycline use 
or otherwise at risk for left ventricular systolic dysfunction.
3.2.10  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. Following antihypertensive medication initiation or 
adjustment, blood pressure (BP) must be re-assessed three times at 
approximately 2-minute intervals. At least 24 hours must have elapsed 
between anti-hypertensive medication initiation or adjustment and BP 
measurement. These three values should be averaged to obtain the mean 
diastolic blood pressure and the mean systolic blood pressure. The mean 
SBP / DBP ratio must be <140/90 mmHg (OR 150/90 mm Hg, if approved by 
PI and the QAM) in order for a patient to be eligible for the study (see Section
5.2.3.6 for details on BP control and re-assessment prior to study enrollment).
3.2.11  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 prior to study treatment are eligible
3.2.12  Major surgery or trauma within 28 days prior to first dose of study treatment 
and/or presence of any non-healing wound, fracture, or ulcer (procedures 
such as catheter placement not considered to be major surgery).
3.2.13  Evidence of active bleeding or bleeding diathesis.
3.2.14  Known endobronchial lesions and/or lesions infiltrating major pulmonary 
vessels that increase the risk of pulmonary hemorrhage
 
Large protruding endobronchial lesions in the main or lobar bronchi 
are excluded; however, endobronchial lesions in the segmented 
bronchi are allowed.
Lesions extensively infiltrating the main or lobar bronchi are 
excluded; however, minor infiltrations in the wall of the bronchi are 
allowed
3.2.15  Recent hemoptysis (≥½ teaspoon [2.5 mL]) of red blood within 8 weeks 
before first dose of study drug).
3.2.16  Any serious and/or unstable pre-existing medical, psychiatric, or other 
condition that could interfere with patient’s safety, provision of informed 
consent, or compliance to study procedures
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
17
3.2.17  Unable or unwilling to discontinue use of strong inducers and inhibitors of 
CYP450 listed in Appendix for at least 14 days prior to the first dose of study 
treatment and for the duration of the study (Appendix A). 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. BCRP and PgP inducers and 
inhibitors should be used with caution if another alternative drug is not able to 
be used (Appendix A and B)
Note: As this list is constantly evolving, if a medication is incorrectly 
documented as prohibited in this protocol, documentation from the site
pharmacist to the contrary will be acceptable for the purposes of registration.
3.2.18  Treatment with any of the following anti-cancer therapies:
   radiation therapy, surgery or tumor embolization within 14 days prior to 
the first dose of study treatment
3.2.19  Administration of any investigational drug within 28 days prior to receiving the 
first dose of study treatment.
3.2.20  Any ongoing toxicity related to prior anti-cancer therapy that is >Grade 1 
and/or that is progressing in severity (exceptions include alopecia, fatigue, 
and hematologic toxicities not included in 3.1.8).
3.2.21  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy 
to drugs chemically related to pazopanib or topotecan.
3.3   Inclusion of Women and Minorities:
Both women and men and members of all races and ethnic groups are eligible for 
this trial.
3.4   Population and Accrual Overview
The target population for this phase II trial is patients with recurrent or metastatic soft 
tissue and bone sarcoma who have failed at least one prior therapy. This will be a 
multi-center trial with the Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University serving as the lead institution and coordinating center. 
Patients at Northwestern may be referred to the Principal Investigator (PI). Patients at 
each of the participating sites may be referred to the respective local PI at each site.  
108 patients (to acquire 92 evaluable patients) with STS may be enrolled in this trial. 
This number does not include the possible up to 20 patients with osteosarcoma and 20 
patients with liposarcoma who may be enrolled into this trial as exploratory cohorts.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
18
4.0
TREATMENT PLAN
4.1   Overview
Patients will take oral pazopanib (800mg starting dose) once daily AND oral toptecan (8 
mg starting dose) on days 1, 8, and 15 of each 28 day cycle. Treatment will continue 
until disease progression or unacceptable toxicity occurs, or until discontinuation per 
patient preference or physician recommendation. Patients who
are removed from study treatment for toxicity should be followed until toxicity resolves to 
grade 1 or baseline. Patients with PD at end of treatment will be followed every 6
months for 2 years (or until death) for survival. Patients without PD at end of
treatment will be followed every 6 months for 5 years (or until death) for survival and 
progression.
4.2   Treatment Administration
Agent
Dose
Route
Schedule
Cycle
Length
Pazopanib
800 mg
(Starting Dose)
PO
Per day
Topotecan
8 mg
(Starting Dose)
PO
Day 1, 8, & 15
of each cycle
4 weeks
(28 days)
4.2.1
Study Drug Administration
Patients will receive pazopanib at a dose of 800 mg/day (4 x 200mg tablets). 
Pazopanib should be taken orally, without food, at least one hour before or 
two hours after a meal, with up to 200 mL of water. Patients will concurrently 
receive topotecan 8 mg (8 x 1-mg capsules) to be taken orally on day 1, 8, 
and 15 of a 28 day cycle. Topotecan can be taken with or without food. 
Cycles will be repeated every 4 weeks.
On days of a scheduled clinic visit, the dose of pazopanib and topotecan 
should be taken after visit procedures are completed. Treatment with 
pazopanib and topotecan will continue if tolerated and in the absence of 
documented disease progression or unacceptable toxicity. If a dose is 
vomited or if a dose is missed for any reason, the dose should not be made 
up. Patients will be given a medication diary to record all doses taken, doses 
missed, and daily adverse events experienced. This will be collected and 
reviewed at study visits.
4.3   Toxicity Management, Dose Delays/Modifications & Supportive care
Any patient who receives at least one dose of study therapy will be evaluable for 
toxicity endpoints. Each patient will be assessed for the development of toxicity 
according to the timeframe referenced in the Schedule of Events table). Toxicity will be 
assessed according to CTCAE v. 4.03.
After cycle 1 day 1 of therapy, defined as 4 weeks of therapy, cycle 1 day 15, cycle 2 
day 1, cycle 2 day 15, cycle 3 day 1, and day one of all subsequent cycles may be 
administered provided the patient meets the following criteria:
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
19
 
ANC ≥ 1500/mm2
 
Platelet count ≥ 75,000
 
Hemoglobin ≥ 9 g/dL (after transfusion if necessary).
 
Non-hematologic toxicity recovered to ≤ grade 1 or tolerable grade 2
 
No evidence of progressive disease
Note: For cycle 1 day 15 and cycle 2 day 15, dosing should only commence AFTER 
day 15 labs have been reviewed to ensure the above criteria are met. If the patient 
does not meet the above criteria, study treatment should be held and labs and 
assessment should be done at least weekly until patient meets the above criteria 
(patient can be assessed earlier than one week at physician’s discretion). If when 
reassessed, the patient meets the treatment criteria above, proceed with treatment at 
the dose the patient was receiving during the previous cycle. If patient does not meet 
the above criteria after a one-week delay, then treatment will continue to be held, and 
the patient will continue to be evaluated weekly. Treatment can be held for a total of 3 
consecutive weeks to allow for treatment related toxicities to resolve. In the case that 
treatment has been held for 3 weeks for treatment related toxicities, the dose reduction 
for the next upcoming cycle should be based on the most severe toxicity experienced in 
the current cycle. If a patient develops another severe toxicity at the reduced dose or if 
they experience a life-threatening toxicity at any time, they will be removed from study 
per the dose modification parameters below. If a subject is able to resume treatment 
after an interruption of ≤3 weeks, missed doses will not be made up (i.e. the cycle 
duration will remain unchanged).
Patients with stable or responding disease may be retreated at the same dose (both 
Topotecan and Pazopanib) or at a reduced dose level, 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. Any 
doses that are held or delayed will be considered skipped and will not be made up. 
Patients should not deviate from the 28 day cycle (+ or – 3 days).
Patients will be withdrawn from the study if they fail to recover to grade ≤ 1 or tolerable 
grade 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) 
from a treatment-related toxicity within 3 weeks, or if the dose is interrupted > 8 weeks 
for a non-treatment related reason, unless the investigators (PI, local PI, and QAM) 
agree that the subject should remain in the study because of evidence that the patient 
is/may continue to derive benefit from continuing study treatment.
Topotecan:
Three dose reductions are permitted, based on side effects experienced, from
8 mg to 6, 6mg to 4, 4mg to 2. Further dose reduction is not allowed. Patients may be 
maintained on the lower dose of topotecan during treatment if deemed to be deriving 
benefit from the drug. Doses that are reduced for topotecan related toxicity will not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
20
Dose Level
Topotecan
0 (starting dose)
8 mg
-1
6 mg
-2
4 mg
-3
2 mg
Pazopanib:
Pazopanib may be held up to 3 weeks waiting for toxicities to resolve. Three dose 
reductions are permitted, from 800 to 600 or from 600 to 400 or from 400 to 200 mg 
daily based on side effects experienced. Further dose reduction is not allowed. 
Patients may be maintained on the lower dose of pazopanib during treatment 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.
Table I- Dose Modification Algorithms for Potential Treatment-Related
Adverse Eventsc
AE Terms & Descriptions
Dose Modification Algorithms
Hypertension
(A). Asymptomatic and persistent 
SBP of 140 and <170 mmHg, or 
DBP 90 and <110 mmHg, or a 
clinically significant increase in 
DBP of 20 mmHg (but still below
110 mmHg).
Step 1. Continue pazopanib and topotecan at the current 
dose.
Step 2. Adjust current or initiate new antihypertensive 
medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlleda blood 
pressure (BP). If BP is not well-controlled within 2 weeks, 
consider referral to a specialist and go to scenario (B).
(B). Asymptomatic SBP 170 
mmHg, or DBP 110 mmHg, or 
failure to achieve well-controlled 
BP within 2 weeks in scenario 
(A).
Step 1.Consider reducing or interrupting pazopanib, as 
clinically indicated. Continue topotecan at the current dose.
Step 2. Adjust current or initiate new antihypertensive 
medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP.
Step 4. Once BP is well-controlled, restart IP dose-reduced 
by 200 mg if IP was interrupted.
(C). Symptomatic hypertension or 
recurring SBP 170 mmHg, or 
DBP 110 mmHg, despite 
modification of antihypertensive 
medication(s)
Step 1. Interrupt pazopanib. Continue topotecan at the 
current dose.
Step 2. Adjust current or initiate new antihypertensive 
medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP. Referral to 
a specialist for further evaluation and follow-up is also 
recommended.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
21
Step 4. Once BP is well-controlled, restart pazopanib dose- 
reduced by 200 mg.
(D). Refractory hypertension 
unresponsive to above 
interventions.
Discontinue patient from protocol treatment and continue 
follow-up per protocol.
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to
ensure accuracy of the reading. The values below refer to manually-read ECGs.
500 msec > QTc  480 msec
Continue pazopanib; monitor as clinically indicated. 
Continue topotecan at the current dose.
QTc 500 msec
Discontinue patient from protocol treatment and continue 
follow-up per protocol.
Proteinuria
UPC <3
Continue pazopanib and topotecan at the current dose;
monitor as clinically indicated
UPC ≥3 or 24-h urine protein 3g
Step 1. Interrupt pazopanib Continue topotecan at the
current dose.
Step 2. Weekly UPC or 24-hr urine protein monitoring until 
UPC is <3 or 24-hr urine protein is <3 grams. Then 
restart pazopanib dose-reduced by 200 mg.
Step 3. If UPC ≥3 or 24-h urine protein 3g recurs at current 
dose, repeat steps 1 and 2.
Step 4. If UPC ≥3 or 24-hr urine protein ≥3 recurs at current 
dose and the pazopanib dose can no longer be reduced, 
discontinue protocol treatment and continue follow-up per 
protocol.
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding
Grade 1
For hemoptysis, interrupt pazopanib and contact the NU
QAM and PI to discuss whether further treatment with 
pazopanib is appropriate. Continue topotecan at the current 
dose.
For other Grade I hemorrhage/bleeding events, continue 
pazopanib and topotecan at the current dose; monitor as 
clinically indicated.
Grade 2
Step 1. If pulmonary or GI bleed (other than hemorrhoidal 
bleeding), discontinue protocol treatment and continue 
follow-up per protocol. Otherwise, interrupt pazopanib until 
the AE resolved to  Grade 1. Continue topotecan at the 
current dose.
Step 2. Restart pazopanib; consider reducing dose and 
monitor as clinically indicated. Continue topotecan at the 
current dose.
Grade 3 or 4, or
Recurrent  Grade 2 event after 
dose interruption/reduction.
Discontinue protocol treatment and continue with follow-up 
per protocol.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
22
Venous Thrombosis (DVT, PE)
Grade 2
Continue pazopanib and topotecan at the current dose;
monitor as clinically indicated
Grade 3
Step 1. Interrupt pazopanib. Continue topotecan at the 
current dose.
Step 2. Initiate and monitor anticoagulation as clinically 
indicated.
Step 3. Resume pazopanib at reduced dose only if all of the 
following criteria are met:
 
The subject must have been treated with 
anticoagulant at the desired level of anticoagulation 
for at least one week.
 
