Clinical trial NCT01184326
Conditions: Solid Tumor Kidney Cancer
Keywords: RAD001 pazopanib everolimus advanced cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2011-01-01; Completion date: 2017-03-01
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This research study is evaluating the combination of pazopanib and everolimus in patients that have a malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective, or metastatic or locally advanced unresectable kidney cancer. In this research study the investigators are testing the safety of the combination of pazopanib and everolimus and finding the appropriate doses to use for further studies.

Detailed description:
This protocol has two parts, Phase I Dose Finding and Phase 1 Expansion. Once the maximum tolerated dose has been identified in the Phase I Dose Finding portion, a Phase I expansion cohort of patients with metastatic or locally advanced unresectable kidney cancer will be enrolled.

Arms: arm 1: Everolimus 5mg + Pazopanib 600 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal. arm 2: Everolimus 5mg + Pazopanib 400 mg once daily for 28 days each cycle Participants were treated until disease progression, unacceptable toxicity or patient withdrawal. arm 3: All phase I dose expansion participants received Everolimus 5mg and Pazopanib at the maximum tolerated dose established in the dose finding part of the study. arm 4: All phase I participants received Everolimus 5mg and Pazopanib according to the established dose escalation schedule or the maximum tolerated dose established in the dose finding part of the study.
Interventions: intervention 1: pazopanib intervention 2: everolimus
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Title: An expanded Phase I study of pazopanib and everolimus in patients with 
advanced solid tumors and previously treated advanced urothelial cancer. 
 
 
 
 
NCT Number: NCT01184326 
 
 
 
 
IRB Approval Date: 27-Aug-2010 


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NCI Protocol #: N/A 
 
 
Local Protocol #: 10-166 
 
 
Protocol Version Date: 11/3/16 
 
 
Title: An expanded Phase I study of pazopanib and everolimus in patients with 
advanced solid tumors and previously treated advanced urothelial cancer. 
 
Principal Investigator: 
Mark Pomerantz, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
D1230 
Boston, MA 02215 
Phone: (617) 632-6328 
Fax: (617) 632-2165 
 
Coordinating Center: Dana-Farber Cancer Institute 
 
Co-Principal Investigator: 
Lauren Harshman, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
D1230 
Boston, MA 02215 
Phone: (617) 632-4524 
Fax: (617) 632-2165 
 
Sub-Investigator: 
Joaquim Bellmunt, MD, PhD 
Dana-Farber Cancer Institute 
Associate Professor of Medicine 
Harvard Medical School 
 
Agents: 
Pazopanib (NSC 737754; IND 65, 747) – Novartis 
Everolimus (NSC 733504; IND 79, 707) – Novartis 


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Start at 
dose level 0 
Treat cohort 
(3 participants) 
No further 
escalation 
 
 
 
 
SCHEMA 
 
 
Phase I Portion 
 
 
 
Start at 
dose level 0 
 
Treat cohort 
(3 participants) 
 
Number 
of DLTs 
 
0 
1 
2 or 3 
 
 
No further 
escalation 
 
 
Recruit 3 more 
participants 
 
 
Escalate dose 
 
 
No 
Yes 
Additional 
DLTs? 
 
Stop 
 
 
 
 
Expansion Cohort 
 
 
 
 
Definitions 
 
Treatment  
Response 
Treatment 
 
R 
CR 
CR - Complete Response 
E 
PR - Partial Response 
G 
Restage every 
PR 
Continue 
PD - Progressive Disease 
 I 
 2 cycles 
SD 
SD - Stable Disease 
S 
everolimus 
T 
P a z o p a n i b 
P D 
( o f f   s t u d y)  
 
E 
R 
 
1 cycle = 28 days 


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TABLE OF CONTENTS 
 
 
 
Page 
 
SCHEMA 
2 
 
1: OBJECTIVES 
6 
1.1 Study Design 
6 
1.2 Phase I Study 
6 
1.3 Expansion Cohort (Urothelial Carcinoma) 
6 
 
2: BACKGROUND 
7 
2.1 Investigational Agents 
7 
2.2 Study Disease 
15 
2.3 Rationale 
17 
 
3: PARTICIPANT SELECTION 
21 
3.1 Eligibility Criteria for Dose Escalation Cohort 
21 
3.2 Eligibility Criteria for Expansion Cohort 
23 
3.3 Exclusion Criteria for Dose Escalation Cohort 
27 
3.4 Exclusion Criteria for Expansion Cohort 
30 
3.5 Inclusion of Women, Minorities and Other Underrepresented Populations 
35 
 
4: REGISTRATION PROCEDURES 
35 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions 
35 
4.2 Registration Process for DF/HCC and DF/PCC Institutions 
35 
4.3 
General Guidelines for Other Participating Institutions 
36 
 
5:  TREATMENT PLAN 
37 
5.1 Phase I 
37 
5.2 Pre-treatment Criteria 
37 
5.3 Agent Administration 
39 
5.4 Definition of Dose-Limiting Toxicity 
41 
5.5 General Concomitant Medication and Supportive Care Guidelines 
43 
5.6 Duration of Therapy 
47 
5.7 Duration of Follow Up 
48 
5.8 Criteria for Removal from Study 
48 
 
6: EXPECTED TOXICITIES AND DOSING DELAY/DOSE MODIFICATIONS 
48 
6.1 Anticipated Toxicities 
50 
6.2 Toxicity Management 
54 
6.3 Dose Modifications/Delays 
61 


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7: DRUG FORMULATION AND ADMINISTRATION 
69 
7.1 Everolimus 
69 
7.2 Pazopanib 
71 
 
8: CORRELATIVE/SPECIAL STUDIES 
72 
8.1 
Pharmacokinetic Studies 
72 
8.2 
Exploratory Studies 
73 
 
9: STUDY CALENDAR 
73 
9.1 
Phase I 
74 
9.2 
Expansion Cohort 
75 
 
10: MEASUREMENT OF EFFECT 
76 
10.1  Anti-tumor Effect – Solid Tumors 
76 
 
11: ADVERSE EVENT REPORTING REQUIREMENTS 
81 
11.1  General 
81 
11.2  Definitions 
81 
11.3  Recording Adverse Events 
83 
11.4  Reporting Adverse Events 
83 
11.5  Novartis and GlaxoSmithKline Notification by Investigator 
84 
11.6  Institutional Review Board (IRB) Notification by Investigator 
85 
11.7  Food and Drug Administration (FDA) Notification by Sponsor-Investigator 
85 
11.8  NIH Office of Biotechnology Activities (OBA) Notification by Investigator 
86 
 
12: DATA AND SAFETY MONITORING 
86 
12.1 Data Reporting 
86 
12.2 Safety Meetings 
86 
12.3 Monitoring 
87 
 
13: REGULATORY CONSIDERATION 
87 
13.1  Protocol Review and Amendments 
87 
13.2  Informed Consent 
88 
13.3  Ethics and Good Clinical Practice (GCP) 
89 
13.4  Study Documentation 
89 
13.5  Records Retention 
90 
13.6  Multi-center Guidelines 
90 
 
14: ST ATISTICAL CONSIDERATION 
90 
14.1 Study Design/Endpoints 
90 
14.2 Sample Size/Accrual Rate 
92 
14.3 Stratification Factors 
92 
14.4 Analysis of Secondary Endpoints 
92 
14.5 Reporting and Exclusions 
94 
 
15: PUBLICATION PLAN 
95 


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16. REFERENCES 
96 
17: APPENDICES 
100 
 
Appendix A 
100 
Performance Status Criteria 
 
Appendix B 
101 
 
Pazopanib Blood Pharmacokinetic collection and Handling 
 
Appendix C 
107 
Instructions for Collecting, Processing, Storing, and Shipping everolimus 
Pharmacokinetic Samples 
 
Appendix D 
110 
Drug Supply Request Form 
 
Appendix E 
111 
Genes in Next-Gen Sequencing Assay 


 
 
 
1. OBJECTIVES 
 
 
 
1.1 
Study Design 
This is a Phase I study with an expansion cohort in advanced urothelial cancer patients. The 
Phase I portion of the study was be an open-label standard 3+3 dose escalation study to 
determine the maximum tolerated dose (MTD) of the combination of pazopanib (GW786034) 
and everolimus in patients with solid tumors who have no standard treatment options available. 
Starting doses will be set at everolimus 5 mg PO QD and pazopanib 400 mg PO QD. Cycle 
length will be 4 weeks. One dose de-escalation will be allowed if the MTD is exceeded in dose 
level 0 (indicated as dose level -1). Initial phase I testing identified pazopanib 400 mg PO daily 
and everolimus 5 mg PO daily as the MTD. Based on the phase I response data, an expansion 
cohort of 25 patients with metastatic urothelial cancer who have received prior chemotherapy, 
but no prior mTOR or VEGF inhibitors, will be enrolled. 
 
 
The protocol is being amended to accrue urothelial carcinoma patients rather than kidney cancer 
patients in the expansion cohort given the significant unmet need in urothelial carcinoma and 
findings of significant activity of the regimen in at least a subset of urothelial carcinoma patients, 
 
 
The primary endpoint of the expansion cohort will be objective response proportion with 
secondary endpoints including safety, progression-free survival, and duration of response. 
 
 
 
1.2 
Phase I study 
 
 
1.2.1 Primary Objective 
 
To determine the maximum tolerated dose and dose limiting toxicities of the 
combination of pazopanib and everolimus. 
 
1.2.2 Secondary Objective 
 
To determine the pharmacokinetics of the combination of pazopanib and everolimus. 
 
 
1.3 
Expansion Cohort (Urothelial Carcinoma) 
 
 
1.3.1 Primary objective 
To determine the objective response rate in patients with locally advanced or metastatic 
urothelial cancer who have had previous treatment with cytotoxic chemotherapy. 
 
 
1.3.2 Secondary Objectives 


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1.3.2.1 To determine the safety, progression-free survival, and duration of response of 
pazopanib and everolimus in patients with metastatic urothelial cancer. 
 
 
 
 
1.3.3 Exploratory Objective 
1.3.2.2 To perform either whole exome or targeted sequencing of selected genes to 
evaluate whether somatic DNA alterations are associated with response or progression 
with pazopanib and everolimus treatment. 
 
 
2. BACKGROUND 
 
2.1 Study Agent(s) 
2.1.1 Everolimus 
 
Everolimus, a novel oral derivative of rapamycin, has been in clinical development since 
1996 as an immunosuppressant in solid organ transplantation and has obtained marketing 
authorization (Certican®) for prophylaxis of rejection in renal and cardiac transplantation in 
a number of countries, including the majority of the European Union. Everolimus has been in 
development for patients with various malignancies since 2002. Everolimus was FDA 
approved in 2009 (Afinitor®) for the treatment of kidney cancer that has progressed after 
sunitinib or sorafenib. Everolimus is being investigated as an anticancer agent based on its 
potential to act: 
 
• Directly on the tumor cells by inhibiting tumor cell growth and proliferation 
• Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced proliferation 
of endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is 
well established, and the mTOR pathway has been implicated in the regulation of tumor 
production of proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
 
At weekly and daily schedules and at various doses explored, RAD0001 is generally well 
tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) 
associated with everolimus therapy are manageable. Non-infectious pneumonitis has been 
reported with mTOR inhibitors but is commonly low-grade and reversible. 
 
2.1.1.1 mTOR pathway and mechanism of action 
 
At cellular and molecular level everolimus acts as a signal transduction inhibitor. 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), a key and a 
highly conserved serine-threonine kinase, which is present in all cells and is a central 
regulator of protein synthesis and ultimately cell growth, cell proliferation, angiogenesis 
and cell survival. mTOR is the only currently known target of everolimus (Reviewed in 
Boulay and Lane, 2007)1. mTOR is downstream of PI3K/AKT pathway, a pathway 


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known to be dysregulated in a wide spectrum of human cancers (e.g. through 
loss/mutation of the PTEN negative regulator; through PI3K mutation/amplification; 
through AKT/PKB overexpression/overactivation; through modulation of TSC1/TSC2 
tumor suppressors). In addition, activation of the PI3K/AKT/mTOR pathway is 
frequently a characteristic of worsening prognosis through increased aggressiveness, 
resistance to treatment and progression. The main known functions of mTOR include the 
following 1,2: 
 
• mTOR functions as a sensor of mitogens, growth factors and energy and nutrient 
levels, facilitating cell-cycle progression from G1 to S phase in appropriate growth 
conditions. 
• The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors. 
• Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and 
activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates 
translation of important massages, including those encoding the HIF-1 proteins, c- 
myc, ornithine decarboxylase, and cyclin D1, as well as ribosomal proteins 
themselves. 
• The activation of mTOR pathway leads to the increased production of pro- 
angiogenic factors (i.e., VEGF) in tumors and to tumor, endothelial and smooth 
muscle cell growth and proliferation. 
• The regulation of mTOR signaling is complex and involves positive regulators, such 
as AKT that phosphorylate and inactivate negative regulators such as the Tuberous 
Sclerosis Complex (TSC1/TSC2). 
 
mTOR is represented by two structurally and functionally distinct multi-protein signaling 
complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR 
complex 2, rapamycin insensitive).3 mTORC1 is mainly activated via the PI3 kinase 
pathway through AKT (also known as PKB, protein kinase B) and the tuberous sclerosis 
complex (TSC1/TSC2) 2. Activated AKT phosphorylates TSC2, which lead to the 
dissociation of TSC1/TSC2 complex, thus inhibiting the ability of TSC2 to act as a 
GTPase activating protein. This allows Rheb, a small G-protein, to remain in a GTP bound 
state and to activate mTORC1. AKT can also activate mTORC1 by PRAS40 
phosphorylation, thereby relieving the PRAS40-mediated inhibition of mTORC1.4 
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, 
possibly by receptor tyrosine kinase (RTK) signaling.4 It has been suggested that 
mTORC2 phosphorylates and activates a different pool of AKT, which is not upstream of 
mTORC1. PHLPP phosphatase plays a role of a negative regulator. mTORC2 is 
rapamycin insensitive and is required for the organization of the actin cytoskeleton.3 
 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone 
rapamycin and its derivatives, such as everolimus. Once these agents bind to the 12 kDa 
cytosolic FK506-binding protein immunophilin FKBP12, the resulting rapamycin- 
FKBP12 complexes bind to a specific site near the catalytic domain of mTORC1 and 
inhibit phosphorylation of mTOR substrates. As a consequence, downstream signaling 


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events involved in regulation of the G1 to S-phase transition are inhibited. This 
mechanism is thought to be responsible for the immunosuppressive effects of rapamycin 
as well as its putative antineoplastic activity. As many cancers are characterized by 
dysregulation of G1 transit (for example, overexpression of cyclin or cyclin-dependent 
kinases), inhibition of mTOR becomes an intriguing target for inducing cytostasis.2 
 
2.1.1.2 Preclinical studies 
 
Pre-clinical investigations have demonstrated that everolimus is a potent inhibitor of 
theproliferation of a range of human tumor cell lines in-vitro with IC50s ranging from 
sub/low nanomolar to micromolar concentrations, concentrations capable of being 
reached in patients at the doses used in clinical trials. 
 
Everolimus was shown to have activity in human tumor cell lines originating from lung, 
breast, prostate, colon, kidney, melanoma and glioblastoma. In a clonogenic assay using 
cells derived from 81 patient-derived tumor xenografts never cultured in vitro (11 human 
tumor types with 3 to 24 tumors each: bladder, colon, gastric, NSCLC [adeno, squamous 
epithelium and large cell], SCLC, breast, ovary, pancreatic, renal, melanoma, and 
pleuramesothelioma), Everolimus inhibited colony formation in a concentration- 
dependent manner. In addition, normal hematopoetic stem cells were insensitive to 
everolimus, with an IC50 about 15 fold higher than the tumor lines. Everolimus also 
inhibits the proliferation of human umbilical vein endothelial cells (HUVECS), with 
particular potency against VEGF-induced proliferation. The inhibition of endothelial 
proliferation and antiangiogenic activity of everolimus was confirmed in vivo, as 
everolimus selectively inhibited VEGF-dependent angiogenic response. Mice with 
primary and metastatic tumors treated with everolimus showed a significant reduction in 
blood vessel density when compared to controls at well tolerated doses. Additionally, 
activity in a VEGF-impregnated subcutaneous implant model of angiogenesis and 
reduced vascularity (vessel density) of Everolimus- treated tumors (murine melanoma) 
provided evidence of in vivo effects of angiogenesis. 
 
Everolimus also inhibits tumor growth in-vivo in xenografted, syngeneic and orthotopic 
animal models, residing longer in tumor tissue than in plasma and demonstrating high 
tumor penetration in a rat pancreatic tumor model. These effects occurred within the dose 
range of 2.5 to 10 mg/kg p.o. daily. Typically, the antitumor activity of everolimus 
monotherapy was that of reduction of tumor growth rates rather than producing 
regressions or stable disease. Everolimus, administred p.o., was a potent inhibitor of tumor 
growth and well tolerated in: 
 
• subcutaneous mouse xenograft model, established from a variety of tumor cell lines of 
diverse histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), including a 
Pgp170 over-expressing multi-drug resistant tumor line; 
• in a series of low-passage tumor xenografts established directly from human tumor 
material, maintained only in vivo and considered highly predictive of therapeutic 
outcome in patients. These included breast (5 lines), colorectal (9 lines), gastric (3 


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lines), lung (22 lines including adenocarcinomas, epidermoid cell, large cell and small 
cell histotypes), melanoma (6 lines), ovarian (4 lines), pancreatic (3 lines) and renal (6 
lines); 
• in two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic 
melanoma) 
Taken together, these data indicate the broad anti-proliferative potential of everolimus. 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
everolimus. Molecular analysis has revealed that relative sensitivity to everolimus in vitro 
correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase 
and the S6 ribosomal protein. PTEN status alone may not be predictive of everolimus 
relative in vitro sensitivity, however in some cases (i.e., GBM) there is also a correlation 
with PTEN status. In preclinical models, the administration of everolimus is associated 
with reduction of protein phosphorylation in target proteins downstream of mTOR, notably 
phosphorylated S6 (pS6) and p4E-BP1, and occasionally with an increase in 
phosphorylation AKT (pAKT). 
 
2.1.1.3 Pre-clinical safety 
 
In safety pharmacology studies, everolimus was devoid of relevant effects on vital 
functions including the cardiovascular, respiratory and nervous systems. Everolimus had 
no influence on QT interval prolongation. Furthermore, everolimus showed no antigenic 
potential. Although everolimus passes the blood-brain barrier, there was no indication of 
relevant changes in the behavior of rodents, even after single oral doses up to 2000mg/kg 
or after repeated administration at up to 40 mg/kg/day. Based on these findings, the 
potential of everolimus to affect vital functions in patients is considered to be low. 
Everolimus is considered to have no genotoxicity or carcinogenicity potential. All 
significant adverse events observed in preclinical toxicology studies with everolimus in 
mice, rats, monkeys and minipigs were consistent with its anticipated pharmacologic 
action as an antiproliferative and immunosuppressant and at least in part reversible after a 
2- or 4-week recovery period with the exception of the changes in male reproductive 
organs, most notably testes. Ocular effects (lenticular disorders) observed in rats were not 
observed in any other species and are considered to be a species-specific disorder. 
 
2.1.1.4 Everolimus Pharmacokinetics 
 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The bioavailability of 
the drug is believed to be 11% or greater. The AUC0-τ is dose-proportional over the dose 
range between 5 to 70 mg in the weekly regimen and 5 and 10 mg in the daily regimen. 
Cmax is dose-proportional between 5 and 10 mg for both the weekly and daily regimens. 
At doses of 20 mg/week and higher, the increase in Cmax is less than dose-proportional. 
The coefficient of variation between patients is approximately 50%. Trough levels (24 
hour post-dose) correlate well with AUC0-τ at steady-state during daily administration. 


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In whole blood, at a daily dose of 10 mg, about 20% of everolimus is confined in plasma 
with 26% being unbound. The remaining 80% is sequestered in blood cells. 
 
Everolimus is extensively metabolized in the liver and eliminated in the bile. Major 
metabolites are inactive. Elimination half-life is approximately 30 hours. The clearance 
of everolimus is approximately halved in patients with mild-moderate hepatic impairment 
(Child-Pugh Class A or B), while renal impairment has little or no impact on the 
pharmacokinetics of everolimus. Age, weight and gender in the adult population do not 
affect the pharmacokinetics of everolimus to a clinically relevant extent. The clearance of 
everolimus is reduced in children. Pharmacokinetic characteristics are not notably different 
between Caucasian and Japanese subjects, whereas in Black patients population 
pharmacokinetic studies have shown an average 20% higher clearance. A high-fat meal 
altered the absorption of everolimus with 1.3 hour delay in tmax, a 60% reduction in Cmax 
and a 16% reduction in AUC. 
 
Everolimus is a substrate of CYP3A4 and a substrate and a moderate inhibitor of the 
multi-drug efflux pump P-glycoprotein (P-gP, MDR1, ABCB1). Hence, its metabolism is 
sensitive to drugs which modify these enzymes (substrates, inducers, or inhibitors of 
these enzymes). Competitive inhibition could occur when Everolimus is combined with 
drugs which are also CYP3A4 or P-glycoprotein substrates. Section 5.4.5 lists examples 
of clinically relevant CYP3A inhibitors and inducers. Please refer to Section 5.4.5 for 
more information on the concomitant use of CYP3A4 inhibitors/inducers and other 
medications. More information on everolimus pharmacokinetics is provided in the 
Investigator’s Brochure. 
 
2.1.1.5 Everolimus Pharmacodynamic studies 
 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the biomarker 
p70S6 kinase 1 [S6K1] in peripheral blood mononuclear cells [PBMC]) suggests that 5- 
10 mg daily should be an adequate dose to produce a high-degree of sustained target 
inhibition. Furthermore, molecular pharmacodynamic (MPD) studies, using 
immunocytochemistry (IHC) in biopsied tumor tissue, assessed the degree of inhibition 
and its duration for pS6, p4E-BP1 and pAKT expression with the daily and weekly 
dosing. There was high inhibition of the downstream markers S6K1 and 4E-BP1 at 
5mg/day, which was complete at 10 mg/day, while preliminary results suggest increase in 
pAKT expression with maximal effect at 10 mg daily 5. More information is provided in 
the Investigator’s Brochure. 
 
2.1.1.6 Clinical experience with everolimus 
 
Everolimus has been investigated as a component of multi-drug immunosuppression in 
solid organ transplantation since 1996 and was approved for the indication of prophylaxis 
of organ rejection in adult patients receiving an allogeneic renal or cardiac transplant on 8 
Jul 2003 by the European Union under the trade name of Certican®. The most frequent 
adverse drug reactions in this context are highly specific to the transplant context. 


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However, certain events are generalizable, most notably myelosuppression, skin disorders 
and increases in blood lipid levels. 
 
 
Everolimus is a novel derivative of rapamycin. It has been in clinical development since 
1996 as an immunosuppressant in solid organ transplantation. Everolimus is approved in 
Europe and other global markets (trade name: Certican®) for cardiac and renal 
transplantation, and in the United States (trade name: Zortress®) for the prevention of 
organ rejection of kidney transplantation. 
Afinitor® and was approved for adults with advanced renal cell carcinoma (RCC) after 
failure of treatment with sunitinib or sorafinib in 2009. In 2010, Afinitor® received 
United States (US) approval for patients with subependymal giant cell astrocytoma 
(SEGA) associated with tuberous sclerosis complex (TSC). everolimus is also available 
as Votubia® in the European Union (EU) for patients with SEGA associated with TSC 
who require therapeutic intervention but are not candidates for curative surgical resection. 
Afinitor® was approved for “progressive pancreatic neuroendocrine tumor (PNET) in 
patients with unresectable, locally advanced, or metastatic disease” in 2011 in various 
countries, including the US and Europe. In 2012 Afinitor® received approval for the 
treatment of postmenopausal women with advanced hormone receptor-positive, HER2- 
negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure 
of treatment with letrozole or anastrozole. Furthermore in 2012, Afinitor® received 
approval for the treatment of patients with TSC who have renal angiomyolipoma not 
requiring immediate surgery. 
 