No Grade 3 or 4 or clinically significant Grade 2, 
hemorrhagic events have occurred while on 
anticoagulation treatment.
Subject should be monitored as clinically indicated during 
anticoagulation treatment and after resuming study 
treatment. When treating with warfarin, international 
normalized ratio (INR) should be monitored within three to 
five days after any change in IP dosing (eg, re-initiating, 
escalating/de-escalating, or discontinuing IP), and then at 
least weekly until the INR is stable. The dose of warfarin (or 
its derivatives) may need to be adjusted to maintain the 
desired level of anticoagulation
Grade 4 and/or PE
Discontinue protocol treatment and continue follow-up per 
protocol.
Arterial Thrombosis/Ischemia
Any Grade
Discontinue protocol treatment and continue follow-up per 
protocol.
Thrombocytopenia: Investigate and document underlying cause
Grade 1
Continue pazopanib and topotecan at current dose; monitor 
as clinically indicated.
Grade 2
Step 1. Interrupt topotecan and pazopanib until toxicity 
resolves to ≤ Grade 1.
Step 2. Restart topotecan and pazopanib at the current dose 
or reduce dose by 1 level per physician discretion.
If no recovery to ≤ Grade 1 within 3 weeks, discontinue 
protocol treatment and follow-up per protocol. If patient is 
deriving clinical benefit, please contact QAM and PI.
Grade 3 or 4
Step 1. Interrupt pazopanib and topotecan until toxicity
resolves to ≤ Grade 1.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
23
Step 2. Restart pazopanib dose-reduced by 200 mg and 
monitor as clinically indicated. Restart topotecan at the 
current dose or reduce dose by 1 level per physician 
discretion.
If no recovery to ≤ Grade 1 or recurrent Grade 3 or 4 
thrombocytopenia at the current dose, discontinue protocol 
treatment and follow-up per protocol.
Neutropenia: Investigate and document underlying cause.
Neutrophils ≥ 1.5
Continue pazopanib and topotecan at current dose; monitor 
as clinically indicated.
Neutrophils < 1.5
1. Interrupt pazopanib and topotecan dosing until neutrophils 
resolve to ≥ 1.5.
2. Restart topotecan and pazopanib at the current dose or 
reduce dose by 1 level per physician discretion.
If no recovery to ≥ 1.5 within 3 weeks, discontinue protocol 
treatment and follow-up per protocol. If patient is deriving 
clinical benefit, please contact QAM and PI.
Anemia: Investigate and document underlying cause.
Hemoglobin ≥ 9
Continue pazopanib and topotecan at current dose; monitor 
as clinically indicated.
Hemoglobin < 9
1. Interrupt pazopanib and topotecan dosing until 
hemoglobin resolves to ≥ 9.
2. Restart topotecan and pazopanib at the current dose or 
reduce dose by 1 level per physician discretion.
If no recovery to ≥ 9 within 3 weeks, discontinue protocol 
treatment and follow-up per protocol. If patient is deriving 
clinical benefit, please contact QAM and PI.
Palmar-plantar Erythrodysesthesia Syndrome
Grade 1
Minimal skin changes or 
dermatitis without pain 
(erythema, oedema, 
hyperkeratosis)
1.   Continue pazopanib and topotecan at present dose
Grade 2
Skin changes with pain; limiting 
instrumental activities of daily 
living (ADLs) (peeling, blisters, 
oedema, bleed, hyperkeratosis)
1.   Hold pazopanib. Continue topotecan at current dose.
2.   Treat as clinically appropriate
3.   Upon resolution to Level 1 or better restart 
pazopanib with a dose reduction to 400 mg
4.   If recurrent at the current dose consider a further 
dose reduction to 200mg or discontinuation
Grade 3
Severe skin changes with pain 
and limiting self care ADLs
1.   Discontinue protocol treatment
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
24
Other Treatment Related Adverse Eventsb,c,.d
Grade 1 or tolerable Grade 2
Continue pazopanib and topotecan at current dose; monitor 
as clinically indicated.
Intolerable Grade 2 or Grade 3
Step 1. Interrupt pazopanib and topotecan until toxicity 
resolves to  Grade 1.
Step 2. Restart topotecan and pazopanib at the current dose 
or reduce dose by 1 level per physician discretion.
Grade 4
Discontinue protocol treatment and continue follow-up per 
protocol.
a.   Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg.
b.   AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 
(NCI CTCAE v4.03)
Abbreviations: BP, blood pressure; IP, investigational product.
c. If patient has completed 12 weeks of combination protocol therapy, and one protocol agent 
should be stopped per the above table, patient may be able to continue single agent therapy 
patient is deriving benefit and if approved by PI and QAM. This is based on how combination 
therapy would be administered outside of a clinical trial setting.
d. Dose modifications should only be made after patient is given adequate supportive care.
Dose Modifications and Management of Liver toxicity
Recommendations for pazopanib dose interruptions/modifications in case of liver-related 
treatment-emergent AEs are provided in Table III. As a general rule, since many subjects 
are taking multiple concurrent medications, it is critical to (a) do a thorough evaluation of 
the subject’s concurrent medications (and ensure all are recorded in appropriate forms) , 
and (b) identify and discontinue those with known hepatotoxicity and replace with a non-
hepatotoxic equivalent for the same indication if necessary. Record alcohol use on 
appropriate forms. Liver dysfunction must be fully evaluated even if clinical signs and 
symptoms indicate progression of liver tumor lesions. Imaging studies must be obtained 
to document potential progression of malignancy.
Table II
Guidelines for Management of Treatment Emergent Hepatotoxicity
Event
Dose Modification Algorithms
(A). ALT of ≤ 3.0 x
ULN
Continue pazopanib and topotecan at current dose with full panel LFTsa
monitored as per protocol.
(B). ALT >3.0 x ULN
to ≤8.0 x ULN 
without bilirubin 
elevation (defined 
as total bilirubinb
<2.0 x ULN or direct 
bilirubin ≤35%) and 
without 
hypersensitivity 
symptoms (e.g., 
fever, rash)
Liver Event Monitoring Criteria:
(1) Continue pazopanib and topotecan at current dose levels.
(2) Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTsa weekly or more frequently if clinically indicated until 
ALT/AST is reduced to Grade 1.
Recurrence – Liver Event Stopping Criteriac:
Discontinue protocol treatment permanently and monitor subject closely 
for clinical signs and symptoms; perform full panel LFTs a weekly or 
more frequently if clinically indicated until ALT/AST is reduced to
Grade 1 or baseline.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
25
(C). ALT >8.0 x ULN 
without bilirubin 
elevation (defined
as total bilirubinb
<2.0 x ULN or direct 
bilirubin ≤35%) and 
without 
hypersensitivity 
symptoms (e.g., 
fever, rash)
 1st occurrence – Liver Event Interruption Criteria:c
(1) Interrupt pazopanib until toxicity resolves to Grade 1 or baseline. 
Continue topotecan at current dose.
(2) Liver imaging and other laboratory investigations should be 
considered as clinically appropriate.
(3) Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTs a weekly or more frequently if clinically indicated until
ALT/AST is reduced to Grade 1 or baseline.
(4) 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 daily and monitor liver 
function weekly for 8 weeks.
Recurrence – Liver Event Stopping Criteriac:
Discontinue protocol treatment permanently and monitor subject closely 
for clinical signs and symptoms; perform full panel LFTs a weekly or 
more frequently if clinically indicated until ALT/AST is reduced to
Grade 1 or baseline.
(D). ALT >3.0 x
ULN with 
concomitant 
elevation in
bilirubinb (defined as
total bilirubin 2.0 x 
ULN; with direct 
bilirubin >35%) or 
with 
hypersensitivity 
symptoms (e.g., 
fever, rash).
Liver Event Stopping Criteriac:
(1) Discontinue protocol treatment immediately.
(2) Monitor subject closely for clinical signs and symptoms; record the 
appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever rash or eosinophilia as relevant 
on the AE report form. Perform full panel LFTs a weekly or more 
frequently if clinically indicated until LFTs are reduced to Grade 1 or 
baseline.
For isolated total
bilirubin elevation 
without concurrent 
ALT increases 
(defined as ALT <3
X ULN).
(1)  Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or
other signs/symptoms of liver injury) does not require dose 
modification. Pazopanib inhibits UGT1A1 and OATP1B1, which can 
cause elevation of indirect (unconjugated) bilirubin in the absence
of liver injury.
(2)  If bilirubin is >1.5 x ULN in the absence of ALT elevation, 
fractionation of bilirubin elevation should be performed. If bilirubin
is >35% direct (conjugated), further evaluation for underlying cause 
of cholestasis should be performed.
a.   Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.
Coagulation tests should be performed as clinically indicated.
b.   Serum bilirubin fractionation should be performed if testing is available. If testing is 
unavailable and a subject meets the criterion of total bilirubin >1.5 x ULN, then the event 
should be promptly reported as an SAE.
c.
Please refer to Investigator’s Brochure, Summary of Data and Guidance for Investigator,
Warnings and Precautions, Hepatic Effects for information about rechallenge dose. 
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; LFT liver 
function tests; ULN upper limit of normal
4.3.1
Pregnancy/Lactation/Contraception
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
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
26
advised to avoid becoming pregnant while receiving treatment with pazopanib or 
topotecan. Pazopanib or topotecan should not be used during pregnancy or lactation.
Acceptable contraception methods, when used consistently and in accordance with 
both the product label and instructions of the physician are as follows:
 
Complete abstinence from sexual intercourse during duration and treatment 
and for at least 30 days after the last dose of investigational product.
 
Oral contraceptive, either combined estrogen/progesterone or progesterone 
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 patient's entry into the study, and this male is the sole 
partner for that patient.
 
Double barrier method: condom and an occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository).
4.4   Concomitant Medications/Treatments
Use of concomitant medications for supportive care purposes will be per treating
investigator’s discretion.
4.4.1
G-CSF Administration
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 treatment.
4.4.2
Antiemetics
The use of antiemetics will be left to the investigators’ discretion.
4.4.3
Palliative Care
Palliative radiation and surgery are allowed on this trial IF they are not being 
used to address a target lesion as defined in RECIST 1.1.  Any patient who 
requires palliative care to a target lesion should be removed from protocol 
treatment. If necessary, the following parameters should be used.
 
Palliative radiation: Protocol treatment should be held 7 days before, 
during, and 7 days after palliative radiation, or at the discretion of the 
site radiation oncologist. If treatment is not resumed within 3 weeks, 
case will be reviewed by QAM and PI to determine whether or not 
patient can restart treatment.
 
Palliative surgery: Protocol treatment should be held 7 days before 
and until the wound is healed. If treatment is not resumed within 3 
weeks, case will be
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
27
reviewed by QAM and PI to determine whether or not patient can 
restart treatment.
4.4.4
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.
4.4.5
Concomitant Medications discouraged while on study
•
Strong inducers and inhibitors of CYP450 listed in Appendix A
•
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.
•
BCRP and PgP inducers and inhibitors should be used with caution if 
another alternative drug is not able to be used (listed in the Appendix 
B).
o
Note: As this list is constantly evolving, if a medication is 
incorrectly documented as prohibited in this protocol, 
documentation from the site pharmacist to the contrary will be 
acceptable
•
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.
4.5   Duration of Therapy
If a patient is felt to be deriving benefit from the agents and is stable at the conclusion of 
the trial, patients are allowed to continue therapy with stable disease by RECIST
1.1. This will be based on discussion with the patient, the PI, and sponsor. It may be 
possible to continue both drugs at that point, assuming availability of agents and no 
change in the status regarding pazopanib or topotecan with respect to sarcomas.
A patient may be removed from therapy if, in the judgment of the investigator, general or 
specific changes in the patient’s condition render the patient unacceptable for further 
treatment.
4.6   Duration of Follow Up
Patients with PD at end of treatment will be followed every 6 months for 2 years (or 
until death) for survival. Patients without PD at end of treatment will be followed 
every 6 months for 5 years (or until death) for survival and progression. Follow-up
may occur over the phone. Patients who are removed from study treatment for toxicity 
should be followed until toxicity resolves to grade 1 or baseline.
4.7   Removal of Subjects from Study Treatment and/or Study as a Whole Patients can 
be taken off the study treatment and/or study as a whole at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include:
 
Patient voluntarily withdraws from treatment (follow-up permitted)
 
Patient withdraws consent (no follow-up permitted)
 
Patient is unable to comply with protocol requirements
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
28
 
Patient demonstrates disease progression
 
Patient experiences unacceptable toxicity
 
Treating physician determines that continuation on the study would not be in the
patient’s best interest
 
Patient becomes pregnant
 
Patient develops a second malignancy that requires treatment which would 
interfere with this study
 
Patient becomes lost to follow-up (LTF)
4.8   Patient Replacement
If a patient is registered but withdraws or is taken off treatment before receiving 
any doses of study medication, he or she will then be replaced.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

5.0
STUDY PROCEDURES
CYCLE 1m
CYCLE 2m
Screening
a,b
Day 1 b
Day 8
Day 15
Day
21
Day 1
Day 8
Day
15
Day 21
D1 - Odd
Cyclesm
D1 -
Even
End of
Txn
Follow Up i
Informed Consent
X
History/ Progress
Notes
X
X
X
X
X
X
Physical Exam
with full Vital
Signsc
X
X
X
X
X
X
Blood Pressure
(BP) onlyc
X
X
X
X
X
X
X
X
ECOG 
Performance 
Status
X
X
X
X
X
X
Toxicity
Assessment
X
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
X
X j
Chemistry labsf
X
X
X
X
X
X
X
X
CBC with
Differentialh
X
X
X
X
X
X
X
X
Pregnancy Test g
X
Urine Protein/ 
Creatinine Ratio
X
X
X
X
X
TSH(T4) e
X
X
X
PT/INR, PTT
X
X
X
X
X
EKG d
X
X
X
MUGA or Echop
X
As clinically indicated
Radiology
Assessment k
X
Radiology assessment at week 6, 12, 20 and every 8 weeks thereafter.
X i
RECIST
X
X
X
Pazopanibq
Days 1-28
Topotecanq
X
X
X
X
X
X
X
X
Correlative blood
samplel
X
X
XI
Xl
Follow-up
Xi

a.
Pre-study procedures done within 7 days of C1D1 do not need to be repeated on C1D1.
b.
Pre-study H&P and all labs must be < 15 days before registration. Tumor measurements and radiologic evaluations must be ≤ 4 weeks before 
registration. Screening EKG must be within 28 days prior to registration. H&P and all labs do not need to be repeated on day 1 if done within 7 days of
treatment initiation.
c.
Vital signs to include height (height is recorded at screen visit only), weight, blood pressure, pulse, temperature and respi rations.  In addition to this full set 
of vitals each cycle, a measurement of blood pressure (BP) should be taken every 7 days (+/- 3). These weekly blood pressure measurements can be 
assessed by any method (i.e. at home or by another physician) as long as the study physician is informed of the measurement, verifies any measurement
that is not normal and takes appropriate action to manage hypertension, as defined by the protocol. A blood pressure log will be maintained to aid in 
monitoring and should be uploaded into NOTIS each cycle for the duration of treatment (See appendices).
d.
EKG: Performed on Cycle 2 day 1 and then day 1 of every even cycle until end of treatment (+/-3 days). EKG for screening must be within 28 days prior 
to registration.
e.
Thyroid function test (TSH) are monitored every 12 weeks (+/-3 days). TSH is mandatory, but T4 should be restricted to only those with abnormal TSH
levels.
f.
Chemistry labs include a comprehensive chemistry panel (Liver function tests (LFT) and Comprehensive Metabolic Panel (CMP)). Monitoring of LFTs: 
Monitor serum liver tests before initiation of treatment with pazopanib and at  Cycle 1 day 15, Cycle 2 day 1, Cycle 2 day 15, and day 1 of every cycle 
thereafter(+/- 3 days). CMP and LFTs should include: Bilirubin, Glucose, BUN, Calcium, Total Protein, Albumin, ALT, AST, GFR, Sodium, Potassium, 
Chloride, Carbon Dioxide, Alk Phos, Creatinine, Magnesium, and GGT.
g.
Only for women of childbearing potential; must be tested within 7 days prior to registration.
h.
Complete Blood Count (CBC): Performed on day 1 and 15 of cycles 1 and 2 (+/- 3 days) then day 1 of each cycle (+/-3 days). For patients 
experiencing significant cytopenias felt possibly 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.
Patients with PD at end of treatment will be followed every 6 months for 2 years (or until death) for survival (from the last day of treatment). Patients 
without PD at end of treatment will be followed every 6 months for 5 years (or until death) for survival and progression (from the last day of treatment). 
Follow-up may occur over the phone.
j.
Patients who are removed from study treatment for toxicity should be followed until toxicity resolves to grade 1 or baseline.
k.
Radiology assessment by CT or MRI will be done at Week 6, Week 12, Week 20 and every 8 weeks (+/- 7 days) thereafter.  After 1 year of protocol 
treatment, patient may be switched to scans every 12 weeks (+/- 7 days) at the discretion of the patient and treating physician.
l.
 Blood samples for mandatory correlative study will be collected at screening or on Cycle 1 Day 1 prior to treatment, and day 1 of Cycle 2, 3, and 4 , 
(+/-3 days) as in section 9.1.
m.   Unless otherwise noted, on-therapy windows for testing will be as follows: imaging scans should be completed within +/- 1 week of the target time point, 
and labs and physical examinations within +/- 3 days of the target time point.
n.
End of treatment visit must occur within 30 days following the last day of treatment, particularly prior to patient starting new treatment.
o.
Patient to call coordinator weekly to report toxicities- if no toxicities to be reported, patient need not call in.  Toxicities should be followed for 30 days after 
last dose of study treatment, however, new toxicities that arise within the 30 day period definitely related to new anti-cancer treatment and NOT related to 
study treatment do not need to be reported.
p.
ONLY required for patients with prior anthracycline use OR otherwise at risk for left ventricular systolic dysfunction. May be assessed by MUGA or 
echocardiogram.
q.
Day 1 of each cycle should be every 28 days. In the event that this day falls on a holiday or other such event, study team should use +/- 3 day window to
complete pre-treatment procedures, and dispense protocol agents to patients with instructions to commence treatment on day 1. Any missed doses will 
not be made up and should be skipped to maintain a 28-day cycle.