Approximately 25,645 cancer patients have been treated with everolimus as of 30-Sep- 
2012: 
• 
13,229 patients in Novartis-sponsored clinical trials 
• 
2,624 patients in the individual patient supply program 
• 
9,792 patients in investigator-sponsored studies. 
• 
In addition, healthy volunteer subjects and non-oncology hepatically impaired 
subjects have participated in the clinical pharmacology studies as described in 
Section 7.2. 
 
A phase II study of single agent everolimus in locally advanced or metastatic urothelial 
cancer after failure of platinum based chemotherapy reported a response rate of 5% in 
this setting(Partial response in 2 of 37 patients).(6) 
 
Overall, the most frequent mild-moderate Grade 1/2 adverse effects have been rash, 
stomatitis, fatigue, neutropenia and to a lesser extent gastrointestinal disorders (nausea, 
anorexia, diarrhea, vomiting), and headache. The primary DLT has been severe (Grade 3) 
stomatitis, and occasionally fatigue, hyperglycemia, and neutropenia. Reduced blood 
counts, hyperlipidemia (mainly hypercholesterolemia) and hyperglycemia are relatively 
frequent laboratory findings. Infections have not been notably frequent or severe. Non- 
infectious low- Grade (Grade 1/2) pneumonitis has led to development of treatment 
guidelines for the disorder (Section 6.2.3). Further detailed information regarding 


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everolimus clinical development, safety and efficacy is provided in the Investigator’s 
Brochure. 
 
2.1.2 Pazopanib (GW786034) 
 
Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, -3, 
PDGFR-α and -β and c-kit, with half-maximal inhibition (IC50) values of 10, 30, 47, 71, 84 
and 74nM, respectively. It inhibits VEGF-induced VEGFR-2 phosphorylation in human 
umbilical vein endothelial cells (HUVEC) as well as in mouse lungs in a dose-dependent 
manner. Data from preclinical studies show pazopanib has significant growth inhibition of a 
variety of human tumor xenografts in mice, and also inhibits basic fibroblast growth factor- 
(bFGF-) and VEGF-induced angiogenesis in two mouse models of angiogenesis, viz., the 
Matrigel plug assay and the cornea micropocket model. 
 
2.1.2.1. Safety 
 
As of September 2007, approximately 1400 cancer subjects have received pazopanib in 
clinical studies. The most common adverse events (AEs) reported to date include diarrhea, 
fatigue, nausea, hypertension, hair color changes (hair depigmentation), anorexia, vomiting, 
dysgeusia, headache, abdominal pain, rash, aspartate aminontransferase (AST) and alanine 
aminontransferase (ALT) increases, constipation, cough, and arthralgia. Most of these events 
were Grade 1 or 2 using the NCI Common Terminology Criteria for Adverse Events Version 
3.0 (NCI-CTCAE). The most frequent Grade 3 or 4 events were hypertension, fatigue, 
diarrhea, and AST and ALT increases. Less common AEs of note include hand- 
foot syndrome, mucositis/stomatitis, proteinuria, venous thrombotic events, and bleeding. 
Intestinal perforations and arterial thromboses were uncommon. 
 
The most common serious adverse events (SAEs) occurring in subjects enrolled in 
pazopanib studies regardless of treatment assignment include vomiting, diarrhea, abdominal 
pain, hypertension/hypertensive crisis, dyspnea, pleural effusion, pyrexia, anemia, 
dehydration, and pulmonary embolism. Evaluation of the safety and efficacy of pazopanib 
in advanced RCC subjects include a recently completed Phase II study in subjects with 
advanced RCC, and a Phase III randomized, double-blind study against placebo which 
completed enrolment in April, 2007 and is currently on-going. To date, 660 subjects with 
advanced/metastatic RCC have been enrolled in these two clinical trials. Safety data from 
the Phase II RCC trial VEG102616 (n=225) are summarized here. The most common AEs 
(defined as AEs experienced by ≥10% of subjects) regardless of causality in decreasing 
order of frequency were diarrhea (63%), fatigue (46%), hair color change (43%), nausea 
(42%), hypertension (41%), anorexia (24%), dysgeusia (24%), vomiting (20%), headache 
(20%), cough (17%), abdominal pain,(16%), rash (16%), constipation (15%) ALT 
elevation (14%), arthralgia (13%), AST elevation (12%), back 
pain (12%), dizziness (12%), handfoot syndrome (11%), alopecia, (10%), dyspepsia (10%), 
and peripheral edema (10%). The majority of these events were Grade 1 and 2 with 
hypertension being observed in 9% of subjects as a Grade 3 event. 


Everolimus-Pazopanib Phase I 
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The most common hematological toxicities of any grade (graded according to NCICTCAE) 
include lymphopenia (47%), thrombocytopenia (28%), neutropenia (23%), and anemia 
(26%) with combined Grade 3 and 4 abnormalities occurring in 7%, 3%, <1%, and 4% of 
subjects, respectively. The most common chemistry abnormality was hyperglycemia, 
observed in 46% of subjects (of which 2% were Grade 3 and no Grade 4). Hyponatremia of 
any grade was observed in 37% of subjects, with Grade 3 or Grade 4 hyponatremia in 8% 
of subjects. Hyperkalemia of any grade was reported in 27% of subjects, with Grade 3 or 4 
hyperkalemia in 5% of subjects. Hyponatremia and hyperkalemia have not occurred 
concurrently in the same subject to indicate adrenal insufficiency. Elevations in amylase 
and lipase of any grade were reported in 23% and 27% of subjects, respectively, with Grade 
3 or Grade 4 events in 4% and 9% of subjects, respectively. There were 2 reports of 
pancreatitis. Increase in TSH was reported in 28% of subjects and a decrease in thyroxine 
(T4) in 1% of subjects. Three subjects initiated treatment with thyroid replacement therapy 
(synthroid or levothyroxine) during the study. ALT elevations of any Grade were reported 
in 53% of subjects with Grade 3 and Grade 4 elevations in 9% and <1% of subjects, 
respectively. AST elevations were reported in 53% of subjects with Grade 3 and Grade 4 
elevations in 5% and <1% of subjects, respectively. Hyperbilirubinemia of any Grade 
occurred in 28% of subjects with Grade 3 elevations in <1% of subjects. No Grade 4 
elevations have been reported. Concomitant elevations in transaminases and bilirubin have 
been observed in 2 (<1% ) subjects. Neither of these patients met the criteria for Hy’s rule. 
Risk factors that may have contributed to the liver dysfunction were identified in the some 
of these subjects, (e.g., large mass at the porta hepatis, hepatotoxic concomitant 
medications). Liver enzyme elevations were reversible upon dose interruption. Two 
patterns of transaminase changes have been observed: (1) transaminase elevations that 
declined over time without dose interruption. (2) transaminase elevations that declined over 
time upon dose interruption. In some subjects, elevations in transaminase recurred upon 
rechallenging and these subjects were permanently discontinued from study treatment. Serial 
adrenocorticotropic hormone (ACTH) stimulation tests were conducted in two Phase I and 
two Phase II trials in cancer subjects with data available in 47 subjects. Twenty-one 
of them had data beyond 24 weeks and 5 subjects had data beyond 52 weeks. None of these 
47 subjects had adrenal insufficiency. 
 
Certain uncommon AEs with significant clinical consequences reported in pazopanib 
clinical trials (denominator for total subject enrolment n=1000 used for calculating 
frequency) include pulmonary embolism (0.6%), venous thrombosis (0.3%), venous 
thrombosis and pulmonary embolism (0.2%), serious hemorrhage (1.4%), bowel 
perforation (0.5%), myocardial infarction/angina (0.7%), cerebrovascular 
accidents/transient ischemia (0.6%), cardiac failure (0.2%), atrial fibrillation (0.3%), renal 
failure (0.8%) and seizures (0.3%). 
 
2.1.2.2. Preliminary Efficacy Summary 
 
VEG102616 is a Phase II study to evaluate the efficacy and safety of pazopanib in subjects 
with advanced/metastatic RCC. Of the 225 subjects enrolled, 155 (69%) had no prior 
systemic therapy, and 70 (31%) had 1 prior therapy of either a cytokine or bevacizumab 


Everolimus-Pazopanib Phase I 
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based therapy. The study utilized a randomized discontinuation design that includes a 12- 
week lead-in phase during which all subjects received 800mg pazopanib daily dose. Based 
on the disease assessment at Week 12, subjects with a complete or partial response would 
continue pazopanib treatment until disease progression; subjects with progressive disease 
(PD) at or prior to Week 12 would discontinue pazopanib treatment; and subjects with stable 
disease (SD) at Week 12 were randomized to receive blinded treatment with 800mg 
pazopanib or placebo for 16 weeks. An interim analysis was performed in September 2006 
when the first 60 enrolled subjects had completed the 12-week Lead-In phase. Based on the 
review of both interim efficacy (12-week response rate) and safety data from this study, the 
Independent Data Monitoring Committee recommended halting further randomization, 
unblinding the study and offering pazopanib treatment to subjects on the placebo arm of the 
randomization phase of the study. As a result randomization at 12 wks was discontinued, 
subjects previously randomized to placebo were crossed over to pazopanib, and all subjects 
could receive pazopanib until progressive disease (PD), unacceptable toxicity, or consent 
withdrawal. 
 
In 2009, the FDA granted approval to pazopanib for the treatment of patients with advanced 
renal cell carcinoma. This was based on the results of a phase III international, randomized, 
double-blind trial comparing pazopanib to placebo in patients with previously untreated 
advanced renal cell carcinoma or patients who had progressed on cytokine therapy. This 
study demonstrated a progression-free survival advantage of 9.2 months with pazopanib vs. 
4.2 months with placebo(7). In 2012 the PISCES phase III randomized trial results were 
presented st the annual European society of Medical Oncology meeting, In this study the 
tolerability of pazopanib was compared to sunitinib and results showed that pazopanib was 
associated with significantly better health related quality of life compared to sunitinib and it 
resulted in less fatigue and less dysgeusia. In 2012, the FDA approved pazopanib 
hydrochloride tablets for the treatment of patients with advanced soft tissue sarcoma (STS) 
who have received prior chemotherapy after it was shown to improve median PFS to 4.6 
months for patients receiving pazopanib hydrochloride compared with 
1.6 months for patients receiving placebo in a phase III study. 
 
 
 
2.2 
Study Disease 
 
While front-line cisplatin-based combination chemotherapy is highly active, more than 85% of 
patients will relapse following initial therapy. There is no standard 2nd-line regimen following 
failure of front-line chemotherapy.  Many agents, including docetaxel, paclitaxel, pemetrexed, 
and ifosfamide, have shown single agent responses (between 10-20%, which improve with 
combination therapy), yet no randomized trial has shown the benefit of one over another. In fact, 
no second-line trial has demonstrated improved survival with any chemotherapy agent. 
9 
 
 
The importance of angiogenesis in invasive and advanced urothelial cancer is well documented. 
Increased microvessel density has been shown to predict advanced disease and poor prognosis in 
urothelial cancer.10-17 Preclinical models in bladder cancer suggest that anti-angiogenic therapies 


Everolimus-Pazopanib Phase I 
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may inhibit progression of bladder cancer.18 VEGF appears to be a major angiogenic factor in 
urothelial carcinoma.15,19-21  The importance of angiogenesis in invasive TCC is well 
documented. Both VEGF mRNA and protein are over-expressed in advanced bladder cancer 
compared with normal bladder epithelium.22-24 In addition to its pro-angiogenic properties, recent 
in vitro experiments also suggest a role for VEGF signaling as an autocrine and paracrine growth 
factor to directly promote bladder cancer growth.25 Furthermore, retrospective evaluation of serum 
VEGF levels in the metastatic setting appears to correlate high levels with poor disease- free 
survival.26 Baseline VEGF mRNA expression levels and microvessel density were found to be 
independent prognostic factors for recurrence and metastasis in 51 patients treated with 
neoadjuvant MVAC chemotherapy and cystectomy.11 In addition to its pro-angiogenic role, 
elevated levels of VEGF in tumors lead to abnormal microvasculature. Excessive angiogenic 
factors recruit endothelial and perivascular cells to form tortuous and dilated blood vessels with 
poor rheological characteristics, leading to abnormal tumor blood flow. Elevated VEGF levels in 
tumors leads to increased vascular permeability.27 By reducing VEGF levels, not only are the 
aberrant tumor-associated blood vessels eliminated, but the microvasculature also appears to be 
remodeled, leading to more “normal” blood vessel architecture. This leads to improved 
transvascular drug delivery directly to tumor cells. 
 
VEGF inhibition alone, which primarily targets endothelial cells does not appear to be sufficient 
as an anti-cancer strategy in advanced urothelial carcinoma. Sunitinib and pazopanib have shown 
modest activity as single agents, with few patients having objective responses, and rates of stable 
disease are low.28-31 Nearly all patients progress on these agents, and a the majority of patients do 
not have any significant disease response or stabilization. 
 
Autocrine and paracrine growth signals to cancer cells are frequently mediated via the PI3 
kinase/Akt pathway.32 PI3 kinase activity results in membrane localization of Akt, leading to the 
generation of activated phospho-Akt. This activated Akt phosphorylates and inactivates TSC2. 
TSC1 and TSC2 form a complex that normally suppresses signaling through mTOR. Inactivation 
of TSC2 results in increased signaling through the mTOR complex, which then leads to 
increased cell metabolism, growth, and survival. These effects appear to be abrogated by mTOR 
inhibition with rapamycin.33 In addition, mTOR may also be directly activated by Akt.34 
 
The PI3 kinase/Akt/mTOR pathway is frequently activated in advanced urothelial carcinoma 
specimens.35,36  mTOR pathway signaling appears active in many urothelial carcinoma 
specimens37 and appears associated with worse survival.38 In addition, deletion of chromosome 
9q spanning the region containing TSC1 is the most frequent genetic alteration in transitional cell 
carcinoma.39 TSC1 is believed to represent a tumor suppressor gene deleted at that site. 
Inactivating mutations are observed in TSC1 in 10-30% of cases.40,41 
 
In addition to chromosome 9q and TSC1 alterations, chromosome 10q loss is frequent in 
transitional cell carcinoma. PTEN, a negative regulator of the Akt pathway located on 
chromosome 10q, shows loss of heterozygosity in approximately 25% of transitional cell 
carcinomas, as well as homozygous deletions and point mutations in a small subset of cases.42,43 
Bladder cancer has also been reported in patients with Cowden disease, caused by autosomal 
dominant mutations in PTEN.44,45 


Everolimus-Pazopanib Phase I 
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Preclinical evaluation of mTOR inhibition with everolimus demonstrates that it inhibits 
urothelial carcinoma cells in vitro46, although did not affect the growth of urothelial carcinoma in 
a chemically-induced mouse urothelial carcinoma model47. A phase II trial of everolimus as a 
single agent enrolled 45 patients. Two partial responses were noted.48, suggesting modest activity 
of this agent. 
 
Based on these data, the PTEN/PI3 kinase/Akt/mTOR pathway may play an important role in 
transitional cell carcinoma, and inhibition of this pathway may be therapeutically useful in 
advanced transitional cell carcinoma patients. The utility of these agents in combination with 
anti-VEGF agents has not yet been thoroughly tested, as synergy between these pathways is 
predicted. 
 
2.3 Rationale 
 
 
Dose Escalation Cohort: Both anti-angiogenic therapy and mTOR inhibition provide significant 
clinical benefit in metastatic kidney cancer patients, although responses to each therapy are 
limited in duration and extent. 
 
Expansion Cohort: There are no standard therapies available for patients with metastatic 
urothelial carcinoma who have progressed following front-line chemotherapy. Novel approaches 
are needed. 
 
Currently approved anti-VEGF tyrosine kinase inhibitors exhibit significant side effects, including 
rash, diarrhea, endocrine abnormalities, cardiotoxicity, and fatigue. Pazopanib appears to have a 
somewhat improved therapeutic index and may be associated with less toxicity yet with 
comparable efficacy. 
 
Pazopanib has been tested in a randomized discontinuation study in patients with metastatic 
clear cell renal cell carcinoma. Pazopanib has resulted in 40% of patients with a partial response 
to induction therapy, and a significant improvement in progression free survival in patients 
randomized to active drug in the randomized discontinuation portion of the protocol. 
 
The most prominent significant toxicity observed has been hypertension. Hepatotoxicity may be 
higher with this agent but fewer dermatologic and gastrointestinal toxicities have been observed 
compared to other anti-VEGF tyrosine kinase inhibitors. The lower toxicity, enhanced 
tolerability, and high activity of pazopanib make it an ideal candidate to combine with other 
targeted therapies. 
 
Addition of another agent targeting other anti-angiogenic pathways may provide either additive 
or synergistic effects with existing anti-VEGF agents. Downstream signal transduction inhibition 
of the PTEN/Akt/mTOR pathway by everolimus may complement upstream VEGF receptor 


Everolimus-Pazopanib Phase I 
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inhibition by either simple additive effects when both targets are inhibited, or by downstream 
blockade of pathways if there is partial resistance to receptor inhibition.  Loss of PTEN function 
via methylation is common in metastatic kidney cancer and appears common in bladder cancer, 
leading to increased Akt activity and cell proliferation.49 Activation of mTOR, a downstream 
effector of Akt, has been shown in preclinical models to increase tumor cell proliferation and 
promote angiogenesis. Everolimus, an oral inhibitor of mTOR, decreases tumor and endothelial 
cell proliferation and tumor cell VEGF production, leading to antitumor and potential anti- 
angiogenic effects. In phase I studies, objective tumor responses with everolimus have been seen 
in a variety of tumor types. Combination of everolimus with angiogenesis inhibitors in 
preclinical studies has led to synergistic anti-angiogenic and antitumor effects.50 Although pre- 
clinical studies with everolimus and pazopanib in combination have not been done, the pre- 
clinical evidence of synergy between anti-VEGF and anti-mTOR drugs provides the rationale to 
test everolimus in combination with pazopanib. Everolimus is FDA approved for the treatment of 
advanced kidney cancer, pancreatic neuroendocrine tumors, and subependymal giant cell 
astrocytomas. – In 2012 Afinitor)® ( received approval for the treatment of postmenopausal 
women with advanced hormone receptor-positive, HER2- negative breast cancer (advanced HR+ 
BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 
 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that 
pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no clinically 
relevant effect on CYP1A2, CYP2C9 or CYP2C19 metabolism. Everolimus is a substrate of 
CYP3A pathways, and a competitive inhibitor of CYP3A and CYP2D6 enzymes. These potential 
interactions require pharmacokinetic evaluation of drug levels of both everolimus and pazopanib. 
As a result, pharmacokinetic data for both drugs will be obtained at day 1 and 15 of cycle 1 for 
all patients on the phase I portion of this study. 
 
 
The starting dose for the initial Phase 1 cohort was chosen as 3/4 of the standard single-agent 
dose of pazopanib, and half-dose of everolimus, primarily based on available pill size. While 
these starting doses were arbitrary, they were both at levels consistent with activity against the 
targets as single agents. 
 
For the dose escalation cohort: Escalation occurred in a 200 mg increment for pazopanib up to 
the standard dose of 800 mg daily. Everolimus will be escalated from 5 mg to 10 mg. One drug 
is escalated alternately in each successive cohort. De-escalation will be allowed to dose level -1 
if there are excessive DLT’s observed in the starting dose level. In addition, dose level +2A will 
be considered if there is a DLT at dose level +2. This dose level would test full dose pazopanib 
800 mg daily in combination with everolimus 5 mg daily. 
 
 
Phase I update as of 3/19/14 


Everolimus-Pazopanib Phase I 
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The first portion of this study of everolimus plus pazopanib in genitourinary and other 
solid malignancies was carried out at the Dana-Farber Cancer Institute. Nine patients were 
enrolled of which five had urothelial carcinoma of the bladder. These nine patients were 
either treated on Dose Level 0: Pazopanib 600 mg PO QD and everolimus 5 mg PO QD 
(n=3) or Dose Level -1: Pazopanib 400 mg PO QD and everolimus 5 mg PO QD (n=6). 
Pharmacokinetic data were collected on everolimus and pazopanib to determine 
whether drug-drug interactions occur. These data are from the 5 patients (3 lung cancer,2 
bladder cancer,1 adrenal cortical carcinoma) treated with pazopanib 400 mg daily and 
everolimus 5 mg daily(Dose Level -1). The Day 15 steady-state whole blood everolimus 
PK parameters were: 
 
 
 
everolimus 
(mean  ± SD values) 
O’Donnell, et al JCO 2008(51) 
(mean ± SD values) 
AUCss(0-24h) 335 ± 189 ng*h/mL (median, 
348 ng*h/mL; range, 162- 
868 ng*h/mL). 
238 ± 77 ng*h/mL 
Cmax,ss 
37.9 ± 2.1 ng/mL 
32 ± 9 ng*h/mL 
Cmin,ss 
6.1 ± 4.9 ng/mL 
5.4 ± 1.8 ng/mL 
 
 
 
 
The percent difference between the mean values of the steady-state PK parameters for 
everolimus given in combination with pazopanib relative to everolimus alone were: 
+13% for Cmin,ss, +18% for Cmax,ss, and +100% for AUCss(0-24h).  These findings 
demonstrate a significant pharmacokinetic interaction between the two drugs resulting in 
a marked decrease in the apparent clearance of everolimus. Pharmacokinetic data for 
pazopanib from the phase I combination trial indicates that there is no effect of 
everolimus on pazopanib pharmacokinetics when evaluated in the context of known 
pazopanib pharmacokinetic data: 
 
 
 
Pazopanib 
(CV, %) 
Hurwitz, et al. Clin Canc Res 
2009 (CV, %) 
AUC0-24 
(µg·h/mL) 
451.6 (41.2) 
447.1 (31.3) 
Cmax (µg/mL) 
26.8 (35.5) 
21.8 (56.3) 
C24 (µg/mL) 
13.9 (49.8) 
10.4 (86.6) 
 
 
 
 
Toxicity 


Everolimus-Pazopanib Phase I 
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Nine patients were enrolled in the phase I portion of this study. Two patients on dose level 
0 (pazopanib 600 mg daily and everolimus 5 mg daily) experienced dose limiting toxicities 
(grade 3 rash and pruritus and grade 3 thrombocytopenia requiring a dose reduction). 
Therefore, three patients were treated at dose level -1 per protocol. None of these three 
patients experienced a protocol-defined dose-limiting toxicity. Therefore, another three 
patients were treated at dose level -1 (pazopanib 400 mg daily and everolimus 5 mg daily) 
without any dose-limiting toxicities. Therefore, per protocol, dose level -1 was defined as 
the maximum tolerated dose. 
 
 
 
Toxicity 
Maximum Grade 
G1 
G2 
G3 
G4 
Febrile neutropenia 
- 
- 
1 
- 
Neutropenia 
1 
- 
- 
- 
Thrombocytopenia 
3 
1 
1 
- 
 
Hematologic toxicities (see table above) included febrile neutropenia (11%), neutropenia 
(11%), thrombocytopenia (56%), and anemia (36%). Grade 3 febrile neutropenia and 
thrombocytopenia each occurred in 1 patient. Non-hematologic toxicities were varied, 
though many were expected based on the known toxicities of everolimus and pazopanib. 
One patient did experience a grade 3 pneumothorax, which was possibly related to study 
therapy. Other non-hematologic toxicities included anorexia (11%), bone pain (11%), 
diarrhea (22%, 11% G3), fatigue (56%), dysgeusia (11%), headache (11%), hypertension 
(22%), mucositis (33%), musculoskeletal (muscle stiffness after prolonged periods of 
sitting,11%), nausea (44%), palmo-plantar erythrodysesthesia syndrome (11%), 
pneumonia (11% G3), pruritus (11% G3), rash (33%, 11% G3), vomiting (33%), and 
weight loss (11%). Toxicities noted in laboratory evaluations were generally consistent 
with what is expected with both agents administered separately. G3 and 4 laboratory 
toxicities included increased ALT, hypophosphatemia, and hypouricemia each in 1 
patient, and increased lipase in 2 patients. 
Treatment was generally well tolerated at the MTD. Two of 6 patients came off treatment 
after 2 cycles because of toxicity. The others stopped treatment due to disease 
progression or physician decision. 
 
Antitumor activity 
 
Encouraging antitumor activity was noted in the bladder cancer patients treated on 
pazopanib and everolimus. Of five urothelial cancer patients evaluable, 3 had stable 
disease for 4 months, 4 months and 5.5 months respectively. One patient had a complete 
response which lasted 14 months. 
 
Tumor type 
(n) 
Best objective response 


Everolimus-Pazopanib Phase I 
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Bladder 
Lung small cell carcinoma 
Adrenocortical carcinoma 
5 
3 
1 
3 SD, 1CR, 1 NE 
2 SD, 1 PD 
1 SD 
Median Age (range) 
59 (49-77) 
 
 
 
SD: stable disease; NE: not evaluable; CR: complete response; PR: partial response; PD: 
progressive disease. 
 
Based on these findings of preliminary increased activity of the regimen in at least a subset 
of urothelial carcinoma patients, the protocol is being amended to accrue urothelial 
carcinoma patients rather than kidney cancer patients in the expansion cohort given the 
significant unmet need in urothelial carcinoma. Since there are no approved treatments for 
patients with progressive disease after front-line cytotoxic chemotherapy, testing novel 
approaches is rational. Metastatic urothelial carcinoma patients treated with 1-3 prior 
regimens of systemic chemotherapy including at least a platinum agent, a taxane, or 
gemcitabine will be enrolled. No prior VEGF receptor or mTOR pathway inhibitors are 
allowed. Patients will continue therapy until progression or unacceptable toxicity. 
 
 
 
3.  PARTICIPANT SELECTION 
 
3.1 Eligibility Criteria for the Dose Escalation cohort 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Phase I: Participants must have histologically confirmed malignancy that is metastatic 
or unresectable and for which standard curative or palliative measures do not exist 
or are no longer effective (or who are intolerant of such therapy). 
 
 
3.1.2 Age ≥ 18 years. 
 
 
3.1.3 Life expectancy of greater than 3 months. 
 
 
3.1.4 ECOG perfor mance status < 1 ( Karnofsky > 70%, see Appendix A) . 
 
 
3.1.5 Participants must have normal organ and marrow function as defined below: 
• 
Leukocytes > 3,000/ mm3 
• 
Absolute neutrophil count > 1,500/mm3 
• 
Platelets > 100,000/ mm3 


Everolimus-Pazopanib Phase I 
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• 
Hemoglobin > 9 g/dL; subjects may not have had an RBC transfusion within 7 
days of screening assessment. 
• 
Total bilirubin ≤ 1.5 X normal institutional limits 
• 
AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal 
• 
Creatinine ≤ 1.5 mg/dL or creatinine clearance > 50 mL/min for subjects with 
creatinine levels about institutional normal 
• 
Partial thromboplastin time (PTT)  1.5 X institutional ULN unless patients are on 
therapeutic anticoagulation with warfarin 
• 
Urine protein to urine creatinine ratio (UPC) < 1.0. If UPC ≥ 1 then a 24 hour urine 
protein must be assessed. Subjects must have a 24-hour urine protein value < 1g to 
be eligible 
• 
Total cholesterol ≤300 mg/dL AND fasting triglycerides ≤ 2.5 x institutional ULN. 
NOTE: In case one or both of these thresholds are exceeded, the patient can only 
be included after initiation of appropriate lipid lowering medication. 
 
 
3.1.6 Able to swallow oral medications 
 
3.1.7 Resolution of any pre-existing toxicity from prior therapy to NCI CTCAE V4.0 grade 
1 except neuropathy (≤ grade 2) and tinnitus (≤ grade 2), and hearing loss (≤ grade 4) 
 
 
3.1.8 A female is eligible to enter and participate in this study if she is of: 
 
 
3.1.8.1 Non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant), including any female who has had: 
• A hysterectomy 
• A bilateral oophorectomy (ovariectomy) 
• A bilateral tubal ligation 
• Is post-menopausal 
 
 
Subjects not using hormone replacement therapy (HRT) must have experienced 
total cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in 
questionable cases, have a follicle stimulating hormone (FSH) value >40 
mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L). 
 
 
Subjects must discontinue HRT prior to study enrollment due to the potential for 
inhibition of CYP enzymes that metabolize estrogens and progestins.  For most 
forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and 
determination of menopausal status; length of this interval depends on the type 
and dosage of HRT.  If a female subject is determined not to be post- 
menopausal, they must use adequate contraception as defined immediately 
below during the trial and for 8 weeks after the last dose. 


Everolimus-Pazopanib Phase I 
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3.1.8.2 Childbearing potential, including any female who has had a negative serum 
pregnancy test within 2 weeks prior to the first dose of study treatment, 
preferably as close to the first dose as possible, and agrees to use adequate 
contraception. Acceptable contraceptive methods, when used consistently and 
in accordance with both the product label and the instructions of the physician, 
are as follow: 
• An intrauterine device with a documented failure rate of less than 1% per 
year. 
• Vasectomized partner who is sterile prior to the female subject’s entry and 
is the sole sexual partner for that female. 
• Double-barrier contraception (condom with spermicidal jelly, foam 
suppository, or film; diaphragm with spermicide; or male condom and 
diaphragm with spermicide). 
 
 
Note: Oral contraceptives are not reliable due to potential drug-drug 
interactions. 
 
 
3.1.8.3 Female subjects who are lactating should not be included in the trial. 3.1.8.4 A 
male with a female partner of childbearing potential is eligible to enter and 
participate in the study if he uses a barrier method of contraception or 
abstinence during the study. 
 
3.1.9  Subjects 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. Procedures conducted as part of the subject’s routine clinical management 
(e.g., blood count, imaging study) and obtained prior to signing of informed consent 
may be utilized for screening or baseline purposes provided these procedures are 
conducted as specified in the protocol. 
 
 
3.2 Exclusion Criteria for the Dose Escalation Cohort 
 
 
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the dose escalation cohort of this study. 
 
3.2.1  Participants who have had chemotherapy or radiotherapy within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who 
have not recovered from adverse events due to agents administered more than 4 
weeks earlier. Current treatment with leuprolide or other GnRH agonists is permitted 
on the Phase I portion of the study. 
 
3.2.2  Participants may not be receiving any other study agents during the study or 
within 4 weeks of the start of the trial. 


Everolimus-Pazopanib Phase I 
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3.2.3  Prior everolimus or pazopanib therapy. Other mTOR inhibitors and tyrosine 
kinase inhibitors are allowed. 
 
3.2.4  History or clinical evidence of central nervous system (CNS) metastases or 
leptomeningeal carcinomatosis, except for individuals who have previously- 
treated CNS metastases, are asymptomatic, and have had no requirement for 
steroids or anti-seizure medication for 6 weeks prior to the first dose of study 
drug. Screening with CNS imaging studies (computed tomography [CT] or 
magnetic resonance imaging [MRI]) is required only if clinically indicated or if 
the subject has a history of CNS metastases. Treated brain metastases are defined as 
having no evidence of progression or hemorrhage after treatment and no ongoing 
requirement for dexamethasone, as ascertained by clinical examination and brain 
imaging (MRI or CT) during the screening period. Anticonvulsants will not be 
allowed. Treatment for brain metastases may include whole brain radiotherapy 
(WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination 
as deemed appropriate by the treating physician. Patients with CNS metastases treated 
by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 
will be excluded. 
 
3.2.5 Known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to pazopanib or everolimus (such as sirolimus or 
temsirolimus) 
 
 
3.2.6 Patients who have any severe and/or uncontrolled medical conditions such as: 
a.   Unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac 
arrhythmia, or any other clinically significant cardiac disease 
b.   Symptomatic congestive heart failure of New York heart Association Class III or 
IV 
c.   Active (acute or chronic) or uncontrolled severe infection, liver disease such as 
cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable 
HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA), 
d.   Known severely impaired lung function (e.g spirometry and DLCO 50% or less 
of normal and O2 saturation 88% or less at or less at rest on room air), 
e.   Active, bleeding diathesis; 
 
3.2.7   Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 
mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. Initiation or adjustment 
of antihypertensive medication(s) is permitted prior to study entry. Blood 
pressure must be re-assessed on two occasions that are separated by a minimum 
of 24 hours. The mean SBP / DBP values from each blood pressure assessment 
must be < 140/90mmHg in order for a subject to be eligible for the study. 
 
3.2.8   History of cerebrovascular accident, pulmonary embolism or untreated deep 
venous thrombosis (DVT) within the past 6 months. Subjects with recent DVT 


Everolimus-Pazopanib Phase I 
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who have been treated with therapeutic anti-coagulating agents for at least 6 
weeks are eligible 
 
3.2.9   Prior major surgery (required as defining general anesthesia) or trauma within 28 
days prior to first dose of study drug, and/or not recovered from effects of that 
surgery, and/or presence of any non-healing wound, fracture, or ulcer (procedures 
such as catheter placement not considered to be major), or patients that may require 
surgery during the course of the study. 
 
3.2.10 Evidence of active bleeding or bleeding diathesis. 
 
3.2.11 Known endobronchial lesions or involvement of large pulmonary vessels by tumor 
 
3.2.12 Hemoptysis within 6 weeks of first dose of study drug. 
 
3.2.13 Use of an investigational agent, including an investigational anti-cancer agent, 
within 4 weeks, whichever is longer, prior to the first dose of study drug. 
 
3.2.14 Clinically significant gastrointestinal abnormalities that may increase the risk for GI 
bleeding including, but not limited to: 
A.  Active peptic ulcer disease 
B.  Known intraluminal metastatic lesion/s with suspected bleeding 
C.  Inflammatory bowel disease 
D.  Ulcerative colitis, or other gastrointestinal conditions with increased risk of 
perforation 
E.  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 28 days prior to beginning study treatment. 
 
3.2.15 “Currently active” second malignancy other than non-melanoma skin cancers. 
Patients are not considered to have a “currently active” malignancy if they have 
completed therapy more than 3 years ago and are considered to have a less than 30% 
risk of relapse based on the enrolling investigator’s assessment and documented in 
the medical record. A history of prostate cancer that was identified incidentally 
following cystoprostatectomy or cystectomy for bladder cancer is acceptable, 
provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score 
≤ 7, negative margins at surgery, and PSA undetectable after surgery. 
 
3.2.16   Presence of uncontrolled infection 
 
3.2.17   Liver disease such as chronic cirrhosis, active hepatitis, or chronic and persistent 
hepatitis 
 
3.2.18   Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
Patients with a known history of impaired fasting glucose or diabetes mellitus 
(DM) may be included, however blood glucose and antidiabetic treatment must be 
monitored closely throughout the trial and adjusted as necessary; 


Everolimus-Pazopanib Phase I 
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3.2.19   Current treatment on another clinical trial 
 
3.2.20   Pregnant or breastfeeding. Pregnant women are excluded from this study because 
pazopanib and everolimus are agents with the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk of adverse 
events in nursing infants secondary to treatment of the mother with either of these 
agents, breastfeeding should be discontinued if the mother is treated with either 
pazopanib or everolimus. These potential risks may also apply to other agents used 
in this study. 
 
3.2.21   Chronic treatment with systemic corticosteroids or other immunosuppressive 
agent. Topical or inhaled corticosteroids are allowed.Patient is unable or 
unwilling to discontinue predefined prohibited medications listed in the protocol 
for 4 weeks of a drug (whichever is longer) prior to Visit 1 and for the duration of 
the study. 
 
3.2.22   Treatment with strong CYP3A4 inhibitors: 
•   Cardiovascular: verapamil and diltiazem 
•   Antibiotics: clarithromycin, telithromycin, troleandomycin, erythromycin 
•   HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, 
lopinavir) 
•  Antifungals: itraconzaole, ketoconazole, voriconazole, fluconazole 
•  Antidepressants: nefazodone 
 
3.2.23 
Other prohibited medications : 
•  Oral hypoglycemics: tolbutamide, chlorpropamide 
•  Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, 
methylergonovine 
•  Neuroleptics: pimozide 
•  Antiarrhythmics: amiodarone, bepridil, flecainide, lidocaine, mexilitine, 
quinidine, propafenone 
•  Immune modulators: cyclosporine, tacrolimus, sirolimus. 
•  Miscellaneous: theophylline, quetiapine, risperidone, tacrine, clozapine, 
atomoxetin 
 
3.2.24 
Treatment with strong CYP3A4 inducers: 
•   Anticonvulsants: phenytoin, carbemazepine, Phenobarbital, oxcarbazepine 
•   HIV antiretrovirals: efavirenz, nevirapine 
•   Antibiotics: rifampin (rifampicin), rifabutin, rifapentene 
•   Miscellaneous: St. John’s Wort, modafinil, pioglitazone, troglitazone 


Everolimus-Pazopanib Phase I 
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3.2.25 
Patients should not receive immunization with attenuated live vaccines within one 
week of study entry or during study period. Patient should also avoid close contact 
with others who have received live attenuated vaccines. Examples of live 
attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral 
polio, BCG, yellow fever, varicella and TY21a typhoid vaccines; 
 
3.2.26   Prolongation of corrected QT interval (QTc) > 480 msecs. 
 
3.2.27   History of malabsorption syndrome, disease significantly affecting gastrointestinal 
function or major resection of stomach or small bowel that could interfere with 
absorption, distribution, metabolism, or excretion of study drugs. 
 
3.2.28   Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is 
progressing in severity. Hypothyroidism treated with medication is not excluded if 
TSH is within normal limits. 
 
3.2.29   Any serious and/or unstable pre-existing medical, psychiatric, or other condition 
(including lab abnormalities) that could interfere with subject safety, obtaining 
informed consent or compliance to study procedures. Examples of such include 
uncontrolled diabetes, nonhealing wound, severe or uncontrolled infection, severe 
malnutrition, severely impaired lung function as defined as spirometry and DLCO 
that is 50% of the normal predicted value and/or 02 saturation that is 88% or less 
at rest on room air, ventricular arrhythmias, active ischemic heart disease, chronic 
liver or renal disease, or active upper GI tract ulceration. 
 
3.2.30  HIV-positive individuals on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with pazopanib and 
everolimus. In addition, these individuals are at increased risk of lethal 
infections when treated with marrow-suppressive therapy. Appropriate studies 
will be undertaken in participants receiving combination antiretroviral therapy 
when indicated. 
 
3.2.31   Patients unwilling or unable to comply with protocol therapy, tests, and visits, or 
with a history of noncompliance with medical regimens. 
 
 
3.3 Eligibility Criteria for the expansion cohort in urothelial carcinoma 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion and exclusion criteria. Results of all baseline evaluations, 
which assure that all inclusion and exclusion criteria have been satisfied, must be 
reviewed by the Principal Investigator or his/her designee prior to enrollment of that 
patient. In addition, the patient must be thoroughly informed about all aspects of the 
study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained from 


Everolimus-Pazopanib Phase I 
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the patient prior to enrollment. The following criteria apply to all patients enrolled onto 
the study unless otherwise specified. 
 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the expansion cohort of this study: 
 
3.3.1 Metastatic or locally advanced unresectable urothelial carcinoma with histologic or 
cytologic confirmation at DFCI or MSKCC. 
 
 
3.3.2 Participants must have measurable disease, as defined by RECIST v1.1. 
 
 
3.3.3 Previously treated with at least one and not more than 3 lines of systemic 
chemotherapy including at least one of the following: a platinum agent, a taxane, or 
gemcitabine. 
 
 
3.3.4 Age ≥ 18years. Because no dosing or adverse event data are currently available on 
the use of pazopanib as an anti-cancer agent in patients <18 years of age, children 
are excluded from this study but may be eligible for future pediatric trials. 
 
 
3.3.5 Life expectancy of greater than 3 months. 
 
 
3.3.6  Karnofs ky  >  70%  or  ECOG  ≤ 1  (see  Appendix  A). 
 
3.3.7  Participants must have normal organ and marrow function as defined below: 
• 
WBC > 3,000/ mm3 
• 
Absolute neutrophil count > 1,500/mm3 
• 
Platelets > 100,000/ mm3 
• 
Hemoglobin > 9 g/dL; subjects may not have had an RBC transfusion within 7 
days of screening assessment. 
• 
Total bilirubin ≤ 1.5 X normal institutional limits 
• 
AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal 
• 
Creatinine clearance > 40 mL/min 
• 
Prothrombin time (PT) or international normalized ratio (INR)  2X institutional 
upper limit of normal (ULN) unless patients are on therapeutic anticoagulation with 
warfarin 
• 
Partial thromboplastin time (PTT)  1.5 X institutional ULN unless patients are on 
therapeutic anticoagulation with warfarin 
• 
Urine protein to urine creatinine ratio (UPC) < 1.0. If UPC ≥ 1 then a 24 hour urine 
protein must be assessed. Subjects must have a 24-hour urine protein value < 1g to 
be eligible 


Everolimus-Pazopanib Phase I 
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• 
Total cholesterol ≤300 mg/dL AND fasting triglycerides ≤ 2.5 x institutional ULN. 
NOTE: In case one or both of these thresholds are exceeded, the patient can only 
be included after initiation of appropriate lipid lowering medication. 
 
 
3.3.8 Able to swallow oral medications 
 
3.3.9 Resolution of any pre-existing toxicity from prior therapy to NCI CTCAE V4.0 grade 
1 except neuropathy (≤ grade 2) and tinnitus (≤ grade 2), and hearing loss (≤ grade 4) 
 
 
 
3.3.10 A female is eligible to enter and participate in this study if she is of: 
 
 
3.3.10.1 Non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant), including any female who has had: 
• A hysterectomy 
• A bilateral oophorectomy (ovariectomy) 
• A bilateral tubal ligation 
• Is post-menopausal 
 
 
Subjects not using hormone replacement therapy (HRT) must have experienced 
total cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in 
questionable cases, have a follicle stimulating hormone (FSH) value >40 
mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L). 
 
 
Subjects must discontinue HRT prior to study enrollment due to the potential for 
inhibition of CYP enzymes that metabolize estrogens and progestins.  For most 
forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and 
determination of menopausal status; length of this interval depends on the type 
and dosage of HRT.  If a female subject is determined not to be post- 
menopausal, they must use adequate contraception as defined immediately 
below during the trial and for 8 weeks after the last dose. 
 
 
NOTE: Women are considered post-menopausal and not of child-bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) 
or have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks prior to randomization. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child- 
bearing potential. 
 
 
3.3.10.2 Childbearing potential, including any female who has had a negative serum 
pregnancy test within 2 weeks prior to the first dose of study treatment, 


Everolimus-Pazopanib Phase I 
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preferably as close to the first dose as possible, and agrees to use adequate 
contraception. Acceptable contraceptive methods, when used consistently and in 
accordance with both the product label and the instructions of the physician, are 
as follow: 
• An intrauterine device with a documented failure rate of less than 1% per 
year. 
• Vasectomized partner who is sterile prior to the female subject’s entry and 
is the sole sexual partner for that female. 
• Double-barrier contraception (condom with spermicidal jelly, foam 
suppository, or film; diaphragm with spermicide; or male condom and 
diaphragm with spermicide). 
 
 
Note: Oral contraceptives are not reliable due to potential drug-drug 
interactions. 
 
 
3.3.10.3 A male with a female partner of childbearing potential is eligible to enter and 
participate in the study if he uses a barrier method of contraception or 
abstinence during the study and for 8 weeks after the end of treatment. 
 
3.3.11  Subjects 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. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, 
imaging study) and obtained prior to signing of informed consent may be utilized for screening 
or baseline purposes provided these procedures are conducted as specified in the protocol. 
 
 
3.4 Exclusion Criteria for the Expansion Cohort 
 
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the study. 
 
3.4.1  Participants who have had chemotherapy or radiotherapy within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who 
have not recovered from adverse events due to agents administered more than 4 
weeks earlier. 
 
3.4.2  Participants may not be receiving any other study agents during the study or 
within 4 weeks of the start of the study. 
 
3.4.3  Prior mTOR pathway inhibitor or VEGF receptor inhibitor therapy. 
 
3.4.4  History or clinical evidence of central nervous system (CNS) metastases or 
leptomeningeal carcinomatosis, except for individuals who have previously- 
treated CNS metastases, are asymptomatic, and have had no requirement for 


Everolimus-Pazopanib Phase I 
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steroids or anti-seizure medication for 6 weeks prior to the first dose of study 
drug. 
• 
Screening with CNS imaging studies (computed tomography [CT] or magnetic 
resonance imaging [MRI]) is required only if clinically indicated or if the 
subject has a history of CNS metastases. 
• 
Treated brain metastases are defined as having no evidence of progression or 
hemorrhage after treatment and no ongoing requirement for dexamethasone, as 
ascertained by clinical examination and brain imaging (MRI or CT) during the 
screening period. 
• 
Anticonvulsants will not be allowed. 
• 
Treatment for brain metastases may include whole brain radiotherapy (WBRT), 
radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as 
deemed appropriate by the treating physician. Patients with CNS metastases treated 
by neurosurgical resection or brain biopsy performed within 3 months prior to Day 
1 will be excluded. 
 
 
3.4.5  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to pazopanib or everolimus (such as sirolimus or 
temsirolimus) 
 
3.4.6   Any serious and/or unstable pre-existing medical, psychiatric, or other condition 
(including lab abnormalities) that could interfere with subject safety, obtaining 
informed consent or compliance to study procedures. 
 
a.   Unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac 
arrhythmia, ventricular arrhythmias, active ischemic heart disease, or any other 
clinically significant cardiac disease, 
b.   Symptomatic congestive heart failure of New York heart Association Class III or 
IV 
c.   Active (acute or chronic) or uncontrolled severe infection 
d.   Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis 
(i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV- RNA) 
e. Known severely impaired lung function (e.g. spirometry and DLCO 50% or less 
of normal and O2 saturation 88% or less at rest on room air)active, bleeding 
diathesis 
f. Severe or uncontrolled infection, severe malnutrition 
g.   Chronic renal disease 
h.   Active upper GI tract ulceration 


Everolimus-Pazopanib Phase I 
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3.4.7 Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 
mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. Initiation or adjustment 
of antihypertensive medication(s) is permitted prior to study entry. Blood pressure 
must be re-assessed on two occasions that are separated by a minimum of 5 
minutes. The mean SBP / DBP values from each blood pressure assessment must be 
< 140/90mmHg in order for a subject to be eligible for the study. 
 
3.4.8   History of cerebrovascular accident, pulmonary embolism or untreated deep venous 
thrombosis (DVT) within the past 6 months. 
 
• 
Subjects with recent DVT who have been treated with therapeutic anti- 
coagulating agents for at least 6 weeks are eligible 
 
3.4.9   Prior major surgery (required as defining general anesthesia) or trauma within 28 
days prior to first dose of study drug, and/or not recovered from effects of that 
surgery, and/or presence of any non-healing wound, fracture, or ulcer (procedures 
such as catheter placement not considered to be major), or patients that may require 
surgery during the course of the study. 
 
3.4.10 Evidence of active bleeding or bleeding diathesis. 
 
3.4.11 Known endobronchial lesions or involvement of large pulmonary vessels by tumor 
 
3.4.12 Hemoptysis within 6 weeks of first dose of study drug. 
 
3.4.13 Use of an investigational agent, including an investigational anti-cancer agent, 
within 4 weeks, whichever is longer, prior to the first dose of study drug. 
 