Amendment- 13            Version Date:06-26-2020
32
6.0
ENDPOINT ASSESSMENT
6.1   Definitions
6.1.1   Measurable Disease
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Lymph nodes are considered measurable in RECIST 1.1 if their short diameter 
exceeds 15 mm. Lymph nodes are considered normal if they have a short axis of less 
than 10 mm; this applies to determination of response as well. Lesions that are 
previously irradiated must show
clear evidence of progression over a minimum of 3 months to include as measurable. 
This period of time is used to discount tumor edema in an irradiated field as a false 
sign of disease progression.
6.1.2   Non Measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter <20 
mm with conventional techniques or <10 mm using spiral CT scan), are considered 
non- measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (specifically abdominal masses not followed by CT or 
MRI), and cystic lesions are all non-measurable.
6.1.3   Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). A sum of the 
longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response
6.1.3.1  Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesion
Partial response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD
Progressive Disease (PD)
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions. Progression must also involve an 
increase in size of measurable lesions by at least 5 mm, to minimize the 
possibility that small changes in a small number of target lesions is falsely 
interpreted as progression.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
33
6.1.4    Non-Target Lesions
All other lesions (or sites of disease) including any measurable lesions over and 
above the 10 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but 
the presence or absence of each should be noted throughout follow-up.
6.1.4.1    Evaluation of Non-Target Lesions
Complete Response (CR)
Disappearance of all non-target lesions
Note: If tumor markers are initially above the upper normal limit, they must 
normalize
for a patient to be considered in complete clinical response.
Incomplete Response/Stable Disease (SD)
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Please refer to the RECIST 1.1 guidelines 
for a discussion of “unequivocal progression”.
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator).
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. Since this is 
not a randomized study, confirmation of a clinical response is required as 
per RECIST 1.1; it is not required for randomized studies in RECIST 1.1.
Target
Lesions
Non-
Target
Lesions
New
Lesions
Overall
Response
Best Response for
this Category Also
Requires:
CR
CR
No
CR
>4 week Confirmation
CR
Non-
CR/Non- 
PD
No
PR
PR
Non-PD
No
PR
>4 week Confirmation
SD
Non-PD
No
SD
documented at least
once >4 week from 
baseline
PD
Any
Yes or
No
PD
Any
PD*
Yes or
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
34
Note:  Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to 
document the objective progression even after discontinuation of 
treatment.
6.2   Antitumor Effect
For the purposes of this study, patients should be re-evaluated for response at 6 weeks,
12 weeks and then every 2 cycles thereafter. In addition to a baseline scan, confirmatory 
scans should also be obtained a minimum of 4 weeks following initial documentation of 
objective response. The investigator may opt to have the follow up scan performed 
according to the schedule (without an extra scan) as this follows the intent of the RECIST 
guidelines.
Response and progression will be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST) Committee, version 1.1.64 Changes in only the largest 
diameter (unidimensional measurement) of the tumor lesions are used in the RECIST 
criteria, as defined below. In contrast, measurable disease in lymph nodes is determined 
based on the lymph node short axis.
6.3   Evaluable for objective response:
All patients enrolled in the study should be assessed for response to treatment, even if 
there are major protocol treatment deviations or patients exhibit objective disease 
progression prior to the end of cycle 1.
All conclusions should be based on all enrolled patients. Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, treating an ineligible patient, major protocol violations, etc.). 
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis 
should be clearly reported. The 95% confidence intervals for response rate should also be 
provided.
All patients who were enrolled on the trial should be included in the main analysis of the 
response rate. Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion. However, if a patient is removed from treatment prior to their 12 week 
assessment for reasons other than disease progression or death, they will be considered 
non-evaluable for response if approved by the DMC.
6.4   Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
35
Chest x-ray
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.
Conventional CT and MRI
These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and neck 
tumors and those of extremities usually require specific protocols.
Cytology, Histology
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease 
is or stable disease (an effusion may be a side effect of the treatment) and progressive 
disease
6.5   Primary Endpoint
Time from enrollment to progression, with progression defined as changes in RECIST 1.1 
defined imaging, progression in non-target lesions as defined by RECIST 1.1,
unequivocal clinical deterioration, or death from any cause.
6.6   Secondary Endpoints
 
The presence of response (ORR- CR+PR) per RECIST version 1.1 in cohort 1.
 
The presence of clinical benefit (CR+ PR + SD) per RECIST version 1.1 in cohort
1.
 
The time from the first dose of the study treatment until death from any cause, up 
to a maximum follow-up of two years.
 
The endpoint is to determine OS for patients with STS treated with combination 
pazopanib and topotecan.
 
The presence of all toxicities outlined in NCI CTCAE version 4.03 from time of 
first treatment.
 
The endpoint for patients with osteosarcoma, time from treatment to progression, 
based upon changes in RECIST 1.1 defined imaging, progression in non-target 
lesions as defined by RECIST 1.1, uniequivocal clinical deterioration, or death 
from any cause.
 
The endpoint for patients with liposarcoma, time from treatment to progression 
based upon changes in RECIST 1.1 defined imaging, progression in non-target 
lesions as defined by RECIST 1.1, uniequivocal clinical deterioration, or death 
from any cause.
6.7   Exploratory Endpoint
For cohort 1 and 3:   Quantify Cell-free circulating tumor DNA (ctDNA) at each time point, 
and correlate these results with demographic, diagnostic, treatment, and outcomes data. 
For cohort 2: Verification of results of Sleijfer et al and to determine if there is an even 
earlier correlation that can be detected between levels of these cytokines and PFR as 
well as OS which may allow us to better predict treatment response early on in therapy
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
36
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
 (http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay2014.pdf). The level 
of risk attributed to this study requires high-intensity monitoring as outlined in the DSMP.
7.1   Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial (see Section 5 for timepoints). In addition, certain 
adverse events must be reported in an expedited manner to allow for optimal monitoring 
and patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:
 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;
 
any abnormal laboratory values have returned to baseline;
 
there is a satisfactory explanation other than the study drug for the changes 
observed; or
 
death.
7.2   Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible. However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
CTCAE v4.03 is available at  http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
37
 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.
 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.
 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.
 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.
 
Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:
 
Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.
 
Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.
 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.
 
Results in persistent or significant disability or incapacity.
 
Is a congenital anomaly/birth defect.
 
Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical
intervention to prevent one of the outcomes listed in the definition of “Serious
Adverse Event“.
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:
 
Is unanticipated in terms of nature, severity, or frequency
 
Places the research subject or others at a different or greater risk of harm
 
Is deemed to be at least possibly related to participation in the study.
7.3   Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data Monitoring Committee (DMC) according to the study’s 
phase and risk level, as outlined in the DSMP.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
38
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment, unless definitely attributable to new anti-cancer treatment and NOT 
study treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy.
Attribution categories are as follows:
 
Definite: AE is clearly related to the study treatment.
 
Probable: AE is likely related to the study treatment.
 
Possible: AE may be related to the study treatment.
 
Unlikely: AE not likely to be related to the study treatment.
 
Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:
 
the current protocol
 
the drug package insert
 
the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form is 
required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:
 
Protocol description and number(s)
 
The patient’s identification number
 
A description of the event, severity, treatment, and outcome (if 
known)
 
Supportive laboratory results and diagnostics
 
The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.
 
Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification.
 
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)
 
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
39
 
All other deaths of NU subjects not previously reported, other non- 
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.3.3.3 Reporting to the FDA
All reporting to the FDA will be completed by the Northwestern Quality
Assurance (QA) department.
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life- 
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual
FDA report.
7.3.3.4 Reporting to Novartis
(NOTE: As of the 2nd March 2015, Novartis has taken over the 
pharmacovigilance activities.)
The principal investigator has the obligation to report all serious adverse 
events to Novartis Pharmaceuticals Drug Safety and Epidemiology 
Department (DS&E)
All events reported to the FDA by the investigator are to be filed utilizing 
the Form FDA 3500A (MedWatch Form).
To ensure patient safety, every SAE, regardless of suspected causality, 
occurring
 
after the patient has provided informed consent and until at least 30 
days after the patient has stopped study treatment/participation
 
after protocol-specified procedures begin (e.g., placebo run-in, 
washout period, double-blind treatment, etc.) and 30 days after the
patient has stopped study treatment
 