3.4.14 Clinically significant gastrointestinal abnormalities that may increase the risk for GI 
bleeding including, but not limited to: 
• Activepeptic ulcer disease 
• Known intraluminal metastatic lesion/s with suspected bleeding 
• Inflammatory bowel disease 
Ulcerative colitis, or other gastrointestinal conditions with increased risk of 
perforation 
 
3.4.15  History of another malignancy within 3 years, except the following: cured 
basal/squamous cell carcinoma of the skin, excised carcinoma in situ of the cervix. 
A history of prostate cancer that was identified incidentally following 
cystoprostatectomy or cystectomy for bladder cancer is acceptable provided that that 
following criteria are met: Stage T2N0M0 or lower, gleason score ≤7, negative 
margins at surgery, and PSA undetectable after surgery. 


Everolimus-Pazopanib Phase I 
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3.4.16  Liver disease such as chronic cirrhosis, active hepatitis or chronic persistent 
hepatitis 
 
3.4.17  Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
Patients with a known history of impaired fasting glucose or diabetes mellitus 
(DM) may be included, however blood glucose and antidiabetic treatment must be 
monitored closely throughout the trial and adjusted as necessary 
 
3.4.18  Current treatment on another clinical trial within one month prior to dosing. 
 
3.4.19  Pregnant or breastfeeding. Pregnant women are excluded from this study because 
pazopanib and everolimus are agents with the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk of adverse 
events in nursing infants secondary to treatment of the mother with either of these 
agents, breastfeeding should be discontinued if the mother is treated with either 
pazopanib or everolimus. These potential risks may also apply to other agents used 
in this study. 
 
3.4.20  Chronic treatment with systemic corticosteroids or other immunosuppressive agent. 
Topical or inhaled corticosteroids are allowed. 
 
3.4.21  Patient is unable or unwilling to discontinue predefined prohibited medications 
listed in the protocol for 4 weeks of a drug or 5 times the half life of a drug 
(whichever is longer) prior to Visit 1 and for the duration of the study. 
 
3.4.22  Treatment with strong CYP3A4 inhibitors: 
•   Cardiovascular: verapamil and diltiazem 
•   Antibiotics: clarithromycin, telithromycin, troleandomycin, erythromycin 
•   HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, 
lopinavir) 
• Antifungals: itraconzaole, ketoconazole, voriconazole, fluconazole 
• Antidepressants: nefazodone 
 
3.4.23  Other prohibited medications : 
•  Oral hypoglycemics: tolbutamide, chlorpropamide 
•  Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, 
methylergonovine 
•  Neuroleptics: pimozide 
•  Antiarrhythmics: amiodarone, bepridil, flecainide, lidocaine, mexilitine, 
quinidine, propafenone 
•  Immune modulators: cyclosporine, tacrolimus, sirolimus. 
•  Miscellaneous: theophylline, quetiapine, risperidone, tacrine, clozapine, 
atomoxetin 


Everolimus-Pazopanib Phase I 
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3.4.24  Treatment with strong CYP3A4 inducers: 
•   Anticonvulsants: phenytoin, carbemazepine, Phenobarbital, oxcarbazepine 
•   HIV antiretrovirals: efavirenz, nevirapine 
•   Antibiotics: rifampin (rifampicin), rifabutin, rifapentene 
•   Miscellaneous: St. John’s Wort, modafinil, pioglitazone, troglitazone 
 
3.4.25  Patients should not receive immunization with attenuated live vaccines within one 
week of study entry or during study period. Patient should also avoid close contact 
with others who have received live attenuated vaccines. Examples of live attenuated 
vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella and TY21a typhoid vaccines; 
 
3.4.26  Prolongation of corrected QT interval (QTc) > 480 msecs. 
 
3.4.27  History of malabsorption syndrome, disease significantly affecting gastrointestinal 
function or major resection of stomach or small bowel that could interfere with 
absorption, distribution, metabolism, or excretion of study drugs. 
 
3.4.28  Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is 
progressing in severity. Hypothyroidism treated with medication is not excluded if 
TSH is within normal limits. 
 
3.4.29  Any serious and/or unstable pre-existing medical, psychiatric, or other condition 
(including lab abnormalities) that could interfere with subject safety, obtaining 
informed consent or compliance to study procedures. 
 
3.4.30  HIV-positive individuals on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with pazopanib and 
everolimus. In addition, these individuals are at increased risk of lethal 
infections when treated with marrow-suppressive therapy. Appropriate studies 
will be undertaken in participants receiving combination antiretroviral therapy 
when indicated. 
 
3.4.31  Patients unwilling or unable to comply with protocol therapy, tests, and visits, or 
with a history of noncompliance with medical regimens. 
 
3.4.32  Female subjects who are pregnant or lactating are not eligible to participate in this 
study. 
 
 
3.4.32  Male patients whose sexual partner(s) are WOCBP who are not willing to use 
adequate contraception, during the study and for 8 weeks after the end of treatment 
 
 
3.5 
Inclusion of Women, Minorities and Other Underrepresented Populations 
Women, minorities, and other underrepresented populations are all eligible for this trial. 


Everolimus-Pazopanib Phase I 
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Screening for hepatitis B 
 
Prior to randomization/start of everolimus, patients should be tested for hepatitis B viral load and 
serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc Ab. 
 
The management guidelines, in Section 6.2.4 are provided according to the results of the baseline 
assessment of viral load and serological markers for hepatitis B. 
 
Screening for hepatitis C 
 
Patients should be tested for hepatitis C using quantitative RNA-PCR. 
 
The management guidelines, in Section 6.2.4 are provided according to the results of the baseline 
assessment of hepatitis C viral load. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 
occur prior to the initiation of therapy. Any participant not registered to the protocol 
before treatment begins will be considered ineligible and registration will be denied. 
 
 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
 
 
Following registration, participants may begin protocol treatment within 14 days. 
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a participant does not receive protocol therapy following registration, the 
participant’s protocol status must be changed. Notify the QACT Registrar of participant 
status changes as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. In emergency situations when a participant must 
begin treatment during off-hours or holidays, call the QACT registration line at 617- 
632-3761 and follow the instructions for registering participants after hours. 
The registration procedures are as follows: 
1. 
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 


Everolimus-Pazopanib Phase I 
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2. 
Complete  the   protocol-specific  eligibility  checklist  using  the   eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies. 
 
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 617-632-2295. 
 
Exception: DF/PCC Affiliate sites must fax the entire signed consent form 
including HIPAA Privacy Authorization and the eligibility checklist to the 
Network Affiliate Office. The Network Affiliate Office will register the 
participant with the QACT. 
 
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on 
the study, and (c) randomize the participant when applicable. 
 
5. 
The  QACT  Registrar will  send  an  email  confirmation of  the  registration 
and/or randomization to the person initiating the registration immediately 
following the registration and/or randomization. 
 
4.3 
General Guidelines for Other Participating Institutions 
 
 
Eligible participants will be entered on study centrally at Dana-Farber Cancer 
Institute by the Study Coordinator and research Nurse. All sites should call the Study 
Coordinator and research Nurse to verify treatment availability. 
 
Following registration, participants should begin protocol treatment within 72 hours 
or as soon as possible. Issues that would cause treatment delays should be discussed 
with the Principal Investigator. If a participant does not receive protocol therapy 
following registration, the participant’s protocol status must be changed. The Study 
Coordinator should be notified of participant status changes as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from the supplier. A participating site may order the agent(s) only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the supplier. 
 
 
 
5. TREATMENT PLAN 


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Treatment will be administered on an outpatient basis. Expected toxicities and potential 
risks as well as dose modifications for pazopanib and everolimus are described in Section 6 
(Expected Toxicities and Dosing Delays/Dose Modifications). No investigational or 
commercial agents or therapies other than those described below may be administered with 
the intent to treat the participant's malignancy other than described in the 
inclusion/exclusion criteria. 
 
 
Phase I dose escalation schema 
 
Dose Level Pazopanib 
Everolimus 
-1 
400 mg PO QD 
5 mg PO QD 
Starting dose→ 
0 
600 mg PO QD 
5 mg PO QD 
+1 
600 mg PO QD 
10 mg PO QD 
+2 
800 mg PO QD 
10 mg PO QD 
+2A 
800 mg PO QD 
5 mg PO QD 
* Dose level +2A is only to be used if the MTD is exceeded on dose level +2. 
 
5.1 Expansion Cohort 
The dose for the expansion cohort is listed below: 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Pazopanib 
400 mg 
Oral 
Daily 
28 days 
(4 weeks) 
Everolimus 
5 mg 
Oral 
Daily 
 
 
 
 
5.2 
Pre-treatment Criteria 
 
5.2.1 Screening evaluation 
 
Within 28 days prior to start of treatment 
• Complete physical examination 
• Complete medical history and demographics 
• Karnofsky or ECOG performance status 
• Record concomitant medications 
• Disease assessments: Baseline CT or MRI of the abdomen and pelvis and CT or 
X-ray of the chest. In patients with osseous lesions, bone X-rays and/or bone 
scans should be obtained. 
 
Within 14 days prior to start of treatment 
• Evaluation of vital signs including pulse, respiratory rate, body weight, and height 
• Two blood pressure measurements should be taken at least 5 minutes apart 
• Urine beta-HCG pregnancy test for women of childbearing potential 
• Electrocardiogram 


Everolimus-Pazopanib Phase I 
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• Urinalysis, urine protein, and urine creatinine 
• Laboratory assessments. Screening laboratory testing performed within 7 days of 
initiation of study therapy may be used for cycle 1 day 1. 
• Compete blood count with differential and platelets 
• Comprehensive Metabolic Panel including: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, calcium, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, total bilirubin, albumin 
• Magnesium, phosphorus, LDH, amylase, lipase, thyroid stimulating 
hormoneTotal cholesterol ≤300 mg/dL AND fasting triglycerides ≤ 2.5 x 
institutional ULN. 
• Fasting lipid panel 
• Screening for hepatitis C (using quantitative RNA-PCR) and hepatitis B using 
serological markers (HBsAg, HBsAb, and HBcAb) for all patients. 
• Prothrombin time (PT) or international normalized ratio (INR)  2X 
institutional upper limit of normal (ULN) unless patients are on therapeutic 
anticoagulation with warfarin 
• Partial thromboplastin time (PTT)  1.5 X institutional ULN unless patients are 
on therapeutic anticoagulation with warfarin 
 
 
 
5.2.1 
Day 1 every cycle 
 
The following will be undertaken prior to initiating study therapy and on day 1 of 
every subsequent cycle: 
• Vital signs including blood pressure, pulse, respiratory rate and body weight. 
Height will be recorded on cycle 1, day 1 only. 
• Karnofsky or ECOG performance status 
• Complete physical examination and toxicity evaluation (CTCAE v 4.0) 
• Update concomitant medications 
• Compete blood count with differential and platelets 
• Comprehensive Metabolic Panel: sodium, potassium, chloride, bicarbonate, 
BUN, creatinine, calcium, alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase, total bilirubin, albumin 
• Magnesium, phosphorous, LDH, amylase, lipase, thyroid stimulating hormone 
• Fasting lipid panel 
• Urine pregnancy test in women of childbearing potential (at screening and cycle 
1 day 1 only) 
• Urinalysis 
• Urine protein & creatinine 
• EKG (for cycles 1-2 only) 
 
5.2.2 Cycles 1-2 day 15 
The following will be undertaken day 15 of cycles 1 and 2: 


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• 
Vital signs including blood pressure, pulse, respiratory rate, body weight, 
and height 
• 
Karnofsky or ECOG performance status 
• 
Complete physical examination and toxicity evaluation (CTCAE v  4.0) 
• 
Update concomitant medications 
• 
Compete blood count with differential and platelets 
• 
Comprehensive Metabolic Panel: sodium, potassium, chloride, bicarbonate, 
BUN, creatinine, calcium, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, total bilirubin, albumin 
• 
Magnesium, phosphorous, LDH 
 
5.2.4 Every 8 weeks 
 
Radiologic disease evaluation: Radiological assessments include a CT or X-ray of the 
chest and abdominal and pelvic CT or MRI scan. In patients with osseous lesions, bone 
X-rays and/or bone scans should be obtained. Tumor measurements should occur every 
8 weeks (within 7 days prior to day 1 of the subsequent cycle). 
 
5.2.5 End of Study 
 
The following will be undertaken 28 days after last dose of study medication: 
 
•  Vital signs including blood pressure, pulse, respiratory rate, body weight, 
and height 
•  Karnofsky or ECOG performance status 
•  Complete physical examination and toxicity evaluation (CTCAE v 4.0) 
•  Update concomitant medications 
•  Compete blood count with differential and platelets 
•  Comprehensive Metabolic Panel: sodium, potassium, chloride, bicarbonate, 
BUN, creatinine, calcium, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, total bilirubin, albumin 
•  Magnesium, phosphorous, LDH, thyroid stimulating hormone 
•  Fasting lipid panel 
•  Urinalysis 
•  Urine protein & creatinine 
 
This visit can be foregone for patients who are too unwell to attend or for other reasons at 
the investigators discretion. Patients may be contacted thereafter by phone to assess 
resolution of toxicities, and may be contacted for survival follow up. 
 
5.3 
Agent Administration 
Pazopanib and everolimus may be taken at the same time. Patients will be instructed 
to take the everolimus AND Pazopanib at the same time every morning, without food, at 
least one hour before or two hours after a meal. Before discharge from the clinic, subjects 


Everolimus-Pazopanib Phase I 
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will be given a study dosing diary to take home. The subject will be instructed to record 
the date and time that each dose of pazopanib and everolimus is self administered. Study 
diaries will be reviewed and collected at each visit during the remainder of the study. 
 
5.3.1 Pazopanib 
 
Pazopanib will be self administered (by the patients themselves). Pazopanib will be 
administered orally as once daily dose continuously from study day 1 until progression 
of disease or unacceptable toxicity. Pazopanib should be taken orally without food at 
least one hour before or two hours after a meal. The tablets should be swallowed whole 
and must not be crushed or broken. The time of day the tablets are taken should be 
relatively constant. Dietary habits around the time of pazopanib intake should be as 
consistent as possible throughout the study. If a dose is missed, the subject should take 
the dose as soon as possible, but not if there are less than 12 hours before the next dose 
is due. If the next dose is due in less than 12 hours, the subject should skip the missed 
dose and take the next dose as scheduled. 
 
If vomiting occurs after taking pazopanib, another dose is not permitted on that day. 
The subject should resume taking pazopanib at the next scheduled dose.  If vomiting 
persists, the subject should be instructed to notify the investigator. 
 
5.3.2 Everolimus 
 
Dosing regimen 
 
The investigator should promote compliance by instructing the patient to take the study 
drug exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the 
investigator if he/she is unable for any reason to take the study drug as prescribed. 
Everolimus should be administered orally once daily at the same time every day, without 
food, at least one hour before or two hours after a meal, at the same time as the 
Pazopanib. If a dose is missed, the subject should take the dose as soon as possible, but 
not if there are less than 12 hours before the next dose is due. If the next dose is due in 
less than 12 hours, the subject should skip the missed dose and take the next dose as 
scheduled. 
 
Tablets 
 
The tablets should be swallowed whole with a glass of water and should not be chewed 
or crushed. For patients unable to swallow tablets, the tablet(s) should be dispersed 
completely in a glass of water (containing approximately 30 mL) by gently stirring, 
immediately prior to drinking. The glass should be rinsed with the same volume of water 
and the rinse completely swallowed to ensure the entire dose is administered. 
 
If vomiting occurs, no attempt should be made to replace the vomited dose. 
 
5.4 
Definition of Dose-Limiting Toxicity 


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5.4.1 Dose escalation rules 
 
General rules: 
• Initial dose is dose level 0 for this trial 
• All patients in a dose cohort will complete 28 days (1 cycle) of combination treatment 
prior to the treatment of any patient at a higher dose level. 
• If a patient does not complete the 28 days of treatment for reasons that are clearly not 
adverse events related to treatment, then that patient will be replaced, up to three per 
dose level. 
• If more than three patients need to be replaced on a dose level, then the reasons will 
be re-evaluated before continuing. 
• There will be no intrapatient dose escalation. 
• To determine that a subject has received study treatment without experiencing DLT, 
the subject must have missed no more than 5 days of dosing during cycle 1, either 
nonconsecutively or consecutively. 
 
Pazopanib and everolimus doses will be escalated according to the following standard 
3+3 dose escalation rules: 
 
1. If 0 of 3 patients in a cohort experience dose limiting toxicities, then the next cohort of 
3 patients will be treated at the next higher dose level. 
 
2. If 1 of 3 patients in a cohort experiences a DLT then the cohort will be expanded to 
treat an additional three patients. If only one of 6 patients experiences a DLT, then the 
next cohort of patients will be treated at the next higher dose level. 
 
3. If two or more patients in a cohort experience a DLT, then the MTD has been 
exceeded. The previous dose level will be considered the MTD. If only 3 patients were 
treated at the previous dose level, an additional three patients will be treated at that dose 
level to confirm the MTD. 
 
4. If the doses of both drugs are escalated to dose level 2 with 0 of 3 or 1 out of 6 patients 
experiencing a DLT, then this will be considered the recommended Phase II dose 
(RP2D) for the expansion cohort. 
 
5. If the MTD is exceeded on dose level 0, then a de-escalation cohort to dose level -1 
will be enrolled. Up to six patients will be treated at this dose level. If one or fewer of 
six patients experiences a DLT, then this will be the RP2D. If two or more patients 
experience a DLT on dose level -1, then the combination will be deemed not feasible 
and the study will be closed. 
 
6. If the MTD is exceeded on dose level 2, then a de-escalation level will be accrued 
(dose level 2A). If 0 of 3 or 1 out of 6 patients experience a DLT on dose level 2A, 


Everolimus-Pazopanib Phase I 
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then this will be considered the RP2D for the expansion cohort. If the MTD is 
exceeded on dose level 2A, then dose level 1 will be the RP2D. 
 
5.4.2 Definition of a DLT 
 
Dose-limiting toxicity (DLT) is based on the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE v4.0). 
 
 
For the purposes of Phase I dose escalation, a DLT will be defined as toxicity occurring 
within the first 28 days of combination therapy related to therapy that meets the criteria 
spelled out below: 
 
1.   Grade 3 or 4 non-hematologic toxicity excluding: 
 
•  Toxicity attributed to underlying malignancy 
 
•  Nausea/vomiting controlled with antiemetics 
 
•  Grade 3 hypertension that resolves to ≤150/90 within 7 days of adjustment or 
addition of oral blood pressure medications. 
 
a.   Hypertension   that   requires   admission   to   the   hospital   or   intravenous 
medication for control will be considered a DLT. 
 
b.   Grade  3  or  greater  hypertension that  does  not  respond  to  adjustment  or 
addition of oral blood pressure medicines to ≤150/90 within 7 days from 
blood pressure medication modification will be considered a DLT. 
 
•  Grade 3 asymptomatic, clinically insignificant laboratory abnormalities, including 
LDH, alkaline   phosphatase   due   to   bone   metastases,   and   asymptomatic 
hypophosphatemia 
 
2.   Hematologic toxicity defined as: 
 
1. 
Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding 
 
2. 
Grade 4 neutropenia which persists for >7 days 
 
3. 
Grade 4 neutropenia associated with fever >38.5C 
 
4. 
Excludes lymphopenia or anemia of any grade 
 
3.   Removal of a patient from therapy due to toxicity attributable to treatment 
 
4.   Patients who miss more than 5 days of the planned doses for drug-related intolerable 
grade 2 toxicity will be considered to have experienced a DLT. During cycle 1, 
patients who miss fewer than 5 days of dosing for drug-related toxicities that do not 
immediately meet the criteria for DLT must recover to </= grade 1 within two weeks, 
or they will be considered to have experienced DLT. 
 
5.   Toxicity related to therapy severe enough to require a dose-reduction 
 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). 


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5.5 
General Concomitant Medication and Supportive Care Guidelines 
5.5.1 Patients should receive full supportive care, including analgesic medication, 
transfusions of blood and blood products, antibiotics, antiemetics, etc., when 
appropriate. Although acetaminophen at doses of 2 g/day is permitted, it should be 
used with caution in subjects with impaired liver function. Anti-diarrheals, such as 
loperamide, may be administered as needed in the event of diarrhea. The reason(s) for 
treatment, dosage, and the dates of treatment should be recorded in the medical record. 
 
5.5.2 Palliative radiation therapy may not be administered while the patient is on study 
treatment. A symptomatic lesion or one which may produce disability (e.g., unstable 
femur) may be irradiated before study initiation, provided other measurable or 
evaluable disease is present and radiation therapy is completed ≥ 4 weeks before start 
of therapy. All eligibility criteria for progression must still be met. Any other 
indications for radiotherapy after protocol treatment has begun will constitute disease 
progression, and the patient will stop protocol treatment. 
 
5.5.3 Erythropoetin/ Darbepoetin: Use of erythropoietin or darbepoetin in this protocol is 
permitted at the discretion of the treating physician after cycle 1 (ie., after the DLT 
determination period). 
 
5.5.4 Filgrastim (G-CSF), pegfilgrastim, and sargramostim (GM-CSF) after cycle 1 (ie. 
After the DLT determination period) 
1. Filgrastim/pegfilgrastim and sargramostim should not be used to avoid dose 
reductions. 
2. Filgrastim, pegfilgrastim, or sargramostim, may be used for secondary prophylaxis 
following an episode of febrile neutropenia. 
3. For the treatment of febrile neutropenia, the use of CSF's should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSF's 
may be indicated in patients who have prognostic factors that are predictive of 
clinical deterioration such as pneumonia, hypotension, multi-organ dysfunction 
(sepsis syndrome) or fungal infection, as per the ASCO guidelines. Investigators 
should therefore use their own discretion in using the CSF's in this setting. The use 
of CSF (filgrastim, pegfilgrastim or sargramostim) must be documented and 
reported in the medical record. 
4. If filgrastim, pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
 
 
5.5.5 Drug Interactions 
 
 
Because there is a potential for interaction of pazopanib and Everolimus with 
other concomitantly administered drugs through the cytochrome P450 system, the 
case report form must capture the concurrent use of all other drugs, over-the- 
counter medications, or alternative therapies. The Principal Investigator (or 


Everolimus-Pazopanib Phase I 
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Protocol Chair) should be alerted if the participant is taking any agent known to 
affect or with the potential to affect selected CYP450 isoenzymes. 
 
 
5.5.5.1 Permitted Medications 
 
All subjects will be asked to provide a complete list of prescription and over-the- 
counter medications that have been taken within the 4 weeks prior to screening. The 
investigator must be informed as soon as possible about any new medication(s) taken 
from the time of screening until the completion of the post-treatment follow-up visit. 
All concomitant medications taken during the study will be recorded in the case report 
form (CRF) with indication, dose information, and dates of administration. 
 
5.5.5.2 Permitted Medications – Use with Caution 
 
• Specific recommendations regarding anticoagulants: 
Results from drug-drug interaction studies conducted in subjects with cancer 
suggest that pazopanib has no effect on the metabolism of S-warfarin. 
Hemorrhagic events, however, have been reported in clinical studies with 
pazopanib; therefore, pazopanib should be used with caution in subjects with 
increased risk of severe bleeding or who are receiving concomitant anticoagulant 
therapy (e.g., warfarin or its derivatives, low molecular weight heparin, 
unfractionated heparin). Subjects taking concomitant anticoagulant therapy 
should be monitored regularly for changes in relevant coagulation parameters as 
clinically indicated, as well as for any clinical bleeding episodes. 
 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no 
interaction with everolimus is expected. However, drug-drug interaction studies 
between macrolide antibiotics and warfarin have produced mixed outcomes and 
the disparity in these findings has led to the conclusion that multiple factors may 
alter the clearance of warfarin. The co-administration of everolimus and oral 
anticoagulants is possible but should be subject to verification of coagulation 
(INR) once steady state is reached (after one week’s treatment). 
 