after the start of any period in which the study protocol interferes with 
the standard medical treatment given to a patient (e.g., treatment 
withdrawal during washout period, change in treatment to a fixed 
dose of concomitant medication) and until 30 days after the patient 
has stopped study treatment
All Events must be reported to Novartis within 24 hours of learning of its 
occurrence. Information about all SAEs is collected and recorded on a 
Serious Adverse Event Report Form; all applicable sections of the form 
must be completed in order to provide a clinically thorough report. The 
investigator must assess and record the relationship of each SAE to
each specific study treatment (if there is more than one study treatment), 
complete the SAE Report Form in English, and send the completed, 
signed form by fax to (fax: 877-778-9739) within 24 hours to the
oncology Novartis DS&E department with the provided FAX cover sheets
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
40
(available as stand-alone documents) Novartis Study Code 
(CPZP034BUS52T) must be on the SAE coversheet. Should the 
designated SAE Fax # be non-functional please send SAEs to the 
designated SAE mailbox: clinicalsafetyop.phuseh@novartis.com. This 
includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol 
therapy must be reported within 5 working days.
Any SAEs experienced after this 30 days period should only be reported 
to Novartis if the investigator suspects a causal relationship to the study 
drug. Recurrent episodes, complications, or progression of the initial 
SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. A SAE 
occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as 
a new event. The end date of the first event must be provided.
The original copy of the SAE Report and the fax confirmation sheet will 
be kept per local standard operating procedures.
Follow-up information is sent to the same fax number as the original SAE 
Report Form was sent, using a new fax cover sheet, stating that this is a 
follow-up to the previously reported SAE, and giving the date of the 
original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless 
of when it occurs. The follow-up information should describe whether the 
event has resolved or continues, if and how it was treated, whether the 
blind was broken or not (if applicable), and whether the patient continued 
or withdrew from study participation.
If the SAE is not previously documented in the Pazopanib Investigator 
Brochure or Package Insert (new occurrence) and is thought to be 
related to the Novartis study drug, a DS&E associate may urgently 
require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to 
inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with Directive
2001/20/EC or as per national regulatory requirements in participating 
countries.
To ensure patient safety, each pregnancy occurring while the patient is 
on study treatment must be reported to Novartis within 24 hours of 
learning of its occurrence.
8.0
DRUG INFORMATION
8.1    Topotecan
8.1.1
Other names: HYCAMTIN (Topotecan hydrochloride)
8.1.2
Classification - type of agent: Topotecan is a topoisomerase 1 inhibitor.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
41
8.1.3
Mode 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.
8.1.4
Storage and stability: Store refrigerated 2º to 8ºC (36º to 46ºF). Store the 
bottles protected from light in the original outer cartons.
8.1.5
Protocol dose specifics: 8 milligrams orally on day 1, 8, 15 of a 28 day cycle.
Drug to be taken with or without food.
8.1.6
Preparation: No preparation is required.
8.1.7
Route of administration for this study: Oral (by mouth)
8.1.8
Incompatibilities: 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%), 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.
NOTE: Refer to Appendix B for oral topotecan drug interactions.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
42
8.1.9
Availability & Supply: Please complete the drug order form located on the 
protocol page in NOTIS. This form includes directions for ordering.
8.1.10  Side effects
Please refer to current IB for details and a complete list of side-effects.
8.1.11  Nursing implications
Bone Marrow Suppression
Inform patients that topotecan decreases blood cell counts such as white blood 
cells, platelets, and red blood cells. Instruct patients to notify their healthcare 
provider promptly for fever or other signs of infection such as chills, cough, or 
burning pain on urination. Advise patients that frequent blood tests will be 
performed while taking topotecan to monitor for bone marrow suppression.
Embryofetal Toxicity
Advise patients on pregnancy planning and prevention. Advise females of 
reproductive potential to use highly effective contraception during treatment and 
for 1 month following treatment with topotecan.
Advise males with a female sexual partner of reproductive potential to use 
effective contraception during and for 3 months after treatment.
Nursing Mothers
Advise patients to discontinue nursing during treatment with topotecan.
Infertility
Advise male and female patients of the potential risk for impaired fertility and 
possible family planning options.
Diarrhea
Inform patients that topotecan capsules cause diarrhea which may be severe and 
life-threatening. Instruct patients how to manage and/or prevent diarrhea and to 
inform their physician if severe diarrhea occurs during treatment with topotecan 
capsules.
8.1.12  Return and Retention of Study Drug: Unused or defective drug will be 
destroyed. Sponsor Novartis should be notified of this action.
8.2    Pazopanib
8.2.1
Other names: Votrient; GW786034B
8.2.2
Classification - type of agent: Multi-target tyrosine kinase inhibitor (TKI)
8.2.3
Mode 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
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
43
factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 74 nM, 
respectively.
8.2.4
Storage and stability: Store at 25°C (77°F); excursions permitted to 15° to 30°C 
(59° to 86°F)
8.2.5
Protocol dose specifics: 800 mg (4x200mg) pazopanib per day should be 
taken orally without food at least one hour before or two hours after a meal.
8.2.6
Preparation
No preparation is required.
8.2.7
Route of administration for this study
Oral (by mouth)
8.2.8
Incompatibilities: Refer to Appendix A1 for a list of general drugs that should be 
avoided with pazopanib.
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 coadministered 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
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
44
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
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 proton pump inhibitors and gastric pH on Pazopanib
Administration of pazopanib with a proton pump inhibitor (PPI) results in a 40% 
reduction in AUC and time to Cmax of pazopanib. Therefore, proton pump 
inhibitors should be avoided with pazopanib. Drugs that raise gastric pH should 
also be avoided. If such drugs are needed, short acting antacids should be 
considered in place of PPIs and H2 receptor antagonists. Separate antacid and 
pazopanib dosing by several hours to avoid reduction in pazopanib exposure.
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.
8.2.9
Availability & Supply: Please complete the drug order form located on the 
protocol page in NOTIS. This form includes directions for ordering.
Currently all sites are using Pazopanib clinical supply that is provided by 
GlaxoSmithKline (GSK). As each site exhausts this supply, sites will transition to 
commercial Pazopanib supply provided by Novartis.
As of March 2016 Votrient (Pazopanib) commercial supply with auxiliary label will 
also be available for the study, provided by Novartis. This commercial supply 
study drug should be administrated and stored according to the instructions 
specified on the drug labels. There is no set date when commercial supply will 
take over the clinical supply. It will depend on when the clinical supply is 
exhausted at each site.
8.2.10  Side effects
Please refer to current IB for details and a complete list of side-effects.
8.2.11  Nursing implications
• Therapy with pazopanib may result in hepatobiliary laboratory abnormalities. 
Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of pazopanib 
and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and 
as clinically indicated. Inform patients that they should report signs and 
symptoms of liver dysfunction to their healthcare provider right away.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
45
• Prolonged QT intervals and torsades de pointes have been observed. Patients 
should be advised that ECG monitoring may be performed. Patients should be 
advised to inform their physicians of concomitant medications.
• Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in 
patients at risk (e.g., prior anthracycline therapy) particularly in association with 
development or worsening of hypertension. Patients should be advised to report 
hypertension or signs and symptoms of congestive heart failure.
• Serious hemorrhagic events have been reported. Patients should be advised to
report unusual bleeding.
• Arterial thrombotic events have been reported. Patients should be advised to
report signs or symptoms of an arterial thrombosis.
• Reports of pneumothorax and venous thromboembolic events including 
pulmonary embolus have been reported. Patients should be advised to report if 
new onset of dyspnea, chest pain, or localized limb edema occurs.
• Advise patients to inform their doctor if they have worsening of neurological 
function consistent with RPLS (headache, seizure, lethargy, confusion, 
blindness, and other visual and neurologic disturbances).
• Hypertension and hypertensive crisis have been reported. Patients should be 
advised to monitor blood pressure early in the course of therapy and frequently 
thereafter and report increases of blood pressure or symptoms such as blurred 
vision, confusion, severe headache, or nausea and vomiting.
• GI perforation or fistula has occurred. Advise patients to report signs and 
symptoms of a GI perforation or fistula.
• VEGFR inhibitors such as pazopanib may impair wound healing. Advise
patients to stop pazopanib at least 7 days prior to a scheduled surgery.
• Hypothyroidism and proteinuria have been reported. Advise patients that thyroid
function testing and urinalysis will be performed during treatment.
• Serious infections including some with fatal outcomes have been reported.
Advise patients to promptly report any signs or symptoms of infection.
• Women of childbearing potential should be advised of the potential hazard to
the fetus and to avoid becoming pregnant.
• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have 
been reported with pazopanib. Patients should be advised how to manage 
diarrhea and to notify their healthcare provider if moderate to severe diarrhea 
occurs.
• Patients should be advised to inform their healthcare providers of all
concomitant medications, vitamins, or dietary and herbal supplements.
• Patients should be advised that depigmentation of the hair or skin may occur
during treatment with pazopanib.
• Patients should be advised to take pazopanib without food (at least 1 hour
before or 2 hours after a meal).
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
46
8.2.12  Return and Retention of Study Drug: Unused or defective drug will be 
destroyed. Sponsor Novartis should be notified of this action.
9.0
CORRELATIVES/SPECIAL STUDIES
For Cohort 1 and 3:
Cell-free circulating tumor DNA (ctDNA) will be analyzed using the CAPP-Seq method [1,2], a 
targeted hybrid capture-based NGS method, or the commercial version of CAPP-Seq called 
AVENIO [3]. Hybrid capture-based NGS was recently developed to improve the detection of 
multiple cancer mutations with high sensitivity and without significant prior knowledge of the 
alterations [4–6]. In this “hybrid capture” approach, relevant DNA sequences are hybridized to 
biotinylated probes [1]. Biotin is bound to streptavidin beads and then unbound DNA is washed 
away to “pull down” the bait DNA for NGS analysis [1]. Using this principle, Newman and Bratman 
et al. implemented an ultrasensitive ctDNA detection technique called Cancer Personalized 
Profiling by Deep Sequencing (CAPP-Seq) [1]. Recurrently mutated genomic regions in the 
population of a given cancer type are identified through bioinformatic analysis of cancer WES 
and/or WGS data from databases such as The Cancer Genome Atlas (TCGA) and Catalog of 
Somatic Mutations in Cancer (COSMIC) [1]. Biotinylated probes are designed against these 
recurrently mutated regions, and are referred to collectively as the “Selector” [1]. The “Selector” is 
applied to cell-free DNA from cancer patients, which is followed by NGS in order to quantitate 
ctDNA with a detection limit of ~0.01% [1,5]. The detection limit was significantly improved to 
~0.001% when a NGS error-correction strategy called integrative digital error suppression (IDES) 
was implemented [2]. This strategy utilized UMIs to reduce the effect of PCR errors and a 
bioinformatic error correction step called “polishing” to reduce the effect of stereotypical 
background artifacts [2].
For this project, we will be applying CAPP-Seq to blood and tissue as we have done previously 
[1,2,7], by isolating DNA from ~10 mL of plasma, inputting ~32 ng into the CAPP-Seq library 
preparation protocol which starts with adapter ligation, performing PCR, then targeted hybrid 
capture, and then NGS on a NovaSeq, HiSeq4000 or a NextSeq. We then will analyze the results 
using the CAPP-Seq or AVENIO bioinformatics pipeline which enables variant-calling and 
calculation of variant allele fractions (VAFs) which are averaged at each time point to yield the 
mean VAF. We will use this measure, as well as the ctDNA concentration (VAF x cfDNA 
concentration) to quantify ctDNA at each time point, and correlate these results with demographic, 
diagnostic, treatment, and outcomes data. 
For Cohort 2:
Sleijfer et al. recently published a translational study in which they evaluated whether cytokine 
levels in the patients enrolled in EORTC 62043, the phase II study of pazopanib in soft tissue 
sarcoma, correlated with PFR and OS. They measured levels of several cytokines at baseline 
and 12 weeks after beginning pazopanib therapy and demonstrated that baseline levels were not 
predictive, but that high sVEGFR2 and low PIGF were associated with a more favorable PFR at
12 weeks (OR 0.636, 95% CI 0.413-0.977, P=0.039) and (OR 1.081, 95% CI 1.007-1.160, 
P=0.0318) respectively. There was also a trend toward high sVEGFR2 at week 12 and increased 
OS and a statistically significant association between low PIGF levels at week 12 and longer OS 
(HR 1.061, 95% CI 1.025-1.099, P=0.0009) 6.
We propose to measure sVEGFR2 and PIGF levels in blood to both verify the results of Sleijfer et 
al and to determine if there is an even earlier correlation that can be detected between levels of 
these cytokines and PFR as well as OS which may allow us to better predict treatment response 
early on in therapy.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
47
9.1   Sample Collection Guidelines (please see the lab manual for full details) 
Mandatory whole blood samples will be collected at screening or predose on Cycle 1 Day 
1, and day 1 of Cycles 2, 3, and 4. Approximately 20 ml of anticoagulated whole blood will 
be collected in 2 EDTA purple top tubes and 1 SST red top tube at each timepoint. Whole 
blood for DNA, mononucleated cells, and serum should be immediately prepared from the 2 
EDTA purple top tubes and SST red top tube, respectively, and frozen down to -80° C prior to 
shipment using standard laboratory techniques. Samples should be labeled with the 
corresponding patient's study ID number, initials, and date of collection.
9.2   Sample Processing, Storage, and Shipment
Prepared, frozen blood samples should be shipped on dry ice to the Van Tine Lab at 
Washington University (see address below). Samples may be sent in batches approximately 
every 2 months. Once received, specimens will be processed in the Tissue
Core Procurement Facility at Washington University to store nucleated blood cells, DNA, 
and serum for potential future molecular biomarker studies.
Blood samples for correlative study should be sent to the following address: 
Oncology – Van Tine lab
4515 McKinley Building, 3rd Floor
4523 Clayton Avenue
St. Louis, MO 63110
9.1   Sample Collection Guidelines (please see the lab manual for full details) 
Mandatory whole blood samples will be collected at screening or predose on Cycle 1 Day 
1, and day 1 of Cycles 2, 3, and 4. Approximately 20 ml of anticoagulated whole blood will 
be collected in 2 EDTA purple top tubes and 1 SST red top tube at each timepoint. Whole 
blood for DNA, mononucleated cells, and serum should be immediately prepared from the 2 
EDTA purple top tubes and SST red top tube, respectively, and frozen down to -80° C prior to 
shipment using standard laboratory techniques. Samples should be labeled with the 
corresponding patient's study ID number, initials, and date of collection.
9.2   Sample Processing, Storage, and Shipment
Prepared, frozen blood samples should be shipped on dry ice to the Van Tine Lab at 
Washington University (see address below). Samples may be sent in batches approximately 
every 2 months. Once received, specimens will be processed in the Tissue
Core Procurement Facility at Washington University to store nucleated blood cells, DNA, 
and serum for potential future molecular biomarker studies.
Blood samples for correlative study should be sent to the following address: 
Oncology – Van Tine lab
4515 McKinley Building, 3rd Floor
4523 Clayton Avenue
St. Louis, MO 63110
10.0
STATISTICAL CONSIDERATIONS
10.1 Study Design/Study Endpoints
This is a single arm two-stage Simon optimum Phase II study of pazopanib and topotecan 
with progression-free rate at 12 weeks as the primary outcome. The historic PD free rate 
at 12 weeks for single agent pazopanib is 55%. To detect a 20% improvement (an 11% 
absolute improvement) with the combination of pazopanib and topotecan in a single-arm 
two-stage optimum design and a one-tailed exact binomial p- value, a total of 92 evaluable 
STS patients is required to detect 55% vs 66% with 80% 
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
48
power and an alpha level of 10%. If 32 out of the first 55 patients are alive and progression 
free at 12 weeks, the trial may enroll up to 108 patients in order to acquire a total of 92 
evaluable patients. At that time, if 56 or more out of 92 are alive and progression-free at 12 
weeks, then the trial will conclude that the true 12 week PFS rate is at least 66%. There is 
a 63% probability of terminating the study after the first stage when the true rate is 55%. 
See sections 6.0 and 7.0 for definitions of evaluable patients for response and adverse 
event information.
Osteosarcoma/Liposarcoma exploratory group:
Up to 36 patients with osteosarcoma and 20 patients with liposarcoma will be enrolled to 
obtain exploratory information for patients with these two histologies. Although the sample 
sizes in these two cohorts were selected for feasibility rather than to power a specific 
hypothesis, 56 subjects will provide estimates of PFR and OS with sufficient
precision to support additional study of pazopanib in these patients.
10.2 Sample Size and Accrual
A total of 92 evaluable STS patients is required to detect 55% vs 66% with 80% power and 
an alpha level of 10%. If 32 out of the first 55 patients are alive and progression free at 12 
weeks, this trial may enroll up to 108 STS patients in order to accrue a total of 92 evaluable 
patients. If the trial has not yet achieved 32 responses, may be suspended to enrollment to 
allow the 55th patient to reach week 12 of treatment for evaluation.
In addition, up to 36 patients with osteosarcoma and 20 patients with liposarcoma will be 
enrolled to obtain exploratory information for patients with these two histologies. Data 
exists to help construct baseline event free survival outcomes that can be used as a 
comparison for future phase II trials for recurrent osteosarcoma (J Clin Oncol. 2016 Sep 
1;34(25):3031-8. doi: 10.1200/JCO.2015.65.5381. Epub 2016 Jul 11.)
 Using a single arm, 2 stage Phase II trial design: For stage I- If 4 or more of 19 patients 
have disease control of greater than 4 months then Stage 2 should be opened. The 
endpoint is that if 11 or more patients/ 36 have disease control at 4 months, then the agent 
is considered sufficiently efficacious for additional study.
 
As the study has been using 12 week and 20 week endpoints, we can use 20 weeks 
instead of 16 weeks as a surrogate endpoint.
 
The DMC reviewed the interim analysis data on 1/11/2017, and has approved cohort 1 to 
reopen to 96 total patients( to obtain 92 evaluable patients). In addition, based on the 
percentage of non-evaluable patients during the interim analysis, it was determined that a 
total of 108 patients would most likely need to be enrolled in order to obtain 92 evaluable 
patients.
The remaining slots have been equally divided in 5 ways among the sites, with an 
expiration date of May 12, 2017. Status of accrual will be reassessed at that time, and 
the remaining slots will be divided accordingly.
The 16 additional osteosarcoma slots will only be available at Northwestern (NMH).
10.3 Data Analyses Plans
PFR and OS will be estimated for each histologic group (STS, osteoscaroma, and 
liposarcoma) using Kaplan-Meier methods. Response rates will be summarized by the 
observed proportion of patients with response, along with a 95% confidence interval. 
Toxicities will be tabulated and summarized by the number of patients experiencing each 
toxicity. A formal hypothesis test for the median PFR of the STS patients is planned; no 
formal hypothesis test is planned for the other two histologic groups.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
49
11.0
STUDY MANAGEMENT
11.1 Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion.
For patients with limited English proficiency who are approached for participation in the 
study, an IRB approved short form will be used. In addition, the services of an interpreter 
fluent in both English and the language understood by the potential study patient will be 
obtained. The patient will be re-consented using the IRB approved translated consent in 
the language understood by the patient, when available. The exact process will be 
conducted in accordance to local IRB guidelines and policies.
11.2 Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or informed 
consent. All amendments will be subject to the review and approval of the appropriate local, 
institutional, and governmental regulatory bodies, as well as by GlaxoSmithKline. 
Amendments will be distributed by the lead institution (Northwestern) to all affiliate sites upon 
approval by the Northwestern University IRB.
11.3 Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will be 
registered centrally through the Clinical Research Office at Northwestern University before 
enrollment to study. Please contact the assigned Quality Assurance Monitor
(QAM) or email the QA Department (croqualityassurance@northwestern.edu) for 
questions regarding patient registration.
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at: 
https://notis.nubic.northwestern.edu. Please note that a username and password is required 
to use this program, and will be provided during site activation prior to training
on the NOTIS system.
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:
 
Patient’s signed and dated informed consent form (upload to NOTIS and keep
original hard copy in a secure location/study chart)
 
Eligibility checklist (signed and dated by the treating physician – upload to
NOTIS)
 
Eligibility eCRF (complete in NOTIS)
 
Copy of the pathology report (upload to NOTIS)
Training on eCRF completion will be provided at the time of site activation.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
50
The QAM will review the registration, register the patient, assign a subject identification 
number, and send a confirmation of registration to study personnel. Registration will then 
be complete and the patient may begin study treatment.
11.4 Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be 
submitted according to the detailed data submission guidelines (provided in a 
separate document). Please see the data submission guidelines located on the 
protocol page in NOTIS.
Please contact  croqualityassurance@northwestern.edu for further details
11.5 Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation 
must be provided to the Clinical Research Office at Northwestern University:
 
Signed and completed Participating Site Questionnaire to participate in the 
study.
 