• Specific recommendations regarding hypoglycemic therapy including insulin: 
Results from drug-drug interaction studies conducted in subjects with cancer 
suggest that there will be no clinically relevant pharmacokinetic interaction 
between pazopanib and hypoglycemic agents. Transient decreases in serum 
glucose (mainly Grade 1 and 2, rarely Grade 3) have been observed in clinical 
studies with pazopanib. In addition, decreases in blood sugar have been recently 
reported in subjects treated with another small molecule tyrosine kinase inhibitor, 
sunitinib (British Journal of Cancer 2008: 99, 1380).  Such changes may require 
an adjustment in the dose of hypoglycemic and/or insulin therapy. Subjects 
should be advised to report symptoms of hypoglycemia (e.g., confusion, visual 
disturbances, palpitations, sweating). Serum glucose should be tested during 
treatment with pazopanib as outlined in the protocol and as clinically indicated. 


Everolimus-Pazopanib Phase I 
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• Specific recommendations regarding oral hypoglycemics: Co-administration of 
pazopanib with some oral hypoglycemics, including glipizide, glyburide 
(glibenclamide), glimepiride, nateglinide, repaglinide, gliclazide, acetohexamide, 
carbutamide, glibornuride, glymidine, metahexamide, and tolazamide, may result in 
an increase in plasma concentrations of the oral hypoglycemic agent. This increase 
may result in hypoglycemia. Therefore, the dose of the oral 
hypoglycemic agent should be reduced by 50% when pazopanib administration 
starts. The blood glucose should be monitored closely, and the subject should be 
instructed to measure their blood glucose if they experience symptoms of 
hypoglycemia and inform their physician if their blood glucose concentration is 
low. After at least 14 days of pazopanib administration, the dose of the oral 
hypoglycemic agent may be increased as necessary to maintain adequate blood 
glucose control. 
 
• The Effects of Pazopanib on Other Drugs 
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, 
CYP2C8, CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and 
CYP2E1.  Pregnane X receptor transient transfection assay suggested some 
potential for human CYP3A4 induction at high concentrations. Results from 
drug-drug interaction studies conducted in subjects with cancer suggest that 
pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but 
had no clinically relevant effect on CYP1A2, CYP2C9 or CYP2C19 metabolism. 
Therefore, concomitant use of pazopanib with certain medications (substrates of 
CYP3A4, CYP2C8, and CYP2D6) with a narrow therapeutic window should be 
undertaken with CAUTION due to the potential for alterations in the 
pharmacologic effects of these medications or an increased risk for serious or life 
threatening adverse events associated with such medications (see below) 
secondary to the inhibition of specific CYP enzymes by pazopanib. In addition, 
the potential for drug interaction with such medications, although diminished, 
may persist after the last dose of pazopanib due to its long half-life (i.e., mean 
30.9 hours); therefore, continue to exercise CAUTION for at least 7 days and up 
to 15 days after the last dose of pazopanib when administering these medications. 
These medications include (but are not limited to): 
• 
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, 
methylergonovine (potential increased risk for developing ergot toxicity 
that includes severe vasospasm leading to peripheral as well as cerebral 
ischemia) 
• 
Neuroleptics: pimozide (potential increased risk for QT interval 
prolongation, ventricular arrhythmia, and sudden death) 
• 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, 
quinidine, propafenone (potential increased risk for QT interval 
prolongation and Torsade de Pointes) 
• 
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential 
increased risk for nephrotoxicity and neurotoxicity) 


Everolimus-Pazopanib Phase I 
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• 
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
 
• The Effects of Other Drugs on Pazopanib and Everolimus 
Results from in vitro studies suggest that the oxidative metabolism of pazopanib 
in human liver microsomes is mediated primarily by CYP3A4, with minor 
contributions from CYP1A2 and CYP2C8.  Furthermore, in vitro data suggest 
that pazopanib is a substrate for p-glycoprotein. Substances that induce or inhibit 
CYP3A4 may alter the pharmacologic effects of pazopanib and should be used 
with CAUTION.  Competitive inhibition could occur when everolimus is 
combined with drugs which are also CYP3A4 substrates. Therefore caution should 
be exercised in such cases. 
 
1.   Concurrent administration of everolimus and moderate CYP3A4 inhibitors (such 
as erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and 
moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) 
should also be avoided if possible, or used subject to caution (e.g. increased 
frequency of safety monitoring, temporary interruption of everolimus). 
2.   Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein 
activity and should therefore be avoided. In addition, patients should avoid Seville 
oranges and star fruit, as well as the juice of these fruits, which are potent 
CYP3A4-inhibitors. 
 
 
5.5.5.3 Prohibited Medications 
 
 
Participants must be instructed not to take any medications (over-the-counter or 
other products) during the protocol treatment period without prior consultation with 
the investigator. The investigator should instruct the participant to notify the study 
site about any new medications he/she takes after the start of study drug. All 
medications (other than study drug) and significant non-drug therapies (including 
physical therapy and blood transfusions) taken within 28 days of starting study 
treatment through the 30-day safety follow up visit should be reported on the CRF. 
 
• Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, 
radiation, or hormonal (other than leuprolide or other GnRH agonists)] while on 
treatment in this study. 
 
• No chronic treatment with systemic steroids or other immunosuppressive agents 
are allowed. Topical or inhaled corticosteroids are allowed. 
 
• Medications that inhibit strongly CYP3A4 may result in increased plasma 
pazopanib and everolimus concentrations. Selection of an alternate concomitant 
medication with no or minimal potential to inhibit CYP3A4 is required. Strong 
CYP3A4 inhibitors which are prohibited include: 


Everolimus-Pazopanib Phase I 
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•   Antibiotics: clarithromycin, telithromycin, troleandomycin 
•   HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, 
amprenavir, lopinavir) 
•   Antifungals: itraconzaole, ketoconazole, voriconazole, fluconazole 
Antidepressants: nefazodone 
 
• Specific recommendation regarding non-dihydropyridine calcium channel 
blockers (verapamil and diltiazem): co-administration of pazopanib with 
calcium channel blockers may result in increased plasma concentrations of the 
calcium channel blocker. Non-dihydropyridine calcium channel blockers, 
verapamil and diltiazem, have potential depressive effects on cardiac conduction 
and contractility. When pazopanib therapy is initiated, the administration of an 
anti-hypertensive or anti-anginal agent other than verapamil and diltiazem is 
recommended in the setting of a prolonged PR interval (greater than 200 msec), 
sinus bradycardia (less than 60 beats per minute), or second or third degree heart 
block, unless the subject has a permanent pacemaker. 
 
• Strong CYP3A4 inducers may decrease plasma pazopanib concentrations. 
Selection of an alternate concomitant medication with no or minimal enzyme 
induction potential is required. Drugs that induce CYP3A4 and may decrease 
pazopanib and everolimus plasma concentrations include (but are not limited 
to): 
• 
Glucocorticoids: cortisone (>50 mg), hydrocortisone (>40 mg), prednisone 
(>10 mg), methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
• 
Anticonvulsants: phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
• 
HIV  antivirals: efavirenz, nevirapine 
• 
Antibiotics: rifampin (rifampicin), rifabutin, rifapentene 
• 
Miscellaneous: St. John’s Wort, modafinil, pioglitazone, troglitazone 
 
Everolimus may affect the response to vaccinations making the response to the 
vaccination less effective. Live vaccines should be avoided while a patient is 
treated with everolimus. 
 
Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during 
treatment with everolimus may therefore be less effective. The use of live vaccines 
should be avoided during treatment with everolimus Examples of live vaccines are: 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, 
varicella, and TY21a typhoid vaccines. 
 
 
5.6 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, 
treatment may continue until one of the following criteria applies: 


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• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Participant decides to withdraw from the study, or 
• General or specific changes in the participant's condition render the 
participant unacceptable for further treatment in the opinion of the 
treating investigator. 
 
5.7 
Duration of Follow Up 
Participants will be followed for 30 days after treatment discontinuation or until 
death, whichever occurs first. Participants removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. Patients may 
be contacted thereafter by phone to assess resolution of toxicities, and may be contacted 
for survival follow up. 
 
5.8 
Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in 
Section 5.6 applies. The reason for study removal and the date the participant 
was removed must be documented in the study-specific case report form 
(CRF). Alternative care options will be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating 
investigators must immediately notify the Principal Investigator, Dr. Mark 
Pomerantz, at (617) 632-6328 or (617) 632-3353 (page operator). 
 
 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS Dose 
delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using NCI Common Terminology Criteria for Adverse Events (CTCAE 
v4.0) which is available at http://ctep.cancer.gov/reporting//ctc.html). 
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
 
Phase I Dose Escalation Cohort: 
 
Individual patient dose reductions for toxicity will be determined by initial starting dose level 
in the Phase I dose escalation cohort. 


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For patients on dose level -1 there will be 1 dose reduction allowed: 
 
 
 
Dose Level 
Pazopanib 
Everolimus 
Starting dose level -1 
400 mg PO QD 
5 mg PO QD 
1st dose reduction 
200 mg PO QD 
5 mg PO QOD 
 
If a patient on dose level -1 requires more than one dose reduction, then the patient will stop 
study therapy 
 
For patients on dose level 0 there will be only one dose reduction: 
Dose Level 
Pazopanib 
Everolimus 
Starting dose level 0 
600 mg PO QD 
5 mg PO QD 
1st dose reduction 
400 mg PO QD 
5 mg PO QOD 
If a patient on dose level 0 requires more than one dose reduction, then the patient will stop study 
therapy. If a patient has pneumonitis related to everolimus, then pazopanib dose level may be 
maintained and everolimus dose reduced or discontinued (see Table 6.2.3). 
 
 
For patients on dose level +1 there will be 2 dose reductions allowed: 
Dose Level 
Pazopanib 
Everolimus 
Starting dose level +1 
600 mg PO QD 
10 mg PO QD 
1st dose reduction 
400 mg PO QD 
5 mg PO QD 
2nd dose reduction 
200 mg PO QD 
5 mg PO QOD 
 
If a patient on dose level +1 requires more than 2 dose reductions, then the patient will stop study 
therapy. If a patient has pneumonitis related to everolimus, then pazopanib dose level may be 
maintained and everolimus dose reduced or discontinued (see Table 6.2.3). 
 
 
For patients on dose level +2 there will be 2 dose reductions allowed: 
Dose Level 
Pazopanib 
Everolimus 
Starting dose level +2 
800 mg PO QD 
10 mg PO QD 
1st dose reduction 
600 mg PO QD 
5 mg PO QD 


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2nd dose reduction 
400 mg PO QD 
5 mg PO QOD 
 
If a patient on dose level +2 requires more than 2 dose reductions, then the patient will stop study 
therapy. If a patient has pneumonitis related to everolimus, then pazopanib dose level may be 
maintained and everolimus dose reduced or discontinued (see Table 6.2.3). 
 
 
For patients on dose level +2A there will be 2 dose reductions allowed: 
Dose Level 
Pazopanib 
Everolimus 
Starting dose level 
+2A 
800 mg PO QD 
5 mg PO QD 
1st dose reduction 
600 mg PO QD 
5 mg PO QOD 
2nd dose reduction 
400 mg PO QD 
discontinue 
If a patient on dose level +2A requires more than 2 dose reductions, then the patient will stop study 
therapy. If a patient has pneumonitis related to everolimus, then pazopanib dose level may be 
maintained and everolimus dose reduced or discontinued (see Table 6.2.3). 
 
Phase I expansion cohort: 
 
Individual patient dose reductions for toxicity will be determined by initial starting dose level 
in the Phase I expansion cohort which was dose level -1 as per results of the first phase of the 
study. 
 
 
 
For patients on dose level -1 there will be 1 dose reduction allowed: 
 
 
Table 6 Dose Expansion cohort: Dose levels. 
 
Dose Level 
Pazopanib 
Everolimus 
Starting dose level -1 
400 mg PO QD 
5 mg PO QD 
1st dose reduction 
200 mg PO QD 
5 mg PO QOD 
If a patient on dose level -1 requires more than one dose reduction, then the patient will stop 
study therapy. If, however, a patient is deriving benefit from one agent, as displayed by stable 
disease or better at restaging, and cannot tolerate the other, the patient may continue on 
monotherapy of the tolerated agent after discussion with the overall PI, Mark Pomerantz, MD. If 
one agent is discontinued for toxicity, a patient may dose-increase to the standard monotherapy 
dose (see Table 7) of the other agent after discussion with the overall PI. 
 
 
Table 7 Standard Monotherapy Dose Levels 
Dose Level 
Pazopanib 
Everolimus 


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Dose level when other 
agent is discontinued 
due to toxicity 
800 mg PO QD 
10 mg PO QD 
 
 
 
If a patient has pneumonitis related to everolimus, then pazopanib dose level may be maintained 
and everolimus dose reduced or discontinued (see Table 6.2.3). 
 
6.1 Anticipated Toxicities 
 
6.1.1 Everolimus 
 
Adverse events most frequently observed with everolimus are rash, stomatitis/oral mucositis, 
fatigue, headache, anorexia, nausea, vomiting, diarrhea. Infections have not been notably 
frequent or severe. Non-infectious pneumonitis has also been observed. The majority of these 
AEs have been of mild to moderate severity (CTC grade 1-2). Overall, the most frequently 
observed laboratory abnormalities include reduced blood counts, hyperlipidemia mostly 
reported as hypercholesterolemia and/or hypertriglyceridemia. 
 
Hyperlipidemia was reported as a serious adverse reaction. It is a recognized side-effect of 
rapamycins. Use of lipid-lowering drugs should be associated with dietary recommendations. 
Monitoring of blood lipid levels requires patients to be fasting so that this aspect must be 
verified when interpreting results. 
 
Hyperglycemia was reported as a serious adverse reaction. Similarly, the fasting state of 
patients should be verified when interpreting results. 
 
Pneumonitis is a recognized adverse effect of rapamycins (sirolimus, temsirolimus, and 
everolimus). Numerous case reports in the literature suggest that rapamycin-associated 
pneumonitis is relatively unaggressive, limited in extent, and reversible upon drug 
discontinuation. The term ‘pneumonitis’ is used here to describe non-infectious, nonmalignant 
infiltration in the lungs which is evident radiologically. More precise diagnosis should follow 
histocytological examination following lung biopsy, generally during bronchoscopy which 
may or may not be symptomatic. Advice on the management of pneumonitis has been 
provided in Table 6.2.3. In oncology studies with everolimus, severe pneumonitis suspected as 
drug-related has been reported as a serious adverse event on 13 occasions and additionally in 
the following associated preferred terms including acute respiratory distress syndrome (n=2), 
alveolitis (n=1) and allergic alveolitis (n=1), interstitial lung disease (n=10), lung infiltration 
(n=23), cryptogenic organizing pneumonia, lung consolidation, pulmonary alvealoar 
haemorrhage, pulmonary toxicity and pulmonary fibrosis (n=1, each). One fatal case of drug-
related pneumonitis was reported for a patient with metastatic infiltrating ductal carcinoma of 
the breast treated with 10 mg/day, which 
developed approximately two months after starting everolimus. Cytology for both the pleural 
and pericardial fluids were positive for malignancy. The death was considered possibly related 
to the underlying late stage tumor and study drug. Additionally, one patient treated 


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with 10 mg/day died due to severe acute respiratory distress syndrome and septic shock. 
Thoracic CT scan demonstrated condensation in the majority of the left lower lobe and 
frosted glass appearance in the left upper lobe, lingula, and right lung. Along with the cases 
of non-infectious pneumonitis, serious opportunistic infections have also been reported in 
cancer patients treated with everolimus: mycobactrium, aspergillus, and fatal candidal sepsis, 
and fatal pneumocystis carnii in particular. Because everolimus, as other rapamycins, inhibits 
proliferation of activated lymphocytes and reduces neutrophil counts, treatment with 
everolimus must be considered as predisposing patients to the risk of infection. This risk will 
be higher in patients severely immunocompromised because of their underlying disease and/or 
co-medications. Outcome may be fatal in case of serious infections. 
 
A reduction in blood cell counts is frequent when everolimus therapy is initiated. Without 
clinical significance and infrequently, anemia and thrombocytopenia have been reported. In 
heavily pretreated patients with aggressive lymphoma, the incidence of grade 3 anemia, 
neutropenia, and thrombocytopenia was reported to be 11%, 16%, and 30%, respectively. 
Serious, suspected drug-related hemorrhages have been exceptional. Nevertheless, 
everolimus should be considered as predisposing patients to hemorrhage, potentially fatal, 
should they develop severe drug-related thrombocytopenia. 
 
Discrete, reversible changes in liver enzymes have been found to occur in numerous patients 
during treatment with everolimus in oncology clinical studies, and in a study in rheumatoid 
arthritis. In oncology studies, these changes may be evident only in patients without severe 
underlying morbidity. The increase in transaminase’s (AST and ALT) generally appears after 
4 weeks of treatment. In all but a few cases it does not exceed Grade 1 (≤ 2.5 x institution 
ULN). 
 
Similarly, mild increases in alkaline phosphatases can coexist. Spontaneous corrections or 
intermittent correction with continued treatment can occur. Serum bilirubin is not increased. 
In studies of patients with advanced cancers, clinically relevant changes in liver enzymes 
have been invariably associated with the presence of liver metastases and/or progression of 
the underlying cancer. 
 
Renal failure has been reported in five suspected cases to date. One patient with no 
alternative explanation made a complete recovery following study drug adjustment and no 
treatment/therapy for the event. The rest or the patients had concurrent morbidities, which 
might have contributed to the reported events. 
 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been reported 
as serious adverse reactions. Electrolytes should be monitored in patients treated with 
everolimus. 
 
6.1.2 Pazopanib 
 
The most common adverse events (AEs) reported to date include diarrhea, fatigue, nausea, 
hypertension, hair color changes (hair depigmentation), anorexia, vomiting, dysgeusia, 


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headache, abdominal pain, rash, aspartate aminontransferase (AST) and alanine 
aminontransferase (ALT) increases, constipation, cough, and arthralgia. Most of these events 
were Grade 1 or 2 using the NCI Common Terminology Criteria for Adverse Events Version 
4.0 (NCI-CTCAE). The most frequent Grade 3 or 4 events were hypertension, fatigue, 
diarrhea, and AST and ALT increases. Less common AEs of note include hand-foot 
syndrome, mucositis/stomatitis, proteinuria, venous thrombotic events, and bleeding. 
Intestinal perforations and arterial thromboses were uncommon. 
 
The most common serious adverse events (SAEs) occurring in subjects enrolled in pazopanib 
studies regardless of treatment assignment include vomiting, diarrhea, abdominal pain, 
hypertension/hypertensive crisis, dyspnea, pleural effusion, pyrexia, anemia, dehydration, 
and pulmonary embolism. 
 
Evaluation of the safety and efficacy of pazopanib in advanced RCC subjects include a 
recently completed Phase II study in subjects with advanced RCC, and a Phase III 
randomized, double-blind study against placebo which completed enrolment in April, 2007 
and is currently on-going. To date, 660 subjects with advanced/metastatic RCC have been 
enrolled in these two clinical trials. Safety data from the Phase II RCC trial VEG102616 
(n=225) are summarized here. The most common AEs (defined as AEs experienced by ≥10% 
of subjects) regardless of causality in decreasing order of frequency were diarrhea (63%), 
fatigue (46%), hair color change (43%), nausea (42%), hypertension (41%), anorexia (24%), 
dysgeusia (24%), vomiting (20%), headache (20%), cough (17%), abdominal pain (16%), 
rash (16%), constipation (15%), ALT elevation(14%), arthralgia (13%), AST elevation 
(12%), back pain (12%), dizziness (12%), handfoot syndrome (11%), alopecia, (10%), 
dyspepsia (10%), and peripheral edema (10%). The majority of these events were Grade 1 
and 2 with hypertension being observed in 9% of subjects as a Grade 3 event. 
 
The most common hematological toxicities of any grade (graded according to NCI-CTCAE) 
include lymphopenia (47%), thrombocytopenia (28%), neutropenia (23%), and anemia (26%) 
with combined Grade 3 and 4 abnormalities occurring in 7%, 3%, <1%, and 4% of subjects, 
respectively. The most common chemistry abnormality was hyperglycemia, observed in 46% 
of subjects (of which 2% were Grade 3 and no Grade 4). Hyponatremia of any grade was 
observed in 37% of subjects, with Grade 3 or Grade 4 hyponatremia in 8% of subjects. 
Hyperkalemia of any grade was reported in 27% of subjects, with Grade 3 or 4 hyperkalemia 
in 5% of subjects. Hyponatremia and hyperkalemia have not occurred concurrently in the same 
subject to indicate adrenal insufficiency. Elevations in amylase and lipase of any grade were 
reported in 23% and 27% of subjects, respectively, with Grade 3 or Grade 4 events in 
4% and 9% of subjects, respectively. There were 2 reports of pancreatitis. Increase in TSH 
was reported in 28% of subjects and a decrease in thyroxine (T4) in 1% of subjects. Three 
subjects initiated treatment with thyroid replacement therapy (synthroid or levothyroxine) 
during the study. 
 
ALT elevations of any Grade were reported in 53% of subjects with Grade 3 and Grade 4 
elevations in 9% and <1% of subjects, respectively. AST elevations were reported in 53% of 
subjects with Grade 3 and Grade 4 elevations in 5% and <1% of subjects, respectively. 


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Hyperbilirubinemia of any Grade occurred in 28% of subjects with Grade 3 elevations in 
<1% of subjects. No Grade 4 elevations have been reported. Concomitant elevations in 
transaminases and bilirubin have been observed in 2 (<1%) subjects. Neither of these patients 
met the criteria for Hy’s rule. Risk factors that may have contributed to the liver dysfunction 
were identified in the some of these subjects, (e.g., large mass at the porta hepatis, 
hepatotoxic concomitant medications). Liver enzyme elevations were reversible upon dose 
interruption. Two patterns of transaminase changes have been observed: 
(1) transaminase elevations that declined over time without dose interruption. 
(2) transaminase elevations that declined over time upon dose interruption. In some subjects, 
elevations in transaminase recurred upon rechallenging and these subjects were permanently 
discontinued from study treatment. 
 
Serial adrenocorticotropic hormone (ACTH) stimulation tests were conducted in two Phase I 
and two Phase II trials in cancer subjects with data available in 47 subjects. Twenty-one of 
them had data beyond 24 weeks and 5 subjects had data beyond 52 weeks. None of these 47 
subjects had adrenal insufficiency. 
 
Certain uncommon AEs with significant clinical consequences reported in pazopanib clinical 
trials (denominator for total subject enrolment n=1000 used for calculating frequency) 
include pulmonary embolism (0.6%), venous thrombosis (0.3%), venous thrombosis and 
pulmonary embolism (0.2%), serious hemorrhage (1.4%), bowel perforation (0.5%), 
myocardial infarction/angina (0.7%), cerebrovascular accidents/transient ischemia (0.6%), 
cardiac failure (0.2%), atrial fibrillation (0.3%), renal failure (0.8%) and seizures (0.3%) 
 
6.2 Toxicity Management 
 
All toxicities, both during and after the DLT-determining period will follow the guidelines laid 
out here in sections 6.2 and 6.3. 
For definition of a DLT, refer back to section 5.4. 
 
6.2.1 Management of stomatitis/oral mucositis/mouth ulcers 


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Adverse Drug Reaction 
Severity 
Everolimus Dose Adjustment and Management 
Recommendations 
Stomatitis 
Grade 1 
No dose adjustment required. 
Manage with non-alcoholic or salt water (0.9%) mouth 
wash severaltimes a day. 
Grade 2 
Temporary dose interruption until recovery to grade ≤1. 
Re-initiate everolimus at same dose. 
If stomatitis recurs at grade 2, interrupt dose until recovery 
to grade ≤1. Re-initiate everolimus at lower dose. 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine,butyl aminobenzoate, tetracaine hydrocholoride, 
methol or phenol)with or without topical corticosteroids 
(i.e. triamcinolone oral paste)*. 
Grade 3 
Temporary dose interruption until recovery to grade ≤1. 
Re-initiate everolimus at lower dose. 
Manage with topical analgesic mouth treatments (i.e. 
benzocaine,butyl aminobenzoate, tetracaine hydrocholoride, 
methol or phenol) with or without topical corticosteroids 
(i.e. triamcinolone oral paste)* 
Grade 4 
Discontinue everolimus and treat with appropriate medical 
therapy. 
* using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as they 
may worsen mouth ulcers. 
 
 
 
 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local 
supportive care. Investigators in earlier trials have described the oral toxicities associated 
with everolimus as mouth ulcers, rather than mucositis or stomatitis. If the examination 
reveals mouth ulcers rather than a more general inflammation of the mouth, the adverse 
event should be classified as mouth ulcers. Please follow the paradigm below for 
treatment of stomatitis/oral mucositis/mouth ulcers: 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth 
wash or salt water (0.9%) mouth wash several times a day until resolution. 
2. For more severe toxicity (Grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or Grade 3 in which case patients cannot maintain 
adequate oral alimentation), the suggested treatments are topical analgesic mouth 
treatments (i.e., local anesthetics such as benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenol) with or without topical 
corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) 
should be avoided in all patients due to their strong inhibition of everolimus 
metabolism, thereby leading to higher everolimus exposures. Therefore, topical 


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antifungal agents are preferred if an infection is diagnosed. Similarly, antiviral agents 
such as acyclovir should be avoided unless a viral infection is diagnosed. 
 
Note: Stomatitis/oral mucositis should be appropriately graded using the functional 
grading given on the NCI-CTC for adverse events, CTCAE v 4.0.  Dose reductions are 
made according to section 6.3.1 (Non-hematological toxicity) and Section 6.3.3. 
 
6.2.2 Management of hyperlipidemia & hyperglycemia 
 
 
 
Adverse Drug Reaction 
Severity 
Everolimus Dose Adjustment and Management 
Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
 
 
 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and monitor. 
Grade 3 
Temporary dose interruption. 
Re-initiate everolimus at lower dose. 
Manage with appropriate medical therapy and monitor. 
Grade 4 
Discontinue everolimus and treat with appropriate 
medical therapy. 
 
 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits 
of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 
hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 3-hydroxy-3- 
methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, fluvastatin) or 
appropriate triglyceride-lowering medication, in addition to diet. 
 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with 
an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, 
markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, acute renal failure 
and sometimes death. The risk versus benefit of using this therapy should be determined for 
individual patients based on their risk of cardiovascular complications of hyperlipidemia. 
 
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in 
patients taking everolimus. Monitoring of blood cholesterol and triglycerides prior to the start of 
everolimus therapy and periodically thereafter as well as management with appropriate medical 
therapy is recommended. 
 
Hyperglycemia has been reported in patients taking everolimus. Monitoring of fasting serum 
glucose is  recommended prior to  the  start of  everolimus and  periodically thereafter. More 
frequent monitoring is recommended when everolimus is co-administered with other drugs that 
may induce hyperglycemia. Optimal glycemic control should be achieved before starting a 
patient on everolimus. 


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6.2.3 Management of non-infectious pneumonitis 
 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious 
pneumonitis (grade 2 = not interfering with activities of daily living or grade 3 = 
interfering with activities of daily living and oxygen indicated) have been noted in patients 
receiving everolimus therapy. Non-infectious pneumonitis has been associated with 
everolimus and other mTOR inhibitors (Atkins 2004). In order to monitor for 
asymptomatic (grade 1) pulmonary infiltrates, a chest X-ray is required if a CT scan of 
chest is not used for bi-monthly disease evaluations. Additional chest CT scans may be 
performed, when clinically necessary. If noninfectious pneumonitis develops, a 
consultation with a pulmonologist should be considered. If the patient develops grade 3 
pneumonitis, treatment with everolimus should be interrupted and the patient should be 
treated as medically indicated (short course corticosteroids, oxygen, etc). Management of 
non-infectious pneumonitis suspected to be associated with everolimus and dose 
modifications instructions are provided in Table 6.2.3. 


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Table 6.2.3 
Management of non-infectious 
pneumonitis 
 
Worst grade 
pneumonitis 
 
Suggested investigations 
Management of 
pneumonitis 
 
everolimus dose adjustment 
Grade 1 
CT scans with lung windows and 
pulmonary function testing including: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat chest x-ray/CT 
scan every 2 Cycles until return to 
baseline. 
Grade 2 
CT scan with lung windows. Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy and/or BAL. 
Monitoring at each visit until return to ≤ 
grade 1 or baseline. Return to initial 
monitoring frequency if no recurrence. 
 
 
 
 
 
 
Grade 3                  CT   scan   with   lung   windows   and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Monitoring at each 
visit until return to ≤ grade 1. Return to 
initial 
monitoring frequency if 
no 
recurrence. Bronchoscopy with biopsy 
and/or BAL is recommended. 
 
 
 
 
 
 
 
 
 
 
Grade 4                  CT   scan   with   lung   windows   and 
required pulmonary function testing, if 
possible, includes: spirometry, DLCO, 
and room air O2 saturation at rest. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency 
if        no        recurrence. 
Bronchoscopy with biopsy and/or BAL 
No specific therapy 
is required 
 
 
 
 
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy if 
symptoms are 
troublesome. 
 
 
 
 
 
 
 
 
Consider 
corticosteroids 
if 
infective   origin   is 
ruled  out.  Taper  as 
medically indicated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consider 
corticosteroids 
if 
infective   origin   is 
ruled  out.  Taper  as 
medically indicated. 
No dose adjustment required for 
Pazopanib or everolimus. 
Initiate appropriate monitoring. 
 
 
 
Rule out infection and consider 
interruption of everolimus (and 
optional pazopanib) until symptoms 
improve to Grade ≤ 1. 
Re-initiate everolimus at one dose 
level lower. 
Discontinue everolimus if failure to 
recover within ≤ 28 days. 
Pazopanib may resume at the 
discretion of the treating physician 
and principal investigator once 
toxicity is recovered to ≤ Grade 1 
even if everolimus is discontinued. 
Rule out infection and interrupt 
everolimus and pazopanib until 
symptoms improve to Grade ≤ 1. 
Consider re-initiating everolimus at 
one dose level lower (approximately 
50% lower than the dose previously 
administered depending on individual 
clinical circumstances) 
Discontinue everolimus if failure to 
recover within ≤ 28 days. 
If toxicity recurs at Grade 3, consider 
discontinuation of everolimus. 
Pazopanib may resume at the 
discretion of the treating physician 
and principal investigator once 
toxicity is recovered to ≤ Grade 1 
even if everolimus is discontinued. 
 
Rule  out  infection  and  discontinue 
everolimus. 
 
Pazopanib  may  resume  at  the 
discretion  of  the  treating  physician 
and  principal  investigator  once 
toxicity  is  recovered  to  ≤  Grade  1 
even if everolimus is discontinued. 
  
is recommended if possible.  
 


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* A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 
 
6.2.4  Management of hepatitis reactivation / flare 
 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have also been seen in this 
setting with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce 
the risk of Hepatitis B virus reactivation and associated morbidity and mortality (Loomba 2008). 
A detailed assessment of Hepatitis B/C medical history and risk factors must be done for all 
patients at screening, with testing performed prior to the first dose of everolimus. 
 
Monitoring and prophylactic treatment for hepatitis B reactivation 
 
Table 6.2.4.1 provides detail of monitoring and prophylactic therapy according to the screening 
results of viral load and serologic markers testing. 
 
Table 6.2.4.1 Action to be taken based on screening hepatitis B results 
 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should 
be started 1-2 weeks prior to 
first dose of everolimus 
Monitor HBV-DNA 
approximately every 4-8 
weeks 
No prophylaxis 
Monitor HBV-DNA 
approximately every 3-4 weeks 
No specific action 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of everolimus. 
For HBV reactivation definition and management guidelines, see Table 6.2.4.2 


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Table 6.2.4.2 Guidelines for the management of hepatitis B reactivation 
 
HBV reactivation (with or without clinical signs and symptoms)* 
 
For patients with baseline 
results: 
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as: 
[Increase of 1 log in HBV- 
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA] 
Treat: Start a second antiviral medication 
AND 
Interrupt everolimus administration until resolution: 
1. ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, everolimus should be re-started at one 
dose lower, if available. If the patient is already receiving the lowest dose of 
everolimus according to the protocol, the patient should restart at the same 
dose after resolution. Both antiviral therapies should continue at least 4 weeks 
after last dose of everolimus. 
If resolution occurs > 28 days Patients should discontinue everolimus but 
continue both antiviral therapies at least 4 weeks after last dose of everolimus. 
For patients with baseline 
results: 
Negative HBV-DNA and 
HBsAg 
AND 
[Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb] 
------------------------------------- 
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication 
AND 
Interrupt everolimus administration until resolution: 
2. ≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, everolimus should be re-started at one 
dose lower, if available. If the patient is already receiving the lowest dose of 
everolimus according to the protocol, the patient should restart at the same 
dose after resolution. Antiviral therapy should continue at least 4 weeks after 
last dose of everolimus. 
If resolution occurs > 28 days Patients should discontinue everolimus but 
continue antiviral therapy at least 4 weeks after last dose of everolimus. 
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations/Other: Viral 
Reactivation), unless considered life threatening by the investigator, in which case they should be recorded as 
grade 4. Date of viral reactivation is the date on which the rise or reappearance of HBV-DNA was recorded. 
 
Monitoring for hepatitis C flare 
 
The following two categories of patients should be monitored every 4–8 weeks for HCV flare: 
 
• Patients with detectable HCV RNA-PCR test at screening. 
 
• Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’) 
 
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to 6.2.4.3 


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Table 6.2.4.3  Guidelines for the management of hepatitis C flare 
 
Baseline results 
HCV flare definition* 
HCV flare management 
Detectable HCV-RNA 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue everolimus 
Knowledge of past hepatitis C 
infection with no detectable 
HCV-RNA 
New appearance of detectable HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations - Other: Viral Flare), 
unless considered life threatening by the investigator; in which case they should be recorded as grade 4. Date of 
viral flare is the date on which both the clinical criteria described above were met. (e.g., for a patient whose 
HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the date 
of viral flare is 22 JAN 2011). 
 
 
 
6.2.5 Management of infections 
 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized  and  systemic  infections,  including  pneumonia,  other  bacterial  infections, 
invasive  fungal  infections,  such  as  aspergillosis  or  candidiasis  and  viral  infections 
including reactivation of hepatitis B virus, have been described in patients taking 
everolimus Some of  these infections have been severe (e.g. leading to respiratory or 
hepatic failure) and occasionally have had a fatal outcome. 
 
Physicians and patients should be aware of the increased risk of infection with everolimus 
Treat pre-existing infections prior to starting treatment with everolimus. While taking 
everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation 
of everolimus. 
 
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and 
treat with appropriate antifungal therapy. 
 
6.2.6 Management of skin toxicity 
 
For  patients  with  grade  1  toxicity,  no  specific  supportive  care  is  usually  needed  or 
indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be 
treated with the following suggested supportive measures at the discretion of the 
investigator: oral minocycline, topical tetracycline, topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral prednisolone (short course), topical corticosteroids, or 
pimecrolimus. 
 
6.3 Dose Modifications/Delays 
 
6.3.1 General dose modification/Delays 


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Dose modifications for toxicities not otherwise covered in section 6.2 are listed in the table 
below. Patients who do not recover to grade 2 or less toxicity within 28 days will be removed 
from protocol therapy except where noted (ie. pneumonitis). In addition, patients may hold 
study intervention (pazopanib and everolimus) for greater than 28 days if the patient's 
physician and the overall principal investigator, Mark Pomerantz, MD, agree that the patient 
is deriving clinical benefit from the study drugs. Dose modifications for specific toxicities are 
covered in sections 6.2 and 6.3. 
 
All toxicities, both during the DLT period and after it has been completed, will follow the 
guidelines laid out here in sections 6.2 and 6.3. 
 
For definition of a Dose Limiting Toxicity, refer back to section 5.4. 
 
Non-hematological toxicity 
Toxicity 
Actions 
Non-Infectious Pneumonitis 
Please refer to section 6.2.3 
Reactivation of HBV or HCV flare 
Please refer to section 6.2.4 
Non-hematological toxicity 
Grade 2 
(except pneumonitis – refer to section 6.2.3) 
(except hypertension, proteinuria, venous or arterial 
thrombosis, QTc prolongation- refer to 
section 6.3.2) 
(except hepatotoxicity – refer to section 6.3.3) 
(except elevated amylase and lipase- refer to section 
6.3.5) 
If the toxicity is tolerable to the patient, maintain the 
same dose. If the toxicity is “intolerable” to patient, 
interrupt pazopanib and everolimus until recovery to 
grade ≤1. Then reintroduce pazopanib and 
everolimus at same dose. If event returns to 
“intolerable” grade 2, then interrupt pazopanib and 
everolimus until recovery to grade ≤1. Then 
reintroduce pazopanib and everolimus at one dose 
level lower. If event is recurrent “intolerable” grade 
2 despite two dose reductions, discontinue pazopanib 
and everolimus. 
Grade 3 or 4 
(except hyperlipidemia1) 
(except pneumonitis – refer to section 6.2.3) 
(except hypertension, proteinuria, venous or arterial 
thrombosis, QTc prolongation- refer to section 6.3.2) 
(except hepatotoxicity – refer to section 6.3.3) 
Interrupt pazopanib and everolimus until recovery to 
grade ≤1. Then reintroduce pazopanib and 
everolimus at one dose level lower. No more than 2 
dose reductions allowed. 
Stomatitis / oral mucositis / mouth ulcers 
See section 6.2.3 Management of stomatitis / oral 
mucositis / mouth ulcers 
Recurrence of grade 3 toxicity after dose reduction 
Reduce dose to the next lower dose level, if available. 
The lowest possible dose level of everolimus is 5 mg 
every other day (2.5 mg daily). Below this level, 
everolimus must be discontinued. 
Interrupt everolimus administration 
until resolution to ≤ grade 1 or baseline 


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Intolerable grade 2 mucositis, or grade 3 AE, except 
hyperglycemia or hypertriglyceridemia or 
hypercholesterolemia (see Section 6.2.2.) 
grade / value. 
If resolution occurs within ≤ 7 days, 
everolimus should be re-started at the 
dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs 
within 28 days, hold everolimus until recovery 
to ≤ grade 1 or baseline grade / value and 
reintroduce everolimus at one dose level 
lower, if available. 
Patients will be withdrawn from the study if they fail 
to recover to  grade 1 or baseline grade / value 
within 28 days. 
Any other grade 4 
Hold everolimus until recovery to grade  1 or 
baseline value 
Reintroduce everolimus at one dose level lower, if 
available. 
Grade 3 or 4 clinical liver failure (asterixis or 
encephalopathy/coma) 
Discontinue everolimus and Pazopanib 
Recurrence of intolerable grade 2 mucositis or grade 
3 event after dose reduction 
Reduce dose to the next lower dose level, if 
available. The lowest possible dose level of 
everolimus is 2.5 mg daily. Below this 
level, everolimus must be discontinued. If 
toxicity recurs at Grade 3, consider 
discontinuation. 
Recurrence of grade 4 after dose reduction 
Discontinue everolimus and Pazopanib 
Any non-hematologic 
toxicity requiring 
everolimus interruption 
for > 28 days 
Discontinue everolimus and Pazopanib 
1Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed using medical 
therapies without dose reduction (see Section 6.2.2). 
 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75 -50x109/L) 
 
 
 
 
 
Grade 3 or 4 Thrombocytopenia (platelets <50 
x109/L) 
 
 
 
 
 
 
Grade 1& 2 Neutropenia (neutrophils ≥ 1 x 109/L) 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt pazopanib and everolimus until recovery to 
grade ≤1 (≥75 x109/L). Then reintroduce pazopanib 
and everolimus at initial dose. If thrombocytopenia 
again returns to grade 2, interrupt pazopanib and 
everolimus until recovery to grade ≤1. Then 
reintroduce everolimus at one dose level lower. No 
more than two dose reductions are allowed. 
 
Interrupt pazopanib and everolimus until recovery to 
grade ≤1 (platelets ≥ 75 x109/L). Then resume 
pazopanib and everolimus at one dose level lower. If 
grade 3 or 4 thrombocytopenia recurs, discontinue 
pazopanib and everolimus. 
 
 
 
 
No modification of dose. 


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Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Grade 3 febrile neutropenia (not life-threatening) 
Grade 4 febrile neutropenia (life-threatening) 
Interrupt everolimus and Pazopanib until resolution 
to grade ≤1 or baseline value 
If AE resolution occurs ≤ 7 days, 
reintroduce everolimus and pazopanib at 
the same dose level. 
If AE resolution occurs > 7 days (within 28 days), 
reintroduce everolimus and pazopanib at one dose 
level lower, if available. Discontinue patient from 
study therapy if recurrent grade 3 or greater 
neutropenia after two dose reductions. 
Interrupt pazopanib and everolimus until recovery to 
grade ≤ 1 (neutrophils ≥ 1.5 x 109/L). Then resume 
pazopanib and everolimus at one lower dose level. If 
grade 3 or grade 4 neutropenia occurs despite two 
dose reductions, discontinue pazopanib and 
everolimus. 
Hold further pazopanib and everolimus until the 
ANC ≥ 1,500/mm3 and fever has resolved and 
antibiotics are discontinued. Then resume pazopanib 
and everolimus at one dose level lower. If febrile 
neutropenia recurs, discontinue pazopanib and 
everolimus. 
Discontinue pazopanib and everolimus. 
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 4 weeks 
Discontinue pazopanib and everolimus 
 
 
 
6.3.2 Management of hypertension, proteinuria, hemorrhage/bleeding, venous and 
arterial thrombosis, QTc prolongation 
 
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. 
Step 1. Pazopanib and everolimus 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). 


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AE Terms & Descriptions 
Dose Modification Algorithms 
(B). Asymptomatic SBP 170 
mmHg, or DBP 110 mmHg, or 
failure to achieve well-controlled 
BP within 2 weeks in scenario (A). 
Step 1.Interrupt  pazopanib and everolimus. 
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. a 
Step 4. Once BP is well-controlled, dose reduce pazopanib and 
everolimus and restart at one dose level lower. 
(C). Symptomatic hypertension or 
recurring SBP 170 mmHg, or 
DBP 110 mmHg, despite 
modification of antihypertensive 
medication(s) 
Step 1. Interrupt pazopanib and everolimus 
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 BPa. Referral to a specialist 
for further evaluation and follow-up is also recommended. 
Step 4. Once BP is well-controlled, dose reduce pazopanib and 
everolimus and restart at one dose level lower. 
(D). Refractory hypertension 
unresponsive to above 
interventions. 
Discontinue pazopanib and everolimus and continue follow-up per 
protocol. 
a. 
Well-controlled BP defined as mean SBP <140 mmHg and mean DBP <90 mmHg. 
Proteinuria 
24-hr urine protein > 3 grams 
Step 1. Interrupt pazopanib and everolimus. 
Step 2. The 24-hour urine protein will be tested weekly until the 
level is < 3 grams.  Then, restart pazopanib and everolimus dose 
reduced one dose level. 
Step 3. If 24-hour urine protein ≥ 3 grams recurs once, repeat Steps 
1 and 2. 
Step 4.  If 24-hour urine protein ≥ 3 grams recurs after 2 dose 
reductions, discontinue pazopanib and everolimus 
Hemorrhage /Bleeding 
Grade 1 
Continue pazopanib and everolimus with current dose; monitor as 
clinically indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal bleeding), 
discontinue pazopanib and everolimus and continue follow-up per 
protocol. Otherwise, interrupt pazopanib and everolimus until the 
AE resolved to  Grade 1. 
Step 2. Restart pazopanib and everolimus; reduce dose by one dose 
level and consult with study PI, monitor as clinically indicated. 
Grade 3 or 4, or 
Recurrent  Grade 2 event after 
Discontinue pazopanib and everolimus and continue with follow-up 
per protocol. 


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AE Terms & Descriptions 
Dose Modification Algorithms 
dose interruption/reduction. 
Venous Thrombosis (DVT, PE) 
Grade 2 
Continue everolimus and pazopanib at the same dose 
Grade 3 
Step 1. Interrupt pazopanib and everolimus. 
Step 2. Initiate and monitor anticoagulation as clinically indicated. 
Step 3. Resume pazopanib and everolimus with one dose reduction 
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 pazopanib 
and everolimus dosing (eg, re-initiating, escalating/de-escalating, or 
discontinuing pazopanib and everolimus), 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 pazopanib and everolimus and continue follow-up per 
protocol. 
Arterial Thrombosis/Ischemia 
Any Grade 
Discontinue pazopanib and everolimus 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. 
QTc   480 < 500 msec 
Continue pazopanib and everolimus; monitor as clinically indicated. 
QTc 500 msec 
Discontinue pazopanib and everolimus and continue follow-up per 
protocol. 


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6.3.3 Dose Interruptions/Modifications for Hepatotoxicity 
 
Recommendations for everolimus and pazopanib dose interruptions/modifications in case of 
liver-related treatment-emergent AEs are provided below. 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 (b) identify and discontinue those 
with known hepatotoxicity and replace with a non-hepatotoxic equivalent for the same 
indication if necessary. 
 
 
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x upper 
limit of normal (ULN) 
Continue pazopanib and everolimus at current dose with full panel liver 
function tests (LFTs)3 monitored as per protocol. 
(B). ALT >3.0 x ULN to 
≤8.0 x ULN without bilirubin 
elevation (defined as total 
bilirubin <2.0 x ULN or direct 
bilirubin ≤35%) and without 
hypersensitivity symptoms 
(e.g., fever, rash) 2 
1.   Continue everolimus and pazopanib at current dose. 
2.   Perform the following assessments for excluding hypersensitivity and 
other contributing factors: 
• 
Eosinophil count 
• 
Viral serology for hepatitis A, B and C 
• 
Liver imaging 
3. Monitor subject closely for clinical signs and symptoms; perform 
full panel LFTs weekly or more frequently if clinically indicated 
until alanine aminotransferase (ALT)/aspartate aminotransferase 
(AST) reduced to Grade 1. 
(C). ALT >8.0 x ULN without 
bilirubin elevation (defined as 
total bilirubin <2.0 x ULN or 
direct bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, rash)2 
1st occurrence 
Interrupt everolimus and pazopanib until toxicity resolves to  Grade 1 
or baseline 
2.   Perform the following assessments for excluding hypersensitivity and 
other contributing factors: 
• 
Eosinophil count 
• 
Viral serology for hepatitis A, B, C and E, cytomegalovirus, 
Epstein-Barr virus IgM antibody, or heterophile antibody, or 
monospot testing) 
• 
Liver imaging 
3.   Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTs weekly or more frequently if clinically indicated until alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) reduced to 
Grade 1. 
• 
* If the potential benefit for reinitiating pazopanib treatment is 
considered to outweigh the risk for hepatotoxicity, then reintroduce 
pazopanib at a reduced dose and measure serum liver tests weekly 
for 8 weeks. Re-challenge may be considered if ALL following 
criteria are met: 
• 
ALT/AST reduced to Grade 1 
• 
Total bilirubin <1.5 x ULN or direct bilirubin 35% 
• 
No hypersensitivity signs or symptoms 
• 
Subject is benefiting from therapy. 
• 
Pazopanib and everolimus will be decreased by one dose level if 
treatment resumes. 
• 
If AST or ALT elevation is > 20x ULN, everolimus should be 
discontinued if resolution takes > 7 days 
Recurrence 


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Event 
Dose Modification Algorithms 
Discontinue everolimus and pazopanib permanently and monitor subject 
closely for clinical signs and symptoms; perform full panel LFTs weekly or 
more frequently if clinically indicated. 
(D). ALT >3.0 x ULN with 
concomitant elevation in 
bilirubin (defined as total 
bilirubin 2.0 x ULN; with 
direct bilirubin >35%) or with 
hypersensitivity symptoms 
(e.g., fever, rash). 
1.   Discontinue everolimus and pazopanib immediately 
2.   Consult a gastroenterologist / hepatologist and perform the following 
assessments to identify potential co-factors: 
• 
Eosinophil count 
• 
Viral serology for hepatitis A, B, C and E, cytomegalovirus, 
Epstein-Barr virus IgM antibody, or heterophile antibody, or 
monospot testing) 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, anti- 
mitochondrial antibody 
• 
Serum creatinine phosphokinase for possible muscle injury caused 
LFT elevation 
• 
Liver imaging (ultrasound or CT scan) 
3.   Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTs weekly or more frequently if clinically indicated until LFTs 
reduced to Grade 1. 
If everolimus 
For isolated total bilirubin 
elevation without concurrent 
ALT increases (defined as 
ALT < 3 X ULN) 
1.   Isolated hyperbilirubinemia (ie 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 the bilirubin is 
predominantly indirect (unconjugated), continue everolimus and 
pazopanib at the same dose. If bilirubin is >35% direct (conjugated), 
stop everolimus and pazopanib and further evaluation for underlying 
cause of cholestasis should be performed. 
3.   If the subject is benefiting from the study treatment, contact Principal 
Investigator for possible re-challenge. Re-treatment may be considered if 
ALL following criteria are met: 
• 
ALT < 3X ULN 
• 
Total bilirubin <1.5 x ULN or direct bilirubin 35% 
• 
No hypersensitivity signs or symptoms 
• 
Subject is benefiting from therapy. 
Pazopanib and everolimus will be decreased by one dose level if 
treatment resumes. 
a. 
3Full panel LFTs include: AST, ALT, alkaline phosphatase, -GT (GGT) and total 
bilirubin. 
 