Signed copy of Northwestern University’s Data Monitoring Committee policy
pertaining to data submission.
 
Draft informed consent form should for review/approval prior to submission 
to the local IRB
 
A copy of the official IRB approval letter for the protocol and informed consent.
 
CVs and medical licensure for the local PI and any sub-investigators who 
will be involved in the study at the site.
 
Form FDA 1572 appropriately filled out and signed with appropriate 
documentation.
Additional activities may be required prior to site activation (i.e. contract execution, 
study- specific training). Full requirements will be outlined in a memo upon receipt of 
the signed Participating Site Questionnaire.
11.6 Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University: 
http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay2014.p
df
The level of risk attributed to this study requires high-intensity monitoring as 
outlined in the DSMP. The assigned QAM, with oversight from the Data Monitoring 
Committee, will monitor this study in accordance with the study phase and risk 
level. Please refer to the Appendices for additional data submission instructions.
11.7 Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.
11.7.1  Emergency Modifications
Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without 
prior IRB approval. 
For any such emergency modification implemented, an IRB modification 
form must be completed within 5 business days of making the change, 
and the QAM must be notified within 24 hours of such change.
11.7.2  Other Protocol Deviations
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
51
All other deviations from the protocol must be reported to the assigned
QAM using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved 
protocol that:
 Is generally noted or recognized after it occurs.
 Has no substantive effect on the risks to research participants.
 Has no substantive effect on the scientific integrity of the research 
plan or the value of the data collected.
 Did not result from willful or knowing misconduct on the part 
of the investigator(s).
A protocol deviation may be considered an instance of Reportable New
Information (RNI) if it:
 Has harmed or increased the risk of harm to one or more 
research participants.
 Has damaged the scientific integrity of the data collected for the 
study.
 Results from willful or knowing misconduct on the part 
of the investigator(s).
 Demonstrates serious or continuing noncompliance with 
federal regulations, State laws, or University policies.
11.8 Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The PI is responsible for personally overseeing the treatment 
of all study patients. The PI must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI
regulations and guidelines regarding clinical trials both during and after study 
completion.
The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected, entered onto the appropriate eCRFs, and 
submitted within the study-specific timeframes. Periodically, monitoring visits may be 
conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. The study may also be subject 
to routine audits by the Audit Committee, as outlined in the DSMP.
11.9 Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with 
the policies and processes set forth in the Lurie Cancer Center DSMP. The assigned 
QAM will prepare a preliminary data summary (to be approved by the DMC) no later 
than 3 months after the study reaches its primary completion date (the date that the 
final subject is examined or receives an intervention for the purposes of final data 
collection for the primary endpoint). If the investigator’s wish to obtain DMC-
approved data prior to this point (or prior to the point dictated by study design), the PI 
must send a written request for data to the QAM which includes justification. If the 
request is approved, data will be provided no later than 4 weeks after this request 
approval. The data will be presented to the DMC at their next available meeting, and 
a final, DMC-approved dataset will be released along with any DMC decisions 
regarding publication. The investigators are expected to use only DMC-approved 
data in future publications. The investigators should submit a copy of the manuscript 
to the biostatistician to confirm that the DMC-approved data are used appropriately. 
Once the biostatistician gives final approval, the manuscript may be submitted to 
external publishers.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
52
REFERENCES
1.
Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. The New England 
journal of medicine. Aug 18 2005;353(7):701-711.
2.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. Jan-
Feb 2014;64(1):9-29.
3.
Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant 
radiation therapy in the treatment of soft tissue sarcomas of the extremity. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. Jan 1998;16(1):197-203.
4.
Alektiar KM, Brennan MF, Healey JH, Singer S. Impact of intensity-modulated radiation therapy 
on local control in primary soft-tissue sarcoma of the extremity. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. Jul 10 2008;26(20):3440-3444.
5.
Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of 
a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. Journal of
clinical oncology : official journal of the American Society of Clinical Oncology. Mar
1996;14(3):859-868.
6.
Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of 
individual data. Sarcoma Meta-analysis Collaboration. Lancet. Dec 6 1997;350(9092):1647-1654.
7.
Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta- 
analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft- 
tissue sarcoma. Cancer. Aug 1 2008;113(3):573-581.
8.
Blay JY, Le Cesne A. Adjuvant chemotherapy in localized soft tissue sarcomas: still not proven.
The oncologist. Oct 2009;14(10):1013-1020.
9.
Stojadinovic A, Leung DH, Allen P, Lewis JJ, Jaques DP, Brennan MF. Primary adult soft tissue 
sarcoma: time-dependent influence of prognostic variables. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. Nov 1 2002;20(21):4344-4352.
10.
Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al. Prognostic factors for the outcome of 
chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with 
anthracycline-containing first-line regimens--a European Organization for Research and 
Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. Jan 1999;17(1):150-157.
11.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. Sep 14
2000;407(6801):249-257.
12.
Coomber BL, Denton J, Sylvestre A, Kruth S. Blood vessel density in canine osteosarcoma.
Canadian journal of veterinary research = Revue canadienne de recherche veterinaire. Jul
1998;62(3):199-204.
13.
Folkman J. Role of angiogenesis in tumor growth and metastasis. Seminars in oncology. Dec
2002;29(6 Suppl 16):15-18.
14.
Italiano JE, Jr., Richardson JL, Patel-Hett S, et al. Angiogenesis is regulated by a novel 
mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules 
and differentially released. Blood. Feb 1 2008;111(3):1227-1233.
15.
Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Seminars in cancer biology.
Oct 2009;19(5):329-337.
16.
Iruela-Arispe ML, Dvorak HF. Angiogenesis: a dynamic balance of stimulators and inhibitors.
Thrombosis and haemostasis. Jul 1997;78(1):672-677.
17.
Zetter BR. Angiogenesis and tumor metastasis. Annual review of medicine. 1998;49:407-424.
18.
Folkman J. Tumor angiogenesis: therapeutic implications. The New England journal of medicine.
Nov 18 1971;285(21):1182-1186.
19.
Hanrahan V, Currie MJ, Gunningham SP, et al. The angiogenic switch for vascular endothelial 
growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence 
during colorectal cancer progression. The Journal of pathology. Jun 2003;200(2):183-194.
20.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nature medicine. Jun
2003;9(6):669-676.
21.
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and 
angiogenesis. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. Feb 10 2005;23(5):1011-1027.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
53
22.
Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nature reviews.
Cancer. Aug 2008;8(8):579-591.
23.
Fischer C, Mazzone M, Jonckx B, Carmeliet P. FLT1 and its ligands VEGFB and PlGF: drug 
targets for anti-angiogenic therapy? Nature reviews. Cancer. Dec 2008;8(12):942-956.
24.
McMahon G. VEGF receptor signaling in tumor angiogenesis. The oncologist. 2000;5 Suppl 1:3-
10.
25.
Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor 
vasculature and stroma. Cytokine & growth factor reviews. Aug 2004;15(4):275-286.
26.
Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G. PDGFRbeta+ perivascular progenitor cells in 
tumours regulate pericyte differentiation and vascular survival. Nature cell biology. Sep
2005;7(9):870-879.
27.
Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell. Jul 18
1986;46(2):155-169.
28.
Li H, Fredriksson L, Li X, Eriksson U. PDGF-D is a potent transforming and angiogenic growth 
factor. Oncogene. Mar 13 2003;22(10):1501-1510.
29.
Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms.
Cytokine & growth factor reviews. Aug 2004;15(4):197-204.
30.
Potti A, Ganti AK, Tendulkar K, et al. Determination of vascular endothelial growth factor (VEGF) 
overexpression in soft tissue sarcomas and the role of overexpression in leiomyosarcoma. 
Journal of cancer research and clinical oncology. Jan 2004;130(1):52-56.
31.
Lammli J, Fan M, Rosenthal HG, et al. Expression of Vascular Endothelial Growth Factor 
correlates with the advance of clinical osteosarcoma. International orthopaedics. Nov
2012;36(11):2307-2313.
32.
Pakos EE, Goussia AC, Tsekeris PG, Papachristou DJ, Stefanou D, Agnantis NJ. Expression of 
vascular endothelial growth factor and its receptor, KDR/Flk-1, in soft tissue sarcomas. 
Anticancer research. Sep-Oct 2005;25(5):3591-3596.
33.
Chao C, Al-Saleem T, Brooks JJ, Rogatko A, Kraybill WG, Eisenberg B. Vascular endothelial 
growth factor and soft tissue sarcomas: tumor expression correlates with grade. Annals of 
surgical oncology. Apr 2001;8(3):260-267.
34.
Yudoh K, Kanamori M, Ohmori K, Yasuda T, Aoki M, Kimura T. Concentration of vascular 
endothelial growth factor in the tumour tissue as a prognostic factor of soft tissue sarcomas. 
British journal of cancer. Jun 15 2001;84(12):1610-1615.
35.
Potti A, Ganti AK, Foster H, et al. Immunohistochemical detection of HER-2/neu, c-kit (CD117) 
and vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcomas. 
Anticancer research. Jan-Feb 2004;24(1):333-337.
36.
Wang J, Coltrera MD, Gown AM. Cell proliferation in human soft tissue tumors correlates with 
platelet-derived growth factor B chain expression: an immunohistochemical and in situ 
hybridization study. Cancer research. Jan 15 1994;54(2):560-564.
37.
Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant 
metastases in human soft tissue sarcoma. Cancer research. Mar 1 1996;56(5):941-943.
38.
Liang D, Yang M, Guo B, Yang L, Cao J, Zhang X. HIF-1alpha induced by beta-elemene protects 
human osteosarcoma cells from undergoing apoptosis. Journal of cancer research and clinical 
oncology. Nov 2012;138(11):1865-1877.
39.
Eisinger-Mathason TS, Zhang M, Qiu Q, et al. Hypoxia-dependent modification of collagen 
networks promotes sarcoma metastasis. Cancer discovery. Oct 2013;3(10):1190-1205.
40.
Kummar S, Allen D, Monks A, et al. Cediranib for metastatic alveolar soft part sarcoma. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology. Jun 20
2013;31(18):2296-2302.
41.
George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of 
nongastrointestinal stromal tumor sarcomas. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. Jul 1 2009;27(19):3154-3160.
42.
Maki RG, D'Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients with metastatic 
or recurrent sarcomas. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. Jul 1 2009;27(19):3133-3140.
43.
Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in 
patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
54
European organisation for research and treatment of cancer-soft tissue and bone sarcoma group 
(EORTC study 62043). Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. Jul 1 2009;27(19):3126-3132.
44.
Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Current 
oncology reports. Mar 2007;9(2):115-119.
45.
Ranieri G, Mammi M, Donato Di Paola E, et al. Pazopanib a tyrosine kinase inhibitor with strong 
anti-angiogenetic activity: a new treatment for metastatic soft tissue sarcoma. Critical reviews in 
oncology/hematology. Feb 2014;89(2):322-329.
46.
Hamberg P, Verweij J, Sleijfer S. (Pre-)clinical pharmacology and activity of pazopanib, a novel 
multikinase angiogenesis inhibitor. The oncologist. 2010;15(6):539-547.
47.
Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from 
mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and 
antiangiogenic activity. Molecular cancer therapeutics. Jul 2007;6(7):2012-2021.
48.
Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research.
Jun 15 2009;15(12):4220-4227.
49.
van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma
(PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. May 19
2012;379(9829):1879-1886.
50.
Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G. Topoisomerase I- 
mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer 
research. Feb 15 2004;64(4):1475-1482.
51.
Reichardt P, Oechsle K, Pink D, et al. An open label, non-comparative phase II study of 
topotecan as salvage treatment for patients with soft tissue sarcoma. Investigational new drugs.
Nov 2003;21(4):481-486.
52.
Miller DS, Blessing JA, Kilgore LC, Mannel R, Van Le L. Phase II trial of topotecan in patients
with advanced, persistent, or recurrent uterine leiomyosarcomas: a Gynecologic Oncology Group
Study. American journal of clinical oncology. Aug 2000;23(4):355-357.
53.
Hanahan D, Bergers G, Bergsland E. Less is more, regularly: oral dosing of cytotoxic drugs can 
target tumor angiogenesis in mice. The Journal of clinical investigation. Apr 2000;105(8):1045-
1047.
54.
Kerbel RS, Kamen BA. The anti-angiogenic basis of oral chemotherapy. Nature reviews. Cancer.
Jun 2004;4(6):423-436.
55.
Pasquier E, Kavallaris M, Andre N. Oral chemotherapy: new rationale for new directions. Nature 
reviews. Clinical oncology. Aug 2010;7(8):455-465.
56.
Tonini G, Schiavon G, Silletta M, Vincenzi B, Santini D. Antiangiogenic properties of oral 
chemotherapy in breast cancer. Future oncology (London, England). Apr 2007;3(2):183-190.
57.
Gasparini G. Oral scheduling: the future of chemotherapy? The lancet oncology. Dec
2001;2(12):733-740.
58.
Bertolini F, Paul S, Mancuso P, et al. Maximum tolerable dose and low-dose oral chemotherapy 
have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. 
Cancer research. Aug 1 2003;63(15):4342-4346.
59.
Kumar S, Mokhtari RB, Sheikh R, et al. Oral oral topotecan with pazopanib is an active 
antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clinical cancer 
research : an official journal of the American Association for Cancer Research. Sep 1
2011;17(17):5656-5667.
60.
Hashimoto K, Man S, Xu P, et al. Potent preclinical impact of oral low-dose oral topotecan 
combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Molecular 
cancer therapeutics. Apr 2010;9(4):996-1006.
61.
Merritt WM, Nick AM, Carroll AR, et al. Bridging the gap between cytotoxic and biologic therapy 
with oral topotecan and pazopanib in ovarian cancer. Molecular cancer therapeutics. Apr
2010;9(4):985-995.
62.
Kerklaan, B et al., "Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in 
combination with oral topotecan in patients with advanced solid tumors." J Clin Oncol 31, 2013 
(suppl; abstr 2536).
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
55
63.
Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable 
high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group 
study. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 
Feb 2012;23(2):508-516.
64.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours:
revised RECIST guideline (version 1.1). Eur J Cancer. Jan 2009;45(2):228-247.
CORRELATIVES/SPECIAL STUDIES REFERENCES:
[1]       Newman AM, Bratman S V., To J, et al. An ultrasensitive method for quantitating circulating tumor 
DNA with broad patient coverage. Nat. Med. 2014;20:548–554.
[2] 
Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved 
detection of circulating tumor DNA. Nat. Biotechnol. 2016;34:547–555.
[3] 
Khan KH, Cunningham D, Werner B, et al. Longitudinal liquid biopsy and mathematical modeling of 
clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer 
clinical trial. Cancer Discov. 2018;1–16.
[4] 
Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC: challenges to implementing ctDNA-based 
screening and MRD detection. Nat. Rev. Clin. Oncol. 2018;
[5] 
Chaudhuri AA, Binkley MS, Osmundson EC, et al. Predicting radiotherapy responses and treatment 
outcomes through analysis of circulating tumor DNA. Semin. Radiat. Oncol. 2015;25:305–312.
[6] 
Wan JCM, Massie C, Garcia-Corbacho J, et al. Liquid biopsies come of age: Towards 
implementation of circulating tumour DNA. Nat. Rev. Cancer. 2017;17:223–238.
[7] 
Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in 
localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 2017;7:1394–1403.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
56
APPENDICES
APPENDIX A1. GENERAL DRUGS TO BE AVOIDED WITH PAZOPANIB