2 Should HCV flare be confirmed, the guidelines for flare must take precedence (See section 6.2.4) 
* Please refer to the Pazopanib Investigator’s Brochure, Summary of Data and Guidance for Investigator, Warnings 
and Precautions, Hepatic Effects for information about rechallenge dose 
 
 
 
6.3.4 Dose modifications for elevated amylase and lipase 
Event 
Dose Modification Algorithm 
Grade 2 elevation of amylase 
and lipase without symptoms 
of pancreatitis 
Monitor amylase and lipase every other week, continue study therapy at the same 
dose level 


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Grade 2 elevation of amylase 
and lipase with symptoms of 
pancreatitis 
Hold study therapy until both labs and symptoms are grade 1 or less. Consider 
restarting study therapy with a dose reduction if the patient is known to be deriving 
clinical benefit 
Grade 3 elevation of amylase 
and lipase without symptoms 
of pancreatitis 
Check amylase and lipase weekly until grade 2 or less, monitor for symptoms 
weekly (phone contact or visit) until grade 2 or less, and continue study therapy at 
the same dose level. Consider GI consultation. 
Grade 3 elevation of amylase 
and lipase with symptoms of 
pancreatitis 
Hold study therapy until both laboratory testing and symptoms are grade 1 or less. 
GI consultation is recommended. Consider restarting study therapy with a dose 
reduction if the patient is known to be deriving clinical benefit from treatment. 
Grade 4 elevation of amylase 
and lipase without symptoms 
of pancreatitis 
Hold study therapy until grade 2 or less, restart with one dose-level reduction if the 
patient is known to be deriving clinical benefit from treatment. GI consultation 
recommended. 
Grade 4 elevation of amylase 
and lipase with symptoms of 
pancreatitis 
Hold study therapy until both laboratory testing and symptoms are grade 1 or less. 
GI consultation is recommended. Consider restarting study therapy with a dose 
reduction if the patient is known to be deriving clinical benefit from treatment. 
 
 
 
 
7. DRUG FORMULATION AND ADMINISTRATION 
 
 
7.1 Everolimus 
Everolimus will be provided by Novartis. Tablets are blister packed under aluminum foil in units 
of 10 tablets, which should be opened only at the time of administration, as everolimus is both 
hygroscopic and light sensitive. 
 
7.1.1 Description 
 
 
everolimus, an inhibitor of mTOR, is an antineoplastic agent. The chemical name of 
everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- 
dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1- 
methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza- 
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone. The 
molecular formula is C53H83NO14 and the molecular weight is 958.2. 
 
7.1.2 Form 
Everolimus is supplied as tablets for oral administration containing 2.5 mg, 5 mg, 7.5 
mg,  and 10 mg of everolimus together with butylated hydroxytoluene, magnesium 
stearate, lactose monohydrate, hypromellose, crospovidone and lactose anhydrous as 
inactive ingredients. Everolimus 5 mg tablet is a white to slightly yellow elongated 
tablet with beveled edge and no score engraved with “5” on one side and “NVR” on 
the other. Everolimus 10 mg tablet is a white to slightly yellow elongated tablet with 
beveled edge and no score engraved with “UHE” on one side and “NVR” on the other 
side. 
 
7.1.3  Storage and Stability 


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Store everolimus tablets at 25° C (77°F); excursions permitted between 15°–30°C (59°– 
86°F). Store in the original container, protect from light and moisture. Keep this and all 
drugs out of the reach of children. Everolimus is both hygroscopic and light-sensitive. 
 
7.1.4  Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
Everolimus tablets should not be crushed. Direct contact of crushed tablets with the skin 
or mucous membranes should be avoided. If such contact occurs, wash thoroughly as 
outlined in the references. Study personnel should avoid exposure to crushed tablets. 
 
7.1.5  Compatibility 
N/A 
 
7.1.6 Availability 
Everolimus is considered an investigational agent in this study and will be supplied free- 
of-charge from Novartis. 
 
 
7.1.7 Preparation 
N/A 
 
 
7.1.8 Administration 
Patients will be instructed to take the everolimus in the morning, without food, at least one 
hour before or two hours after a meal, at the same time as the Pazopanib. 
 
7.1.9   Ordering 
Everolimus can be ordered from Novartis using a drug order form e-mailed to Novartis. 
 
7.1.10  Accountability 
All missed doses must be documented in the drug accountability log and the subject’s 
medical record. Unused agent that is returned by subject is not held, but destroyed 
according to institutional policy. The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the inventory and disposition of the 
agent. This should be kept current and contain: 
• 
Dates and quantities of investigational product received from Novartis 
• 
Packaging lot numbers for product received 
• 
Subject’s identification 
• 
Date and quantity of investigational product dispensed 
• 
The initials of the dispenser 
 
7.1.11  Destruction and Return 


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At the end of the study, unused supplies of everolimus should be destroyed according 
to institutional policies unless otherwise instructed by supplier Novartis. 
Destruction/return will be documented in the Drug Accountability Record Form. 
 
 
7.2 Pazopanib 
 
7.2.1 Description 
Pazopanib, 5-[[4-[(2,3-Dimethyl-2H=indazol-6-yl)-2-pyrimidinyl]amino]-2- 
methylbenzenesulfonamide monohydrochloride, is an orally bioavailable angiogenesis 
inhibitor. Its molecular formula is C21H23N7O2S●HCl. Excipients in the tablet 
include microcrystalline cellulose, povidone, sodium starch glycolate, magnesium 
state, and a film-coat. 
 
 
7.2.2 Form 
Pazopanib monohydrochloride is supplied as a series of aqueous film-coated tablets 
containing 200mg and 400mg of the freebase: 
• 200mg, oval-shaped, white, packaged in bottles containing 34 tablets each 
• 400mg, oval-shaped, white, packaged in bottles containing 68 tablets each 
 
7.2.3 Storage and Stability 
Pazopanib 200mg and 400mg should be stored up to 25°C. Pazopanib has a 48 month 
shelf-life. 
 
 
7.2.4 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective 
environment. Pazopanib tablets should not be crushed. Direct contact of crushed 
tablets with the skin or mucous membranes should be avoided. If such contact occurs, 
wash thoroughly as outlined in the references. Study personnel should avoid exposure 
to crushed tablets. 
 
7.2.5 Compatibility 
N/A 
 
7.2.6 Availability 
Pazopanib will be provided by GlaxoSmithKline free of charge. 
 
7.2.7 
Preparation 
N/A 
 
 
7.2.8 Administration 


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Patients will be instructed to take the Pazopanib in the morning, without food, at least 
one hour before or two hours after a meal, at the same time as the everolimus. The 
tablets should be swallowed whole and must not be crushed or broken. 
 
 
7.2.9 Ordering 
GlaxoSmithKline will ship labeled pazopanib bottles in a sealed carton (68 tabs per 
bottle for pazopanib 400mg and 34 tabs per bottle for pazopanib 200mg). A label will 
be affixed to each carton identifying the product, strength and number of bottles. In 
addition, a packing slip will be enclosed with the drug name, strength, lot/batch 
number, storage conditions, and expiration/retest date. 
 
7.2.10   Accountability 
All missed doses must be documented in the subject’s medical record and patient 
diary. Unused agent that is returned by subject is not held, but destroyed according to 
institutional policy. The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of the 
agent. This should be kept current and contain: 
• 
Dates and quantities of investigational product received from GlaxoSmithKline 
• 
Packaging lot numbers for product received 
• 
Subject’s identification 
• 
Date and quantity of investigational product dispensed 
• 
The initials of the dispenser 
• 
Dose preparation records 
 
7.2.11  Destruction and Return 
At the end of the study, unused supplies of Pazopanib should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
 
8. CORRELATIVE/SPECIAL STUDIES 
 
 
8.1 
Pharmacokinetic Studies 
Phase I: Patients will have pharmacokinetic specimens drawn at 0, 1, 2, 4, 6 and 24 hours post- 
dose on cycle 1 days 1 and 15. If patients are treated on dose level -1, there will be a 48 hour 
blood draw (pre-dose) as well. Two samples will be drawn for each time point. Pharmacokinetic 
specimens should be collected as close to the indicated window as possible. Whole blood 
samples (2 mL) should be collected in EDTA vacutainers for everolimus pharmacokinetics. 
Whole blood samples for the determination of plasma pazopanib concentrations will be 
collected into separate 2mL EDTA vacutainers. The 24 hour pharmacokinetic specimen should 
be collected prior to drug dosing on day 2 and day 16. If patients are treated on dose level -1, 
there will be an additional 48-hour post-dose blood draw obtained prior to everolimus dose. In 
addition, two 2mL blood samples for everolimus and pazopanib concentration determination 
will be obtained cycle 2 day 1 and cycle 4 day 1. 


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Testing will be done on whole blood including plasma. See Appendices B and C for details on 
blood specimen procurement and shipping. 
 
 
Expansion Cohort: Pharmacokinetic studies will not be performed in the expansion cohort 
 
 
 
9. STUDY CALENDAR 
Scans must be done <4 weeks prior to the start of therapy. In the event that the participant's 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
All assessments must be performed prior to administration of any study medication. All 
study assessments and medications should be administered within + 3 days of the 
protocol-specified date, unless otherwise noted. 


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X 
X 
X 
X 
X 
X 
X 
X 
 
 
9.1 Phase I: 
 
Treatment cycles 
 
 
 
 
Screening1 
Cycles 1, 2 
Subsequent 
cycles 
 
 
Day 1 
Day 15 
Day 1 
 
 
 
Off Study 
 
Informed Consent 
X 
History 
X 
X 
X 
X 
Concurrent meds 
X 
X 
X 
X 
Physical exam (Ht, 
Wt, BSA) 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
CBC with differential/ 
platelets 
EKG 
X 
X 
B 
 
Urinalysis, urine 
protein & creatinine2 
Serum chemistry 3 
X 
X 
X 
X 
X 
Fasting Lipid Panel 
X 
X 
X 
X 
Qualitative -HCG4 
X 
X 
X 
Hepatitis B and C 
screen 5 
X 
Pazopanib 
X--------------------------------------------------X 
Everolimus 
X--------------------------------------------------X 
Adverse event 
evaluation 
 
X--------------------------------------------------X 
X 
Tumor measurements 
X 
A 
A 
X 
 
Radiologic evaluation 
X 
A 
X 
 
1. Screening labs may be used as cycle 1 day 1 labs if performed within 7 days of initiation of study therapy. 
2. If UPC ≥ 1 then a 24 hour urine protein must be assessed. 
3: Albumin, alkaline phosphatase, total bilirubin, calcium, fasting glucose, LDH,  phosphorus, total protein, 
SGOT [AST], SGPT [ALT], serum sodium, potassium, chloride, bicarbonate, BUN, magnesium, uric acid, 
amylase, lipase, thyroid stimulating hormone (day 1 of each cycle only). 
Monitor serum liver tests before initiation of treatment with pazopanib and at weeks 3, 5, 7 and 9. Thereafter, 
monitor at Month 3 and Month 4, and as clinically indicated. Periodic monitoring should continue after Month 
4. Urine or serum pregnancy test (women of childbearing potential) at screening and day 1 of each cycle (+/- 3 
days). 
5. Screening for hepatitis B : Prior to registrations, patients will be tested for hepatitis B viral load and 
serologic markers, HBV-DNA, HBsAg, HBs Ab, and HBc Ab. Patients with risk factors for hepatitis C should 
be tested using quantitative RNA-PCR 
 
A. Tumor measurements should occur in the cycle 2 week 3, and every 2 cycles thereafter. Confirmatory scans 
should also be obtained 4 weeks following initial documentation of an objective response. If scans have been 
performed within 30 days before coming off treatment, they do not need to be repeated. If scans cannot be 
obtained (patients coming off treatment to go to hospice or have died), please document in study file. 
B. Pre-dose EKG obtained at baseline, cycle 1 days 1, 15, and cycle 2 day 1 only. 


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9.2 Expansion cohort 
 
 
 
Test/Procedure 
 
 
 
Screening 
Treatment Cycles 1, 2 
(28 day cycles) 
 
 
Subsequent cycles 
(28 day cycles) 
Off Study 
 
 
 
Survival 
-28 
days 
 
Informed Consent 
X 
-14 
days 
Day 11 
(±3 days) 
Day 15 
(±3 days) 
Day 1 
(±3 days) 
28 days after 
last dose (+/- 
7 days)9 
History                                              X                        X                   X                         X                         X 
Concurrent Medications                   X                       X                   X                         X                         X 
Physical Exam                                  X                       X                    X                         X                         X 
Vital Signs                                                     X            X                    X                         X                         X 
Performance Status                           X                       X                    X                         X                         X 
CBC with Differential/ 
Platelets                                                         X            X                    X                         X                         X 
Amylase and lipase                                       X            X                                                X 
EKG                                                               X            X 
Urinalysis, Urine Protein & 
Creatinine2                                                                               X            X                                                X                         X 
Serum Chemistry 3                                                            X            X                    X                         X                         X 
TSH                                                               X            X                                                X 
PT/INR, PTT                                                 X 
HbA1c7                                                                                       X 
Fasting Lipid Panel                                       X            X                                                X                         X 
Qualitative -HCG4                                                          X            X 
Hepatitis B and C Screen 8                                          X 
Pazopanib                                                               X----------------------------------------------------X 
Everolimus                                                               X--------------------------------------------------X 
Adverse Event Evaluation                                     X----------------------------------------------------X           X 
Radiologic Evaluation5,6                            X                                                                            X                        X 
Survival Follow-Up                                                                                                                                                                         X 
 
1. 
Cycle 1 Day 1 evaluations are to be conducted within 1-week prior to start of protocol therapy. Screening labs may be used as Cycle 1 Day 1 
labs if drawn within 7 days of initiating study therapy. 
2.     If UPC ≥ 1, then a 24 hour urine protein must be assessed. 
3. 
Albumin, alkaline phosphatase, total bilirubin, calcium, fasting glucose, total protein, SGOT [AST], SGPT [ALT], serum sodium, potassium, 
chloride, bicarbonate, BUN, uric acid, magnesium, LDH, phosphorus 
4.     Urine pregnancy test (women of childbearing potential) at screening and cycle 1 day 1 only. 
5.     Radiological imaging should occur every 8 weeks, following cycle 1 day 1. 
6. 
If scans have been performed within 30 days before coming off treatment, they do not need to be repeated as an off-study assessment. If scans 
cannot be obtained (e.g. patients coming off treatment to go to hospice or patients have died), please document in study file. 
7.     Applies to patients with uncontrolled diabetes mellitus 
8. 
Screening for hepatitis: Prior to registrations, all patients will be tested for hepatitis B serologic markers (HBsAg, HBs Ab, and HBc Ab, HBV- 
DNA) and for hepatitis C (using quantitative RNA-PCR) 
9.     This visit can be foregone for patients who are too unwell to attend or for other reasons at the investigator’s discretion. Patients may be 
contacted by phone to assess resolution of toxicities and may be contacted for survival follow up. 


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10. MEASUREMENT OF EFFECT 
Objective response rate is the primary endpoint of the expansion cohort of this trial and 
participants will be assessed by RECIST v1.1 criteria. For the purposes of this study, 
participants should be reevaluated every 8 weeks. In addition to a baseline scan, 
confirmatory scans should also be obtained at least 4 weeks following initial 
documentation of an objective response. 
 
10.1 
Antitumor Effect– Solid Tumors 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee v. 1.1 57. Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. 
 
10.1.1   Definitions 
 
Evaluable for toxicity. All participants who receive at least one dose of study treatment 
will be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response. All participants who receive at least one dose of study 
treatment will be evaluable for response from the time of their first treatment. These 
participants will have their response classified according to the definitions stated 
below. 
 
 
10.1.2  Disease Parameters 
 
 
Measurable disease. Measurable disease is the presence of at least one (1) lesion 
that can be accurately measured in at least one dimension with longest diameter  >20 
millimeters (mm) using conventional techniques (CT, MR1, x-ray) or  >10 mm with 
spiral CT scan. Measurable lesions must be at least 2 times the slice thickness in mm. All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
A lesion in a previously irradiated area is not eligible for measurable disease unless there is 
objective evidence of progression of the lesion prior to study enrollment. Lesions in 
previously irradiated areas must be clearly identified as such. 
 
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, 


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abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non- 
measurable. 
 
 
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. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis of the 
lymph node is added into the sum. The baseline sum will be used as the reference by 
which to characterize the objective tumor response. 
 
 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of <10mm. Case report forms or other data collection methods may therefore be 
designed to have target nodal lesions recorded in a separate section where, in order to qualify 
for CR, each node must achieve a short axis <10mm. For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
 
 
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 at each follow-up. 
 
 
10.1.3 
Methods for Evaluation of Measurable Disease 
 
 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. 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 anti-tumor effect of a treatment. 
 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 


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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. 
 
 
10.1.4 
Response Criteria 
10.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. 
 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions (or short axis for lymph nodes), taking as reference the 
baseline sum. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the target lesions, 
taking as reference the s m a l l e s t s u m r e c o r d e d s i n c e t h e treatment started or the 
appearance of one or more new lesions (new lesions must be > slice thickness). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum since the 
treatment started. 
 
 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
 
Note: If tumor response data is missing, an overall assessment cannot be done. 
However, if there is missing or unevaluable data for non-target lesions, but data is 
available for all target lesions, the overall response for that time point will be assigned 
based on the sum of all target lesions. Additionally, the assessment of CR cannot be 
made if there is missing or unevaluable data for non-target lesions. In this case, the 
overall assessment would be PR. 
 
10.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a subject to be considered in complete clinical response 
Incomplete Response/Stable Disease (SD): Persistence of one or more non- 
target lesions and/or maintenance of tumor marker level above the normal limits. 


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Progressive  Disease  (PD):  Appearance  of  one  or  more  new  lesions  (new 
lesions must be > slice thickness) and/or unequivocal progression of existing 
non-target lesions. 
 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
 
 
Note: Although a clear progression of "non-target" lesions only is exceptional, in 
such circumstances, the opinion of the treating physician should prevail and the 
progression status should be confirmed at a later time by review of the Principal 
Investigator (or Protocol Chair). Additionally, the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment is 
mandatory to differentiate between stable or progressive disease status. 
 
 
10.1.4.3 
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 participant's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Ov era l l 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Participants 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. 
 
 
10.1.5  Duration of Response 
 
Duration of overall response: The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrence or PD is objectively documented, 
taking as reference for PD the smallest measurements recorded since the 
treatment started. 
 
 
Duration of overall complete response:  The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
 
 
10.1.6   Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of 
treatment to time of objective disease progression or death, or is censored at the 
time of last disease evaluation. 


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11. ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1General 
 
Adverse event collection and reporting is a routine part of every clinical trial. This study 
will use the descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0) that is available at 
http://ctep.cancer.gov/reporting//ctc.html. 
 
Information on all adverse events, whether reported by the participant, directly observed, 
or detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported as described in the following sections. 
 
Adverse events experienced by participants will be collected and reported from initiation 
of study medication, throughout the study, and within 30 days (or 5 half-lives, whichever 
is longer) of the last dose of study medication. Participants who experience an ongoing 
adverse event or related to a study procedures and/or study medication beyond 30 days 
will continue to be contacted by a member of the study team until the event is resolved, 
stabilized, or determined to be irreversible by the participating investigator. 
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event 
occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study. 
 
11.2 Definitions 
 
11.2.1  Adverse Event (AE) 
 
An adverse event is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests. 
 
11.2.2  Serious adverse event (SAE) 
 
A serious adverse event is an undesirable sign, symptom, or medical condition 
which: 
• is fatal or life-threatening; 
• requires or prolongs inpatient hospitalization; 


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• results in persistent or significant disability/incapacity; 
• constitutes a congenital anomaly or birth defect; or 
• jeopardizes the participant and requires medical or surgical intervention to 
prevent one of the outcomes listed above. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
• respite care and social reasons in the absence of any deterioration in the 
patient’s general condition 
 
11.2.3  Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.' 
 
11.2.3.1  Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk. 
 
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agent(s). 
 
11.2.3.2. Unexpected adverse event 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk. 
 
11.2.4  Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 


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• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
 
11.3 
Recording Adverse Events 
 
Adverse event information will be obtained at each contact with the participant. All 
adverse events will be recorded on the appropriate study-specific case report forms 
(CRFs). 
 
11.4 
Reporting Adverse Events 
 
Each adverse event will be assessed to determine if it meets the criteria for serious 
adverse event. If a serious adverse event occurs, expedited reporting will follow local 
policies, and federal guidelines and regulations as appropriate. 
 
It is the responsibility of the participating investigator to notify the Principal 
Investigator (or Protocol Chair), IRB, and others of all serious adverse events as 
required in the protocol. 
 
The Principal Investigator (or Protocol Chair) will provide information with respect to 
adverse events and safe use of the study treatment (e.g., safety reports, Action Letters) 
to all participating investigators as soon as the information becomes available. 
 
 
 
All SAEs, regardless of “expectedness” or “causality” must be reported to the Principal 
Investigator (or Protocol Chair), Dr. Mark Pomerantz, via fax within 24 hours of 
learning of the event. In the event that the participating investigator does not become 
aware of the serious adverse event immediately (e.g., participant sought treatment 
elsewhere), the participating investigator is to report the event within 24 hours after 
learning of it and document the time of his or her first awareness of the adverse event. 
All SAEs should be recorded on a MedWatch 3500a form. Please fax all supporting 
documentation as it becomes available. 
 
The contact information for SAE reporting is as follows: 
Mark Pomerantz, MD 
Dana-Farber Cancer Institute 
mark_pomerantz@dfci.harvard.edu 


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11.5 
Novartis and GlaxoSmithKline Notification by Investigator 
 
11.5.1  Serious Adverse Event Reporting Requirements 
 
All events meeting the criteria for Serious Adverse Event (see Section 11.2.2) 
that occur after the start of the initial dose of study treatment, during treatment, 
or within 30 days of the last dose of treatment must be reported as serious 
adverse events. 
 
The participating investigator must report each serious adverse event, 
regardless attribution, to the Principal Investigator (or Protocol Chair) within 
24 hours of learning of the occurrence. In the event that the participating 
investigator does not become aware of the serious adverse event immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is 
to report the event within 24 hours after learning of it and document the time of 
his or her first awareness of the adverse event. 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information 
should describe whether the event has resolved or continues, if and how the 
event was treated, and whether the participant will continue or discontinue study 
participation. The principal investigator has the obligation to report all serious 
adverse events to the FDA, IRB, Novartis Pharmaceuticals Drug Safety and 
Epidemiology Department (DS&E), and Glaxo-Smithkline. All events reported 
to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form). All events must be reported to both Novartis 
Pharmaceuticals DS&E Department [by FAX (877-778-9739)], and to 
GlaxoSmithkline [by e-mail to USNAPS@gsk.com and 
kamalnayan.h.bhatt @gsk.com OR fax to US-Case Management Group 
(fax 919-483-5404) and Kamal Bhatt (fax: 610-675-2632) within 24 hours 
of learning of the event’s occurrence. 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 serious adverse 
event occurring after the patient has started the first dose of study treatment 
and until 30 days after the patient has stopped study participation must be 
reported. This includes the 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). Serious adverse events occurring more than 30 days after study 
discontinuation need only be reported if a relationship to the GlaxoSmithkline 
or Novartis study drugs is suspected. 