CYP3A4 STRONG INHIBITORS

CYP3A4 STRONG INDUCERS

CYP SUBSTRATES

SIMVASTATIN (USED WITH CAUTION)

PROTON PUMP INHIBITORS AND H2 RECEPTOR BLOCKERS
APPENDIX A2. Table of Drugs known to be metabolized by CYP450 isoenzymes 2D6 and
3A4 (to be avoided with pazopanib)
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
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
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
57
Dronabinol 
Enalapril 
Erythromycin 
Estradiol
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Flutamide 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
lfosfamide 
lmipramine 
lndinavir 
lsradipine 
ltraconazole 
Ketoconazole 
Lansoprazole 
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
Omeprazole (sulfonation) 
Ondansetron
Oral contraceptives
Orphenadrine
Paclitaxel 
Pantoprazole 
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
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
58
Inducers
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)
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
59
APPENDIX B. TABLE OF 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
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
60
APPENDIX C. 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
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
62
APPENDIX D – DATA COLLECTION & SUBMISSION GUIDELINES
Please see the data submission guidelines located on the protocol page in NOTIS.
APPENDIX E – DATA SAFETY MONITORING PLAN
http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay2014.pdf
Note: Link inserted in appropriate sections
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
63
APPENDIX F- PATIENT MEDICATION DIARY
NU 14S03: Topotecan
Dispensed date:   
Patient’s Study ID 
Patient’s Initials  
Cycle #  
Instructions to the Patient:
1.  You will take capsules of topotecan by mouth once a week for the first three weeks. On the 
fourth week you will not take topotecan.
2.  You should swallow the capsules whole with at least 1 cup (8 ounces) of water, with or 
without food.
3.  If you vomit on a day where you take both medications, you will take your next dose of 
topotecan one week later and your next dose of pazopanib the following day.
Topotecan dose:  
mg
Day
Date
Time Taken
Comments (please note if you vomit/and 
any other symptoms you experience)
1
 
a.m.
 
p.m.
2
3
4
5
6
7
DO NOT TAKE TOPOTECAN ON THESE DAYS.
8
 
a.m.
 
p.m.
9
10
11
12
13
14
DO NOT TAKE TOPOTECAN ON THESE DAYS.
15
 
a.m.
 
p.m.
16
17
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
64
18
19
20
21
22
23
24
25
26
27
28
DO NOT TAKE TOPOTECAN ON THESE DAYS.
Physician’s office will complete this section:
1.
Total # of pills dispensed:  
2.
Total # of pills taken this cycle: 
3.
Total # of pills returned:_ 
4.
Patient’s signature:  
Date:_ 
5.
Reviewer’s signature:_ 
 Date: 
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
65
NU 14S03 Medication Diary:  Pazopanib
Dispensed date:   
 Patient’s Study ID_ 
 
Patient’s Initials  
Cycle# 
Instructions to the Patient:
1.  Take pazopanib by mouth 1 time every day at about the same time each day. Take it on an 
empty stomach (at least 1 hour before and 2 hour after eating) with about 1 cup (8 ounces) 
of water.
2.  If you vomit on a day where you only take pazopanib, the next dose would be the following 
day. If you vomit on a day where you take both medications, you will take your next dose of
topotecan one week later and your next dose of pazopanib the following day.
Pazopanib  
 mg once daily
Day
Date
Time Taken
Comments (please note if you vomit/and 
any other symptoms you experience)
1
 
a.m.
 
p.m.
2
 
a.m.
 
p.m.
3
 
a.m.
 
p.m.
4
 
a.m.
 
p.m.
5
 
a.m.
 
p.m.
6
 
a.m.
 
p.m.
7
 
a.m.
 
p.m.
8
 
a.m.
 
p.m.
9
 
a.m.
 
p.m.
10
 
a.m.
 
p.m.
11
 
a.m.
 
p.m.
12
 
a.m.
 
p.m.
13
 
a.m.
 
p.m.
14
 
a.m.
 
p.m.
15
 
a.m.
 
p.m.
16
 
a.m.
 
p.m.
17
 
a.m.
 
p.m.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
66
18
 
a.m.
 
p.m.
19
 
a.m.
 
p.m.
20
 
a.m.
 
p.m.
21
 
a.m.
 
p.m.
22
 
a.m.
 
p.m.
23
 
a.m.
 
p.m.
24
 
a.m.
 
p.m.
25
 
a.m.
 
p.m.
26
 
a.m.
 
p.m.
27
 
a.m.
 
p.m.
28
 
a.m.
 
p.m.
Physician’s office will complete this section:
1.   Total # of pills dispensed: 
2.   Total # of pills taken this cycle: 
3.   Total # of pills returned:_ 
4.   Patient’s signature:  
Date: 
5.   Reviewer’s signature:_ 
Date: 
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
67
APPENDIX G – BLOOD PRESSURE LOG
Protocol Number  
Institution  
_
Subject Initials   
Study ID #  
Cycle  
Date of 
assessment
Time of 
assessment
Systolic/Diastolic
(mmHg)
Comments
Week 1
Week 2
Week 3
Week 4
Blood pressure should be recorded weekly during the treatment (+/- 3 days).
CRA Initials Date of Completion
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
68
Appendix H- Protocol History of Changes
Original Version Submitted to the IRB – December 02, 2014
Amendment 1 – February 04, 2015
Approved by SRC – February 04, 2015
Section(s)
Affected
Prior Version
Amendment 1
Changes
Rationale
Title Page
Sub-Investigators list
Thomas McFarland, MD
and Keith Skubitz, MD
removed
Administrative
Title Page
IND Number: TBD
Revised to “IND Number:
EXEMPT”
Administrative
Study Schema, 
Study Summary, 
Sections 3.0, 10.1,
10.2
Up to 20 patients will be
enrolled (if the first five 
patients are alive and 
continuing therapy at 12 
weeks, the remaining 15 
patients will be enrolled in 
the osteosarcoma and 
liposarcoma groups)
Up to 20 patients will be 
enrolled in the osteosarcoma 
and liposarcoma groups
The osteosarcoma 
and liposarcoma 
groups are 
exploratory and 
need 20 patients 
accrued to evaluate 
activity.
Section 5.0 (Study
Procedures)
Footnote f includes “CMP
and LFTs should include:
ALT, AST.”
Revised to list all tests
included in the CMP and
LFTs
Revised for 
accuracy
Amendment 2 –April 1, 2015
Approved by Scientific Review Committee- April 15, 2015
Sections(s)
Affected
Prior Version
Amendment 2
Changes
Rationale
3.1.3 
(Inclusion 
Criteria)
“Patients must have 
a histologically 
confirmed diagnosis 
of :
•
metastatic
soft tissue sarcomas
(non-liposarcoma)
•
metastatic 
osteosarcoma
•
metastatic 
liposarcoma- high 
grade, de- 
differentiated, or 
myxoid
NOTE: Pathology is 
not required to be 
reviewed at the 
treating institution.
A copy of the 
pathology report is 
sufficient for 
eligibility purposes”
Revised to “Patients must 
have a histologically 
confirmed diagnosis of 
metastatic or locally 
advanced unresectable :
 
soft tissue sarcomas
(non-liposarcoma)
 
osteosarcoma
 
liposarcoma- high 
grade, de-
differentiated, or
myxoid
NOTE: Pathology is not 
required to be reviewed at
the treating institution. A
copy of the pathology report 
is sufficient for eligibility 
purposes”
Revised to clarify 
that patients must 
have both 
metastatic or 
locally advanced 
unresectable soft 
tissue sarcomas 
(non-liposarcoma), 
Osteosarcoma, or 
liposarcoma- high 
grade, de- 
differentiated, or 
myxoid
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
69
5.0 (Study
Procedures)
n/a
Revised to add to “X”
n
Chemistry labs on C1D1
advertently missed
on previous 
amendment
Amendment 3 –June 2, 2015
Approved by Scientific Review Committee- September 2, 2015
Sections(s)
Affected
Prior Version
Amendment 3 Changes
Rationale
All
Multiple fonts
All text changed to one font
Consistency
3.1.1 Inclusion
Criteria
Patients must have had a 
minimum of 1 and a 
maximum of 4 prior 
chemotherapy regimens for 
recurrent/metastatic 
disease. It will be up to the 
investigator to determine
what constitutes a “regimen”
in each case
Cohort 1: Patients must
have had a minimum of 1 and 
a maximum of 4 prior 
chemotherapy regimens for 
recurrent/metastatic disease. 
It will be up to the
investigator to determine 
what constitutes a “regimen” 
in each case.
Cohort 2 and 3: Patients
must have had a minimum of
1 and maximum of any 
number of prior 
chemotherapy regimens for 
recurrent/metastatic disease.
As cohorts 2 and 3 
are exploratory 
only, the 
chemotherapy 
regimen maximum 
does not apply to 
these cohorts.
3.2.10 Exclusion
Criteria
Patients with a history of 
cerebrovascular accident 
including transient ischemic 
attack (TIA), pulmonary 
embolism, or untreated deep 
venous thrombosis (DVT). 
Patients with DVT must
have received appropriate 
therapy for at least 6 months 
to be considered eligible
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
Updated based on 
previous studies 
using this 
combination of 
drugs.
4.3 Toxicity
Management
N/A
Added clarification of how
toxicity should be assessed 
within cycles
Clarification
5.0 Study
Parameters
N/A
Removed reconsenting
requirement within 30 days. 
Clarified T4 only needed 
done if TSH was abnormal. 
Clarified when correlative 
samples should be drawn.
Clarification
Amendment 4 – February 02, 2016
Approved by Scientific Review Committee - January 5, 2016
Sections(s)
Affected
Prior Version
Amendment 4 Changes
Rationale
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
70
3.2.10 Exclusion
Criteria
Rhabdomyosarcoma 
(embryonal, alveolar, 
pleomorphic)
Removed pleomorphic
Rhabdomyosarcoma
Pleomorphic 
subtype will now be 
eligible
3.2.17 Exclusion
Criteria
Treatment with any of the 
following anti-cancer 
therapies:
• radiation therapy, surgery 
or tumor embolization within
14 days prior to the first 
dose of therapy
• chemotherapy, 
immunotherapy, biologic 
therapy, investigational 
therapy or hormonal therapy
within 14 days or five half- 
lives of a drug (whichever is
longer) prior to the first dose
of therapy
Removed chemotherapy, 
immunotherapy, biologic 
therapy, investigational 
therapy or hormonal therapy 
within 14 days or five half- 
lives of a drug (whichever is 
longer) prior to the first dose 
of therapy.
To update that the 
excluded treatment 
categories.
4.1 Overview & 4.2
Treatment 
Administration 
sections
N/A
“Starting dose” indicated for 
pazopanib & topotecan, 
where applicable
Clarification
In the case that treatment
has been held for 3 weeks 
for treatment related 
toxicities, the dose reduction 
(in the case of pazopanib)
for the upcoming cycle 
should be based on the 
most severe toxicity 
experienced in the current 
cycle.
In the case that treatment 
has been held for 3 weeks 
for treatment related 
toxicities, the dose reduction 
for the upcoming cycle
should be based on the most 
severe toxicity experienced
in the current cycle.
Redundant to 
mention, “in the 
case of pazopnaib”.
4.3 Toxicity 
Management, Dose 
Delays/Modifications
& Supportive care
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.
Patients with stable or 
responding disease may be 
retreated at the same dose 
(both Topotecan and 
Pazopanib) or at a reduced 
dose level, 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.
To update, that 
dose reduction will 
be permitted for 
topotecan also.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
71
N/A
Topotecan:
Three dose reductions are 
permitted, based on side 
effects experienced, from 8 
mg to 6, 6mg to 4, 4mg to 2. 
Further dose reduction is not
allowed. Patients may be
maintained on the lower 
dose of topotecan during 
treatment if deemed to be 
deriving benefit from the
drug. Doses that are reduced 
for topotecan 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 topotecan may 
have the dose re-escalated 
after completion of one cycle 
with toxicities less than or 
equal to grade 1.
To update that the 
dose of topotecan 
will/can be reduced 
based on the 
adverse events.
Topotecan can be held up to
3 weeks waiting for toxicity 
to resolve to <Grade 2. 
Topotecan may be resumed
at that time at same dose. 
Topotecan dose will not be 
reduced. If toxicity does not
resolve in 3 weeks, patient
will be removed from 
treatment.
Topotecan can be held up to
3 weeks waiting for toxicity to 
resolve to <Grade 2. 
Topotecan may be resumed 
at that time at same dose or
with a dose reduction by 1 
level per physician
discretion. If toxicity does not
resolve in 3 weeks, patient 
will be removed from 
treatment.
To update that the 
dose reduction for 
topotecan is now 
permitted.
Table I- Dose 
Modification 
Algorithms for 
Potential Treatment- 
Related Adverse 
Events
N/A
New table added, indicating 
the dose levels for 
topotecan.
Updated based on 
the new amendment 
allowing dose 
reduction for 
topotecan.
Table III Guidelines 
for Management of 
Treatment Emergent 
Hepatotoxicity
For isolated total bilirubin 
column - Error! Reference 
source not found
Deleted
Hyperlink error, now 
deleted.
5.0 Study
Procedures
N/A
Added bilirubin to the LFTs 
list in the footnote ‘f’
Clarification
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
72
N/A
Added a new footnote ‘o’ for 
toxicity management
To update that the 
patient has to call-in 
weekly to report 
toxicities.
Amendment 5 – March 16, 2016
Approved by Scientific Review Committee – March 16, 2016
Sections(s) 
Affected
Prior Version
Amendment 3 Changes
Rationale
Title page
One sub-PI from NU
Funding Source: Glaxo
Smith Kline
Added
one more sub-I from NU: 
Valerie Nelson
Funding Source: changed to
Novartis
Per PI
As of March 2016, 
Votrient 
(Pazopanib) 
commercial supply 
with auxiliary label 
will also be 
available for the 
study, provided by 
Novartis.
There is no set date 
when commercial 
supply will take over 
the clinical supply. It 
will depend on
when the clinical 
supply will be 
exhausted at each 
site
As of Oct 2015, 
Novartis has taken 
over all 
pharmacovigilance 
activities
Section 3.1.6
Inclusion criteria
The last dose of systemic
therapy much have been 
given at least 4 weeks prior 
to initiation of therapy
Wash-out period changed
to 28 days:
“The last dose of systemic 
therapy much have been 
given at least 28 days prior 
to initiation of therapy”
Per PI
Section 3.2.16
Exclusion criteria
BCRP and PgP inducers
and inhibitors will also be 
prohibited
(Appendix A and B)
BCRP and PgP inducers and
inhibitors should be used with 
caution if another alternative 
drug is not able to be used 
(Appendix A and B)
Per PI and QA
(to correct 
conflicting 
information within 
the protocol)
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
73
Section 3.2.16
Exclusion criteria
Unable or unwilling to
discontinue use of inducers 
and inhibitors of CYP450 
listed in Appendix 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 
(Appendix).
Unable or unwilling to
discontinue use of inducers 
and inhibitors of CYP450 
listed in Appendix for at least
14 days prior to the first dose 
of study drug and for the 
duration of the study 
(Appendix A).
Per PI
Section 3.2.17
Exclusion criteria
Treatment with any of the 
following anti-cancer
therapies:
radiation therapy, surgery or 
tumor embolization within
14 days prior to the first 
dose of therapy
Wash-out period changed
to 28 days:
“Treatment with any of the 
following anti-cancer 
therapies:
radiation therapy, surgery or 
tumor embolization within
28 days prior to the first 
dose of therapy”
Per PI
Section 3.2.18
Exclusion criteria
Administration of any non- 
oncologic investigational 
drug within 30 days or 5
half-lives whichever is longer 
prior to receiving the first 
dose of study treatment
Wash-out period changed
to 28 days:
“Administration of any 
investigational drug within
28 days prior to receiving 
the first dose of study 
treatment”
Per PI
Exclusion Criteria
Section 3.2.7
Corrected QT interval (QTc)
> 480 msecs using Bazett’s 
formula (QTc= QT/√RR),
Added:
EKG for screening must be ≤
4 weeks before registration
Per PI
Section 4.4.4.
BCRP and PgP inducers
and inhibitors will be also 
prohibited, listed in the 
Appendix B
BCRP and PgP inducers and
inhibitors should be used with 
caution if another alternative 
drug is not able to be used 
(listed in the Appendix B).
Per PI and QA
(to correct 
conflicting 
information within 
the protocol)
Section 5.0
Study procedures 
table
Footnote d:
EKG:
Cycle 2 day 1 and then 
day 1 of every even cycle until 
end of treatment (+/-3 days)
Added:
EKG for screening must be ≤ 4
weeks before registration
Per PI
Section 7.0
Adverse events
Reference to appendix for
the NU DSMP
Removed: Reference to
DSMP
Inserted: DSMP link 
inserted in text.
Per NU template
Section 7.3.3.2
Reporting to the NU 
IRB
Previous information
Added:
“Any death of an NU subject 
that is actively on study 
treatment (regardless of 
whether or not the event is
Per NU IRB
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
74
Any death of a non-NU 
subject that is unanticipated 
and at least possibly related 
and any other UPIRSOs will 
be reported to the NU IRB 
within 10 working days of 
notification
possibly related to study
treatment)”
Any death of a non-NU 
subject that is unanticipated 
and at least possibly related 
and any other UPIRSOs will 
be reported to the NU IRB 
within 5 working days of 
notification.
Section 7.3.3.4
Reporting to sponsor
Instructions about
reporting to
GlaxoSmithkline
Removed:
GlaxoSmithKline reporting 
instructions
Added:
Instructions about reporting 
to Novartis
Per sponsor.
As of Oct 2015, 
Novartis has taken 
over all 
pharmacovigilance 
activities
Section 8.1.9
Drug Availability and
Supply
Drug(Topotecan) ordering
and shipment information 
inserted
Removed:
Drug shipment information
Added:
“Please complete the drug 
order form located on the 
protocol page in NOTIS. 
This form includes 
directions for ordering”
Per PI and QA
Section 8.2.9
Drug Availability and
Supply
Drug (Pazopanib) ordering
and shipment information 
inserted
Removed:
Drug shipment information
Added:
“Please complete the drug 
order form located on the 
protocol page in NOTIS. 
This form includes 
directions for ordering”
Inserted:
Currently all sites are using 
Pazopanib clinical supply 
that is provided by 
GlaxoSmithKline (GSK).As 
each site uses up this
supply , they will l transition 
to the commercial 
Pazopanib supply provided 
by Novartis.
Per PI, QA 
And sponsor
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
75
As of March 2016, Votrient
(Pazopanib) commercial 
supply with auxiliary label 
will also be available for the 
study, provided by Novartis. 
This commercial supply 
study drug should be 
administrated and stored 
according to the instructions 
specified on the drug labels. 
There is no set date when 
commercial supply will take 
over the clinical supply. It
will depend on when the 
clinical supply will be 
exhausted at each site.
11.4 Data 
submission
Data submission guidelines
available as Appendix D
Removed: Appendix D
details
Inserted: New section on
Data Submission.
(Rest of the sub-sections 
under 11.0 have been re- 
numbered accordingly)
Per NU QA
Appendix D
Data Collection and
Submission Guidelines
Removed:
Data Collection and
Submission Guidelines
Inserted:
“Please see the data 
submission guidelines 
located on the protocol page 
in NOTIS”
Per NU QA
Appendix E
DSMP details
Removed: details
Added: Link inserted in 
appropriate sections
Per NU QA
Amendment 6 – July 27, 2016
Sections(s) 
Affected
Prior Version
Amendment 6 Changes
Rationale
Study Schema
Patients with recurrent or
metastatic and 
unresectable  or bone or 
soft tissue sarcoma who 
failed at least 1 prior 
therapy
The ‘or’ has been removed
Correction of error
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
76
Inclusion criteria
Section 3.1.6
Cohort 2 and 3 requirements
were stated together
Cohort 1: Patients must 
have had a minimum of 1 
and a maximum of 4 prior 
chemotherapy regimens for 
recurrent/metastatic 
disease.
Cohort 2: Patients must 
have had a minimum of 1 
and maximum of any 
number of prior 
chemotherapy regimens for
recurrent/metastatic disease
Cohort 2 and 3 have been
separated.
Cohort 3: Patients may have 
had any number of prior 
therapies for 
recurrent/metastatic or
locally 
advanced/unresectable 
disease. There are no 
restrictions.
Cohort 1: Patients must have 
had a minimum of 1 and a 
maximum of 4 prior 
chemotherapy regimens for 
recurrent/metastatic or 
locally 
advanced/unresectable 
disease.
Cohort2: Patients must have 
had a minimum of 1 and 
maximum of any number of 
prior chemotherapy
regimens for 
recurrent/metastatic or 
locally 
advanced/unresectable
disease.
Improve clarity, 
since all 3 cohorts 
have different 
requirements.
Inclusion criteria
Section 3.1.8
Patients must have
adequate organ function 
within 7 days prior to 
registration.
Serum creatinine and 
creatinine clearance tests 
were both listed as part of 
organ function tests.
Urine protein to creatinine 
ratio and 24 hr urine tests 
were both listed as part of 
organ function tests.
Patients must have adequate 
organ function within 14
days prior to registration.
Now, either Serum creatinine
‘OR’ creatinine clearance 
listed as part of organ 
function tests.
Clarified that function tests.
24- hour urine protein test is 
to be done only when 
UPC≥1.
Mention of ‘reference of 
appropriate appendix’ has 
been removed, since the 
protocol does not have such 
appendix listed.
Increase accrual 
by making criteria 
less restrictive.
Clarification
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
77
Exclusion criteria
Section 3.2.7
Corrected QT interval (QTc)
> 480 msecs using Bazett’s 
formula (QTc= QT/√RR). 
EKG for screening must be 
before registration
Modified to:
Corrected QT interval (QTc)
> 480 msecs using Bazett’s 
formula (QTc= QT/√RR). 
EKG for screening must be 
within 28 days prior to 
registration.
For clarity,
specifying the 
screening period.
Exclusion criteria
Section 3.2.8
History of Cardiovascular
events did not include Left 
ventricular ejection fraction
Added :
Left ventricular ejection 
fraction < 45% in patients 
with prior anthracycline use 
or otherwise at risk for left 
ventricular systolic 
dysfunction
Added for safety
purposes.
Exclusion criteria
Section 3.2.10
Section 3.2.11 
section 3.2.17
Subjects with recent DVT 
who have been treated with 
therapeutic anti-
coagulating agents for at
least 6 weeks are eligible
Major surgery or trauma 
within 28 days prior to first 
dose of investigational 
product and/or presence of 
any non-healing wound, 
fracture, or ulcer 
(procedures such as 
catheter placement not 
considered to be major 
surgery).
radiation therapy, surgery or 
tumor embolization within 28 
days prior to the first dose of 
therapy
Modified: The time periods in 
these three criteria are 
specified to be prior to first 
dose of study treatment
For clarity
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
78
Exclusion criteria
3.2.16
Unable or unwilling to 
discontinue use of  inducers 
and inhibitors of CYP450 
listed in Appendix.
Unable or unwilling to 
discontinue use of strong 
inducers and inhibitors of 
CYP450 listed in Appendix.
ADDED:
Note: As this list is constantly 
evolving, if a medication is
incorrectly documented as
prohibited in this protocol, 
documentation from the site 
pharmacist to the contrary 
will be acceptable for the 
purposes of registration.
Added for clarity. It 
provides for 
specificity.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
79
Section 4.3
Toxicity 
Management, Dose 
Delays/Modifications
& Supportive care
After cycle 1, defined as 4
weeks of therapy, additional 
cycles of therapy may be 
administered provided the 
patient meets the following 
criteria.
Modified:
“After cycle 1 day 1 of 
therapy, defined as 4 weeks 
of therapy, cycle 1 day 15, 
cycle 2 day 1, cycle 2 day
15, cycle 3 day 1, and day 
one of all subsequent cycles 
may be administered 
provided the patient meets 
the following criteria.”
Other language added or 
modified to include details 
about lab assessment 
timelines and delayed/held 
doses.
Deleted:
Table 1: Dose Modification 
Algorithms for potential 
treatment-related adverse 
events for Topotecan
Modified:
Table II which had dose 
modification algorithms for 
Pazopanib has been 
changed to Table 1 and 
details about “continue 
Topotecan at current dose” 
has been added to this table 
wherever appropriate.
Other information added per 
current IB
Other updates
Table II updated according 
to current Pazopanib 
Investigator’s brochure(IB).
Table III containing
‘Guidelines for management 
of Treatment Emergent 
Hepatotoxicity has been 
reanmed Table II and has 
been updated according to 
current Pazopanib IB
For clarity
clarifications were 
added for safety 
monitoring purposes 
and to align with 
current version of 
Pazopanib IB
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
80
Section 4.4.3
No section on Palliative care
Added section on
Palliative Care. Palliative 
radiation and surgery are 
allowed on this trial IF they 
are not being used to 
address a target lesion. 
Parameters to be used have 
been stated.
Clarification added
to enhance patient 
care.
Section 4.4.5
Concomitant 
medications 
discouraged while on 
study
“inducers and inhibitors of
Cyp450 listed in appendix A”
“strong inducers and
inhibitors of Cyp450 listed in
appendix A”
Added:
Note: As this list is constantly 
evolving, if a medication is 
incorrectly documented as 
prohibited in this protocol, 
documentation from the site 
pharmacist to the contrary
will be acceptable.
Added for clarity. It
provides for 
specificity.
Section 5.0
Study Procedures
Footnote a
Informed consent must be 
signed within 30 days of 
registration.
Footnote b: Contains
timelines for labs and 
radiologic evaluations
Footnote c:
Information about ‘vitals’
Footnote K:
“Radiology assessment by CT 
or MRI will be done at Week 6, 
Week 12, Week 20 and every 8 
weeks thereafter.”
N/A
Footnote ‘a’ modified to
“Pre-study procedures done 
within 7 days of C1D1 do not 
need to be repeated on C1D1. 
Footnote b: Added timeline 
for EKG as well.
Footnote c:
Language regarding vitals 
modified for clarity. Added 
statement that ‘Blood 
pressure log to be updated in 
NOTIS each cycle for
duration of treatment.’
Footnote k modified: 
“Radiology assessment by CT 
or MRI will be done at Week 6, 
Week 12, Week 20 and every 8 
weeks (+/- 7 days) thereafter. 
After 1 year of protocol 
treatment, patient may be 
switched to scans every 12 
weeks (+/- 7 days) at the 
discretion of the patient and 
treating physician.”
Footnote p added in relation to
new row added in table
‘MUGA or ECHO’
Footnote p states that ‘ONLY 
required for patient’s with prior 
anthracycline use OR otherwise 
at risk for left ventricular systolic 
dysfunction.  Can be assessed 
by MUGA or echocardiogram.”
Improve clarity
and safety 
monitoring
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
81
N/A
Footnote q added in relation 
to Pazopanib and Topotecan 
administration schedule 
added as new rows in the 
table:
Footnote q states “Day 1 of 
each cycle should be every 28 
days.  In the event that this day 
falls on a holiday or other such 
event, study team should use
+/- 3 day window to complete 
pre-treatment procedures, and 
dispense protocol agents to
patients with instructions to 
commence treatment on day 1 
as usual. Similarly, any missed 
doses will not be made up and
should be skipped to maintain
28 day cycle.”
Section 6.3
Evaluable for
Objective response
Language stating different
categories in which patients 
will be allocated depending 
on response.
This language has been
removed.
Added statement: 
“However, if a patient is 
removed from treatment prior 
to their 12 week assessment 
for reasons other than 
disease progression or
death, they will be
considered non-evaluable for 
response if approved by the 
DMC. “
Clarification
regarding 
evaluable patients.
Section 7.3.3.4
Reporting to Novartis
The date was stated as 19th
of October 2015
The original copy of the SAE 
Report and the fax 
confirmation sheet must be 
kept within the Trial Master 
File at the study site.
The date has been updated 
to 2nd March 2015.
Language modified to say 
that these will be kept per 
local standard operating 
procedures.
Per update from 
the sponsor 
Novartis
Clarification
Section 8.2.10
Pazopanib side- 
effects
Some side effects listed
Inserted sentence:
‘Please refer to current IB 
for more details and a 
complete list of side-effects’
Added for safety
purposes, and to 
be in alignment 
with IB updates
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
82
Section 8.1.12 and
8.2.12
language to notify GSK
about destruction of 
unused/defective drug
GSK replaced with Sponsor
Novartis
Study take-over by
Novartis from
GSK.
Sites will start 
using Novartis 
drug supply when 
they exhaust local 
GSK supplies.
Section 9.2
Sample processing, 
storage, shipment
Dr. Brian Van Tine’s address
listed
Dr.Tine’s address has been
updated.
Administrative
Appendix A1
List of CYP3A4
Inhibitors
List of CYP3A4 inducers
The word ‘strong’ has been
added to both indicating 
strong inducers and 
inhibitors.
Increase clarity
and specificity. 
Maintain 
consistency with 
rest of the 
protocol.
Appendix E
Reference to DSMP
DSMP link inserted here as 
well
Administrative
Appendix F and G
Patient Medication Diary
Blood pressure Log
Both modified with 
appropriate details
For clarity and to 
be in alignment
with current 
template
Amendment 7  – January 24th , 2017
Section(s) Affected
Prior Version
Amendment 7 Changes
Rationale
Study summary and
Section
10.2(statistics)
Original statistical details 
and sample size.
Added language:
The DMC reviewed the 
interim analysis data on
1/11/2017, and has
approved cohort 1 to reopen 
to 96 total patients( to
obtain 92 evaluable 
patients).  In addition, based 
on the percentage of non- 
evaluable patients during
the interim analysis, it was
determined that a total of
108 patients would most 
likely need to be enrolled in
Changes made 
following review 
by DMC on
1/11/17.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
83
order to obtain 92 evaluable
patients.
The remaining slots have 
been equally divided in 5 
ways among the sites, with
an expiration date of May 12,
2017. Status of accrual will 
be reassessed at that time, 
and the remaining slots will 
be divided accordingly.
Study summary and 
section 3.0
A total of 136 patients may 
be enrolled including 96 
patients with STS (to acquire
92 evaluable patients)
The number 136 has been 
updated to 148 and 96 has 
been updated to 108.
Based on the 
percentage of 
non-
evaluable patients 
during the interim 
analysis by DMC, 
it was determined 
that a total of 108 
patients would 
most likely need 
to
be enrolled in 
order to obtain 92 
evaluable patients.
Throughout
96 STS patients to get 92 
evaluable patients
Updated to 108 STS 
patients to get 92 evaluable 
patients
Based on the
percentage of 
non- evaluable 
patients during 
the interim 
analysis by DMC, 
it was determined 
that a total of 108 
patients would 
most likely need 
to
be enrolled in order
to obtain 92 
evaluable 
patients.
Section 3.1.8
Inclusion criteria
Creatinine clearance (ClCR):
30 mL/min to 50 mL/min
Modified to :
Creatinine clearance (ClCR):
50 mL/min
For clarity, and to 
be consistent with 
other current 
related studies.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
84
Section 4.3
Table 1 Dose 
Modification 
Algorithms for 
Potential Treatment- 
Related Adverse 
Events
(for Pazopanib)
For Proteinuria:
UPC ≥3 or 24-h urine protein
3g
Step 3. If UPC ≥3 or 24-h 
urine protein 3g recurs, 
repeat steps 1 and 2.
Step 4. If UPC ≥3 or 24-hr 
urine protein ≥3 recurs and 
the pazopanib dose can no 
longer be reduced, 
discontinue protocol 
treatment and continue 
follow-up per protocol.
For thrombocytopenia:
If no recovery to ≤ Grade 1 
or recurrent Grade 3 or 4 
thrombocytopenia, 
discontinue protocol 
treatment and follow-up per 
protocol.
For palmar-plantar 
erythrodysesthesia 
syndrome:
If recurrent consider a further 
dose reduction to 200mg or 
discontinuation
Language modified to state:
“ recurs at current dose”
Similarly, language added to 
state: “If no recovery to ≤ 
Grade 1 or recurrent Grade 3 
or 4 thrombocytopenia at 
current dose”
Similarly, language added to 
state:
“If recurrent at the current
dose”
For clarity
Amendment 8 – May 25th, 2017
Sections(s) 
Affected
Prior Version
Amendment 8 Changes
Rationale
Section 3.1.9 and 
3.1.10
Two exclusionary criteria  
were clubbed together in 
section 3.1.9
Exclusionary criterion pertaining 
to ‘hypertension’ was separated 
from the ‘ejection fraction’ 
exclusionary criterion. 
Section 3.1.10 was designated 
for the criterion related to 
hypertension. 
The subsequent criteria were 
re-numbered accordingly.
Correction of 
formatting error
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
85
Section 3.1.18
Washout period for anti-
cancer therapies-radiation, 
surgery or tumor 
embolization was 28 days
Washout period for anti-cancer 
therapies-radiation, surgery or 
tumor embolization changed to  
14 days
For ease of 
enrollment. 
(14 day washout 
period adequate 
for safety).
Section 5.0
Study Procedures
table 
Footnote n:End of 
treatment must occur 30 
days following the last day 
of treatment
Footnote o: patient 
required to call in weekly to 
report toxicities.
Footnote n modified to state : “ 
End of treatment visit must 
occur within 30 days following 
the last day of treatment, 
particularly prior to patient 
starting new treatment.”
Footnote o modified to state: 
Toxicities should be followed for 
30 days after last dose of study 
treatment, however, new 
toxicities that arise within the 30 
day period definitely related to 
new anti-cancer treatment and 
NOT related to study treatment 
do not need to be reported.
For added clarity
Section 6.3 
Details about evaluation of 
Objective response. 
Stated that all conclusion 
and main analysis would 
be based on all eligible 
patients.
Conditions for sub 
analyses defined. 
Language modified to increase 
clarity.
Modified to state that 
conclusion and main analysis  
will be based on all enrolled 
patients.
Treatment of’ ineligible patients’ 
added to examples of protocol 
deviations and these will not be 
included for sub analyses of 
different subsets of patients.
For increased 
clarity 
Section 7.3.2
Determining if 
Expedited Reporting 
is Required
Expedited reporting is 
required for all events that 
occur within 30 days of the 
last dose of protocol 
treatment.
Added language to this to state 
that the event need not be 
reported if it is definitely 
attributable to new anti-cancer 
treatment and is NOT related to 
study treatment .
For added clarity 
and to be in 
alignment with 
update made to 
the procedures 
table footnote o
Section 5.0 Footnote L 
and Section 9.1 
Peripheral blood samples 
to be collected for 
correlative studies
Removed the word 
‘peripheral’to just state that 
blood samples will be collected 
for correlative studies
For convenience
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
86
Section 10.1 
A total of 108 patients 
required to obtain 92 
evaluable patients
Modified to state:
‘A total of 108 STS patients 
needed to obtain 92 evaluable 
patients’.
Term STS(soft tissue sarcoma) 
added in other appropriate 
sentences.
 For clarity
Amendment 9: February 2nd , 2018
Sections(s) Affected
Prior Version
Amendment 9 Changes
Rationale
Study schema
and Study summary
and section 3.0
Cohort 2 osteosarcoma 
patients was 20. 
The accrual number for 
osteosarcoma has been 
expanded to 36. To 
accommodate this, the total 
accrual limit has been 
increased to 164.
Original 20 
osteosarcoma 
patients were 
evaluated. Now, 
expansion to 36 
patients is being  
done to evaluate 
efficacy of the 
regimen.
Section 1.8 
Previous rationale 
language 
Added  rationale for  increasing 
accrual for osteosarcoma 
patients.
 Rationale to 
support the 
expansion of 
osteosarcoma 
cohort from 20 to 
36.
Section 10.2
Originally 20 osteosarcoma 
patients were listed. 
Expansion to 36 patients in the 
osteosarcoma cohort. The 16 
additional osteosarcoma slots 
will only be available at (NMH).
Originally, 20 
osteosarcoma 
patients were 
evaluated. Now, 
expansion to 36 
patients is being  
done to evaluate 
efficacy of the 
regimen.
Amendment 10 dated 3.28.19
Sections(s) Affected
Prior Version
Amendment 10 Changes
    
    Rationale
Study summary,
Section 2.3 and 
Section 6.7
Exploratory objectives 
and endpoints
Exploratory objective was 
to evaluate the correlation 
of PFR and OS to levels of 
sVEGFR2 and PIGF.
Added new exploratory 
objective for Cohort 1 and  3 :
“Quantify Cell-free circulating 
tumor DNA (ctDNA) at each 
time point, and correlate these 
results with demographic, 
diagnostic, treatment, and 
outcomes data”.
These 2 cohorts are closed to 
accrual.
Cohort 1 and 3 
samples have been 
collected and is 
closed to accrual. 
Decision made by 
PI to use these 
samples for said 
exploratory 
analysis. 
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
87
Section 9.0
Correlative/Special 
studies 
Details regarding original 
exploratory objective as 
stated above. 
 Updated with details regarding 
new exploratory objective for 
Cohort 1 and 3. The details for 
Cohort 2 remains the same. 
To align with 
updates made to 
the exploratory 
objectives of this 
study. 
Section 5.0 
Study procedures 
table
Footnote h
Day 1 of each cycle was 
stated to have a window of 
(+/3days).
The window has been updated 
to (+/-3 days). 
Footnote ‘m’ already states this. 
Correction of 
discrepancy
Section 9.2
Sample shipment
Address listed for Dr.Van 
Tine’s lab
Address presented in the 
correct manner, as listed in the 
lab manual. Address remains 
the same. 
 For consistency
References
List of references used in 
the body of the protocol
Added list of references used 
for adding new exploratory 
objective. Details reflected in  
Section 9 
To align with 
updates made to 
the exploratory 
objectives of this 
study.
Amendment 11 dated 12.02.19
Sections(s) Affected
Prior Version
Amendment 11 Changes
Rationale
Coverpage
Lists Alfred W. Rademaker 
as statistician
Updates to list Hui Zhang as 
the statistician
Administrative 
update
Study Summary
Patients must have had a 
minimum of 1 and a 
maximum of 4 prior 
chemotherapy regimens for 
recurrent/metastatic 
disease. It will be up to the 
investigator to determine 
what constitutes a “regimen” 
in each case.
Patients must have had a 
minimum of 0 and a maximum 
of 4 prior chemotherapy 
regimens for 
recurrent/metastatic disease 
determined by cohort 
assignment. It will be up to 
the investigator to determine 
what constitutes a “regimen” in 
each case.
Updated to 
reflection more 
accurate 
inclusion 
criteria for 
cohorts
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
88
Inclusion criteria 
Section 3.1.6
Cohort 2: Patients must 
have had a minimum of 1 
and maximum of any 
number of prior 
chemotherapy regimens for 
recurrent/metastatic or 
locally advanced/ 
unresectable disease.
Cohort 3: Patients may have 
had any number of prior 
therapies for 
recurrent/metastatic or 
locally 
advanced/unresectable 
disease. There are no 
restrictions.
Inclusion criteria for Cohort 
2 and 3 have been switched:
Cohort 2: Patients may have 
had any number of prior 
therapies for 
recurrent/metastatic or locally 
advanced/unresectable 
disease. There are no 
restrictions.
Cohort 3: Patients must have 
had a minimum of 1 and 
maximum of any number of 
prior chemotherapy regimens 
for recurrent/metastatic or 
locally advanced/ 
unresectable disease.
Correction of 
error from 
amendment 6
Amendment 12 dated 02.13.20
Sections(s) Affected
Prior Version
Amendment 12 Changes
Rationale
8.2.10 (Side effects of 
pazopanib)
Following side effects are 
listed under “Likely 
(occurring in more than 
20% of patients)” 
decreased albumin, 
hypomagnesemia, 
hypophosphatemia, hair 
loss, painful blisters and/or 
rash on palms and soles, 
tumor pain, dysgeusia, 
headache, gastrointestinal 
pain, musculoskeletal pain, 
weight loss, myalgia.
These side effects were moved 
to “Common (occurring in 3-
20% of patients)”
Administrative 
update to match 
these side effects 
to current 
frequencies 
experienced with  
pazopanib as 
listed in IB.
Amendment 12.1 dated 05.14.20
(Updates to Amendment 12 prior to IRB approval of Amendment 12)
Sections(s) Affected
Prior Version
Amendment 12.1 Changes
Rationale
8.1.10 (Side effects of 
topotecan)
8.2.10 (Side effects of 
pazopanib)
Provided information from 
the IB on current side 
effects and frequencies 
experienced.
Removed language of all side 
effects and frequencies and 
incorporated the sentence into 
these sections:
 “Please refer to current IB for 
details and a complete list of 
side-effects.”
Administrative 
update to match 
current 
interventional 
protocol template 
to prevent further 
protocol 
amendments due 
to risk updates 
and in response 
to IRB questions.
Amendment 12.2 dated 06.10.20
Sections(s) Affected
Prior Version
Amendment 12.2 changes
Rationale
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.

Amendment- 13            Version Date:06-26-2020
89
11.1 (Institutional 
Review Board (IRB) 
Approval and 
Consent)
N/A
Adds language for the process 
of consenting patients with 
limited English proficiency
IRB requested 
update
Amendment 13 dated 06.26.20
Sections(s) Affected
Prior Version
Amendment 13 changes
Rationale
Lists Mark Agulnik as the 
PI for the study
Updates to list Mary Mulcahy 
as the PI and provides her 
contact details
Change due to PI 
leaving 
Northwestern.
Lists the IND holder as 
Mark Agulnik 
Updates to “IND-EXEMPT” 
Coverpage
Lists the previous 
statisticians email address
Updates the email to current 
statisticians email address
Correction of 
error
3.0 (Patient Eligibility);
3.4  (Population and 
Accrual Overview)
Lists the PI by name with 
phone number
PI name and phone number 
removed
Change due to PI 
leaving 
Northwestern and 
the study is 
closed to further 
accrual.
IRB #: STU00200112 Approved by NU IRB for use on or after 9/2/2020 through 8/16/2021.