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If the SAE is not previously documented in the everolimus 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. 
 
For Concomitant Medications, all serious adverse experiences will be 
forwarded to the product manufacturer by the investigator. 
 
11.5.2 
Non-Serious Adverse Event Reporting Requirements 
 
Non-serious adverse events will be reported to the Principal Investigator (or 
Protocol Chair) on the toxicity Case Report Forms. 
 
11.6 
Institutional Review Board (IRB) Notification by Investigator 
 
The participating investigator will report all adverse events and serious adverse events 
to the Principal Investigator (or Protocol Chair) and to the IRB according to the local 
IRB’s policies and procedures in reporting adverse events. 
 
In the event of a multi-center study, the Principal Investigator (or Protocol Chair) will 
report adverse events and serious adverse events from all participating sites to the DFCI 
IRB according to the IRB’s policies and procedures in reporting adverse events. 
 
11.7 
Food and Drug Administration (FDA) Notification by Sponsor-Investigator 
 
If this study is not IND-exempt, the Sponsor-Investigator will report to the FDA any 
adverse event that is serious, unexpected and reasonably related (i.e., possible, probable, 
definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later than 7 
calendar days after initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 15 calendar days 
after initial receipt of the information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800- 
FDA-0178) using Form FDA 3500A (Mandatory Reporting Form for investigational 


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agents) or FDA Form 3500 (Voluntary Reporting Form for commercial agents). Forms 
are available at http://www.fda.gov/medwatch/getforms.htm. 
 
 
 
11.8   Hospital Risk Management Notification by Investigator 
 
The participating investigator will report to the Principal Investigator (or Protocol Chair) 
and to local Risk Management any subject safety reports or sentinel events that require 
reporting according to institutional policy. 
 
12. DATA AND SAFETY MONITORING 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The QACT will collect, manage, and monitor data for this study. 
 
12.1.2 Data Submission 
 
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows: 
 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
 
12.2 
Safety Meetings 


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There will be monthly conference calls between the research team at the DF/HCC and the 
research team at Memorial Sloan-Kettering Cancer Center during the expansion phase of 
the trial to monitor safety and accrual. The attendee’s for this will routinely include the 
principal investigators (or their designees), research coordinators, Research Nurses, and, as 
needed, investigational pharmacists. In addition, input during these teleconferences may be 
obtained from the clinical development teams both at Novartis and GlaxoSmithKline, as 
needed. 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical specialists 
with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual 
data. Information to be provided to the committee may include: up-to-date participant 
accrual; current dose level information; DLT information; all grade 2 or higher unexpected 
adverse events that have been reported; summary of all deaths occurring within 30 days for 
Phase I or II protocols; for gene transfer protocols, summary of all deaths while being 
treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will 
be provided upon request. 
 
12.3 
Monitoring 
 
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated 
by the Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these 
audits or inspections is to examine study-related activities and documents to determine 
whether these activities were conducted and data were recorded, analyzed, and 
accurately reported in accordance with the protocol, institutional policy, Good Clinical 
Practice (GCP), and any applicable regulatory requirements. 
 
All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and 
will continue during protocol performance and completion. 
 
13. REGULATORY CONSIDERATIONS 
 
13.1 
Protocol Review and Amendments 
 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 


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necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location. 
 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The Principal Investigator (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators. 
 
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
Any change or addition (excluding administrative) to this protocol requires a written 
protocol amendment that must be reviewed by Novartis and the investigator before 
implementation. Amendments significantly affecting the safety of subjects, the scope of 
the investigation or the scientific quality of the study require additional approval by the 
IRB at each study center. A copy of the written approval of the IRB must be provided to 
Novartis. Examples of amendments requiring such approval are: 
 
1.   Increases in drug dose or duration of exposure of subjects, 
 
2.   Significant changes in the study design (e.g. addition or deletion of a control group), 
 
3.   Increases in the number of invasive procedures, 
 
4.   Addition or deletions of a test procedure required for monitoring of safety. 
 
These requirements for approval should in no way prevent any immediate action from 
being taken by the investigator or by Novartis in the interests of preserving the safety of 
all patients included in the trial.   If an immediate change to the protocol is felt to be 
necessary by the investigator and is implemented for safety reasons Novartis must be 
notified  and  the  IRB  at  the  center  must  be  informed  immediately.      Amendments 
affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval but the IRB must be kept informed of such administrative 
changes. Examples of administrative changes not requiring formal protocol amendments 
and IRB approval include: 
 
• Changes in the staff used to monitor trials 
• 
Minor changes in the packaging or labeling of study drug. 
 
13.2 
Informed Consent 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file. 


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13.3 
Ethics and Good Clinical Practice (GCP) 
 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
 
• ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm 
 
• US Code of Federal Regulations (CFR) governing clinical study conduct 
and ethical principles that have their origin in the Declaration of Helsinki 
 
▪ Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
 
▪ Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 
 
▪ Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 
 
▪ Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 
 
▪ Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 
 
• State laws 
 
• Institutional research policies and procedures 
www.dfhcc.harvard.edu/clinical-research-support/clinical-research- 
operations-cro/policies-and-procedures 
 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy. 
 
13.4 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each research 
participant. This information enables the study to be fully documented and the study data 
to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded 


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data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, and/or x-rays. 
 
13.5 
Records Retention 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies. 
 
13.6 
Multi-center Guidelines 
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard 
Cancer Center. The specific responsibilities of the Principal Investigator (or 
Protocol Chair), Coordinating Center, and Participating Institutions are presented in 
the Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(see Appendix D. 
 
 
• The Principal Investigator/Coordinating Center is responsible for distributing all 
IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required. 
 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
 
• Except in very unusual circumstances, each participating institution will order 
the agent(s) directly from the supplier. A participating site may order the 
agent(s) only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center. 
 
14. STATISTICAL CONSIDERATIONS 
 
This is a standard 3+3 design Phase I study with an expansion cohort at the recommended 
Phase II dose to further explore the activity and safety of the regimen. 
 
14.1 
Study Design/Endpoints 
 
Phase I: 
The primary endpoint is to determine the MTD and DLT’s of the combination of everolimus and 
pazopanib. Safety and incidence of dose-limiting toxicities will be the primary outcome 
parameters. All patients in a dose cohort will complete 28 days (1 cycle) of combination treatment 
prior to the treatment of any patient at a higher dose level. If a patient does not complete the 28 
days of treatment for reasons that are clearly not adverse events related to 
treatment, then that patient will be replaced, up to three per dose level. If more than three patients 
need to be replaced on a dose level, then the reasons will be re-evaluated before continuing. 
There will be no intrapatient dose escalation. Pazopanib and everolimus will be escalated 
according to the standard 3+3 Phase I methodology and dose escalation rules (described in detail 
in Section 5.3.1). Once it is documented that the last patient in a cohort has completed 28 days of 


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therapy without evidence of excessive dose limiting toxicity, approval will be requested from the 
DF/HCC DSMB for dose escalation to the next dose level will occur. Successive cohorts of 
patients will be accrued to determine the maximum tolerated dose that results in <33% dose- 
limiting toxicities with the combination of everolimus and pazopanib in patients with metastatic 
kidney cancer. Up to six patients will be treated at the MTD before proceeding to the expansion 
cohort. 
 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Toxicities will be 
summarized as number and percent of patients, separately by dose cohort. Other safety data (e.g. 
electrocardiogram, vital signs, special tests) will be considered as appropriate. 
 
Adverse events will be summarized by presenting, for each dose cohort, the number and 
percentage of patients having any adverse event, having an adverse event in each body system, 
and having each individual adverse event. Any other information collected (e.g. severity or 
relatedness to study medication) will be listed as appropriate. Descriptive statistics will be 
calculated to characterize the disease and previous treatment features as well as the details of 
protocol therapy. Toxicities will be tabulated by grade for each dose cohort and overall for all 
patients accrued to the Phase I study. 
 
The probabilities of dose escalation for various true DLT rates are summarized below: 
 
True Probability of DLT at Current Dose 
0.10 
0.20 
0.30 
0.40 
0.50 
0.60 
0.70 
Probability that 
dose is escalated 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
 
 
Expansion cohort: 
 
The primary objective is to evaluate the safety and efficacy of the combination of 
pazopanib and everolimus in previously treated advanced urothelial carcinoma patients. 
The proportion of patients achieving objective response (OR) defined as complete or 
partial response per RECIST criteria as their best overall response is the primary 
endpoint. Simon’s two-stage design is employed to minimize accrual if treatment with 
pazopanib and everolimus is not effective. Achieving objective response in this 
population has historically been difficult. There no FDA approved second line therapy for 
urothelial cancer. The only European approved therapy in this setting is Vinflunine with a 
response rate of 9%.(48) The null hypothesis for this study is assumed to be 10%. 
 
 
 
Twenty-nine patients will be enrolled. Only eligible patients who start protocol therapy 
will be included in the response analysis. The first stage will accrue n=20 patients (n=18 
eligible treated patients). If 3 or more objective responses are observed among the first 
stage cohort then an additional 9 patients will be accrued (n=8 eligible treated patients). If 
5 or more responses are observed in the 26 eligible patients who started protocol therapy 


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then the combination of pazopanib with everolimus will be considered promising. The 
operating characteristics of this design are summarized below. If the true OR rate is 10%, 
the probability of stopping early at the first stage is 0.734 and the probability of accepting 
treatment for further study is 0.099 (Type I error). If the true OR rate is 30%, the 
probability of concluding the treatment is promising is 0.904 (power). Upon completion 
of the study, the true response rate will be estimated and an exact 90% confidence 
interval constructed. 
 
 
True Underlying Response Rate 
20% 
25% 
30% 
Probability of 
Stopping Early 
(<3/18) 
0.271 
0.135 
0.060 
Overall 
Probability of 
Concluding 
Effective (>5/29) 
0.577 
0.781 
0.904 
 
 
14.2  Sample Size/Accrual Rate 
 
 
Phase I: 2 patients per month, with a maximum of 30 patients 
Expansion cohort: 3 patients per month, with a maximum of 25 patients 
 
14.3   Stratification Factors 
N/A 
 
 
14.4 Analysis of Secondary Endpoints 
Phase I: 
 
Pharmacokinetic parameters will be analyzed to determine whether pharmacologically 
significant drug interactions are present between everolimus and pazopanib. The 
concentration of everolimus in whole blood and plasma will be determined using a 
validated assay involving high performance liquid chromatography with electrospray 
ionization mass spectrometric detection. Time points will be determined as the 
difference between the midpoint of the blood collection interval and starting time of dose 
administration. Concentration-time profiles will be analyzed by noncompartmental 
methods and/or nonlinear least squares regression using Professional version 4.0.1 
software package (Pharsight Corp., Cary, NC).  Pharmacokinetic parameters and 


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variables will be calculated according to standard equations.  Descriptive summaries of 
PK parameters (Ctrough, T1/2 and Cmax) will be provided by dose cohort. 
 
Secondary 
 
Secondary endpoints will evaluate safety, progression-free survival (PFS), overall 
survival (OS) and duration of response. Duration of response is calculated for objective 
responders and defined as the time in months from the first observation of a response 
(e.g., the first time that the appropriate RECIST 1.1 criteria was observed for confirmed 
responders) to the first documented progression or death due to any cause, whichever 
occurs first. Duration of response is censored at the date of last disease evaluation for 
patients who are known to be alive and who have not relapsed after a CR or PR. 
Progression-free survival is calculated as the months between registration and 
documented PD as determined by RECIST 1.1, or death due to any cause, whichever 
occurs first. Overall survival is defined as the time in months from registration to death 
due to any cause or, censored at the date last known alive. Patients alive without disease 
progression will be censored at the date of last disease evaluation. Time to event data will 
be estimated with the Kaplan-Meier method. Efficacy will further be described by 4- and 
12-month PFS and OS rates along with 90% CIs. Descriptive statistics will be used to 
characterize the disease and previous treatment features as well as the details of protocol 
therapy. 
 
Toxicity 
 
All patients who receive treatment will be included in toxicity analyses. A summary of 
the incidence of all treatment-related grade 3-5 toxicities will be provided as maximum 
grade by toxicity type and body system. Any other information collected (e.g. severity or 
relatedness to study medication) will be listed as appropriate. Overall maximum grade 3 
or higher treatment-related toxicity rates in all treated patients will be calculated. The 
table below shows the 90% confidence intervals for 0, 2, 4, and 6 patients with grade 3 or 
higher toxicity in a total of 29 treated patients. 
 
Observed 
Number of 
Patients with 
Grade > 3 
Toxicity 
Grade > 
3 
Toxicity 
Rate 
90% Confidence 
Interval for True 
but Unknown 
Grade > 3 
Toxicity Rate 
0 
0.0% 
(0.0%, 9.8%) 
2 
6.9% 
(1.3%, 20.2%) 
4 
13.8% 
(4.9%, 28.9%) 
6 
20.7% 
(9.4%, 36.8%) 


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Exploratory 
Relevant somatic and germline alterations will be identified by adaptation and 
modification of discovery-oriented algorithms in common use at the Broad Institute 
and MSKCC. We will also apply a series of computational algorithms that predict 
neutral, detrimental or activating variants. Upon completion, we will deliver a list of 
somatic and germline variants that perturb cancer genes and associated cellular 
pathways, associated with response to therapy in this cohort. Relevant associations 
between mutation status and treatment outcome will be assessed on an exploratory 
basis,  and  relevant  targeted  sequencing  may  be  performed  in  non-responders  to 
further understand the association between response to study therapy and somatic 
alterations. 
 
 
14.5 
Reporting and Exclusions 
 
 
14.5.1   Evaluation of toxicity. Any participant who has received at least one dose of 
study therapy will be evaluable for toxicity. Patients who experience toxicity not 
meeting the definition of DLT but do not complete 28 days of study treatment will 
be replaced. Reasons for not completing 28 days of therapy will be reviewed. 
 
14.5.2   Evaluation of response.  All participants who received treatment will be assessed 
for response to treatment, even if there are major protocol treatment deviations. 
Patients who did not receive any dose of study medication will not be included in the 
analysis.  Each  participant  will  be  assigned  one  of  the  following  categories:  1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, and 
unknown (not evaluable, insufficient data). 
 
All  conclusions  should  be  based  on  all  eligible  and  treated  participants  who 
received protocol therapy. Subanalyses will then be performed on the basis of a 
subset of participants, excluding those for whom major protocol deviations have been 
identified. However, these subanalyses will not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding participants 
from the analysis will be clearly reported. The 95% confidence intervals will be 
provided. 
 
Pregnancy 
 
Preclinical data regarding reproductive toxicity is described in the most recent 
Investigator Brochure. The potential reproductive risk for humans is unknown.  Women 
of childbearing potential should be advised to use highly effective contraception 
methods while they are receiving everolimus and up to 8 weeks after treatment has 
been stopped. 
 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth 


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defects, congenital abnormalities, or maternal and/or newborn complications. The 
newborn will be followed for at least 12 months. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department 
(DS&E). Pregnancy follow-up should be recorded on the same form and should include 
an assessment of the possible relationship to the study treatment and any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
 
15. PUBLICATION PLAN 
 
The phase I results of this study will be submitted for presentation as an abstract in 
2012. Full results will plan on being published in a peer reviewed publication in 2013. 
The expansion cohort results will be submitted for abstract presentation in 2014 and 
submitted for publication in 2015. 


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16. REFERENCES 
1. Boulay A, Lane HA: The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res 172:99-124, 2007 
2. Bjornsti MA, Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev 
Cancer 4:335-48, 2004 
3. Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell 
124:471-84, 2006 
4. Manning BD, Cantley LC: AKT/PKB signaling: navigating downstream. Cell 129:1261- 
74, 2007 
5. Tabernero J, Rojo F, Calvo E, et al: Dose- and schedule-dependent inhibition of the 
mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic 
study in patients with advanced solid tumors. J Clin Oncol 26:1603-10, 2008 
6. Amato RJ, Jac J, Giessinger S, et al: A phase 2 study with a daily regimen of the oral 
mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. 
Cancer 115:2438-46, 2009 
7. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449-56, 
2008 
8. Sternberg CN, Szczylik C, Lee E, et al: A randomized, double-blind phase III study of 
pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell 
carcinoma (RCC). J Clin Oncol (Meeting Abstracts) 27:5021-, 2009 
9. Motzer RJ, Russo P: Systemic therapy for renal cell carcinoma. J Urol 163:408-17, 2000 
10. 
Bochner BH, Cote RJ, Weidner N, et al: Angiogenesis in bladder cancer: relationship 
between microvessel density and tumor prognosis. J Natl Cancer Inst 87:1603-12, 1995 
11. 
Inoue K, Slaton JW, Karashima T, et al: The prognostic value of angiogenesis factor 
expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant 
chemotherapy and radical cystectomy. Clin Cancer Res 6:4866-73, 2000 
12. 
Philp EA, Stephenson TJ, Reed MW: Prognostic significance of angiogenesis in 
transitional cell carcinoma of the human urinary bladder. Br J Urol 77:352-7, 1996 
13. 
El-kott AF, El-baz MA, Mokhtar AA: Proliferating cell nuclear antigen (PCNA) 
overexpression and microvessel density predict survival in the urinary bladder carcinoma. Int 
Urol Nephrol 38:237-42, 2006 
14. 
Chaudhary R, Bromley M, Clarke NW, et al: Prognostic relevance of micro-vessel 
density in cancer of the urinary bladder. Anticancer Res 19:3479-84, 1999 
15. 
Dickinson AJ, Fox SB, Persad RA, et al: Quantification of angiogenesis as an 
independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74:762-6, 1994 
16. 
Jaeger TM, Weidner N, Chew K, et al: Tumor angiogenesis correlates with lymph node 
metastases in invasive bladder cancer. J Urol 154:69-71, 1995 
17. 
Canoglu A, Gogus C, Beduk Y, et al: Microvessel density as a prognostic marker in 
bladder carcinoma: correlation with tumor grade, stage and prognosis. Int Urol Nephrol 36:401- 
5, 2004 
18. 
Inoue K, Slaton JW, Davis DW, et al: Treatment of human metastatic transitional cell 
carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor 
receptor monoclonal antibody DC101 and paclitaxel. Clin Cancer Res 6:2635-43, 2000 


Everolimus-Pazopanib Phase I 
v. 11/3/16 
- 97 - 
 
 
 
 
19. 
Dinney CP, Bielenberg DR, Perrotte P, et al: Inhibition of basic fibroblast growth factor 
expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic 
interferon-alpha administration. Cancer Res 58:808-14, 1998 
20. 
Tanaka Y, Kawamata H, Fujimoto K, et al: Angiogenesis inhibitor TNP-470 suppresses 
tumorigenesis in rat urinary bladder. J Urol 157:683-8, 1997 
21. 
Campbell SC, Volpert OV, Ivanovich M, et al: Molecular mediators of angiogenesis in 
bladder cancer. Cancer Res 58:1298-304, 1998 
22. 
Crew JP, O'Brien T, Bradburn M, et al: Vascular endothelial growth factor is a predictor 
of relapse and stage progression in superficial bladder cancer. Cancer Res 57:5281-5, 1997 
23. 
O'Brien T, Cranston D, Fuggle S, et al: Different angiogenic pathways characterize 
superficial and invasive bladder cancer. Cancer Res 55:510-3, 1995 
24. 
Yang CC, Chu KC, Yeh WM: The expression of vascular endothelial growth factor in 
transitional cell carcinoma of urinary bladder is correlated with cancer progression. Urol Oncol 
22:1-6, 2004 
25. 
Wu W, Shu X, Hovsepyan H, et al: VEGF receptor expression and signaling in human 
bladder tumors. Oncogene 22:3361-70, 2003 
26. 
Bernardini S, Fauconnet S, Chabannes E, et al: Serum levels of vascular endothelial 
growth factor as a prognostic factor in bladder cancer. J Urol 166:1275-9, 2001 
27. 
Dvorak HF, Brown LF, Detmar M, et al: Vascular permeability factor/vascular 
endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 
146:1029-39, 1995 
28. 
Gallagher DJ, Milowsky MI, Gerst SR, et al: Phase II Study of Sunitinib in Patients 
With Metastatic Urothelial Cancer. Journal of Clinical Oncology 28:1373-1379, 2010 
29. 
Bellmunt J, Gonzalez-Larriba JL, Maroto JP, et al: First-line treatment with sunitinib 
monotherapy in patients with advanced urothelial cancer ineligible for cisplatin-based 
chemotherapy: Pretreatment levels of IL8 and Hounsfield units as predictors of clinical benefit. 
ASCO Meeting Abstracts 28:4540, 2010 
30. 
Necchi A, Nicolai N, Ortega C, et al: Updated results of INT70/09 phase II study of 
pazopanib (PZP) monotherapy for patients with relapsed/refractory urothelial cancer (UC). 
ASCO Meeting Abstracts 29:4618, 2011 
31. 
Pili R, Qin R, Flynn PJ, et al: MC0553: A phase II safety and efficacy study with the 
VEGF receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer. 
ASCO Meeting Abstracts 29:259, 2011 
32. 
Kwiatkowski DJ, Manning BD: Tuberous sclerosis: a GAP at the crossroads of multiple 
signaling pathways. Hum. Mol. Genet. 14:R251-258, 2005 
33. 
Edinger AL, Thompson CB: Akt maintains cell size and survival by increasing mTOR- 
dependent nutrient uptake. Mol Biol Cell 13:2276-88, 2002 
34. 
Sekulic A, Hudson CC, Homme JL, et al: A direct linkage between the 
phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in 
mitogen-stimulated and transformed cells. Cancer Res 60:3504-13, 2000 
35. 
Wu X, Obata T, Khan Q, et al: The phosphatidylinositol-3 kinase pathway regulates 
bladder cancer cell invasion. BJU International 93:143-150, 2004 
36. 
Benistant C, Chapuis H, Roche S: A specific function for phosphatidylinositol 3-kinase 
alpha (p85alpha-p110alpha) in cell survival and for phosphatidylinositol 3-kinase beta 


Everolimus-Pazopanib Phase I 
v. 11/3/16 
- 98 - 
 
 
 
 
(p85alpha-p110beta) in de novo DNA synthesis of human colon carcinoma cells. Oncogene 
19:5083-90, 2000 
37. 
Park SJ, Lee TJ, Chang IH: Role of the mTOR Pathway in the Progression and 
Recurrence of Bladder Cancer: An Immunohistochemical Tissue Microarray Study. Korean J 
Urol 52:466-473, 2011 
38. 
Sun C-H, Chang Y-H, Pan C-C: Activation of the PI3K/Akt/mTOR pathway correlates 
with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary 
bladder. Histopathology 58:1054-1063, 2011 
39. 
Knowles MA, Habuchi T, Kennedy W, et al: Mutation Spectrum of the 9q34 Tuberous 
Sclerosis Gene TSC1 in Transitional Cell Carcinoma of the Bladder. Cancer Res 63:7652-7656, 
2003 
40. 
Mhawech-Fauceglia P, Cheney RT, Schwaller J: Genetic alterations in urothelial 
bladder carcinoma. Cancer 106:1205-1216, 2006 
41. 
Sjodahl G, Lauss M, Gudjonsson S, et al: A systematic study of gene mutations in 
urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. PLoS One 6:e18583, 2011 
42. 
Cairns P, Evron E, Okami K, et al: Point mutation and homozygous deletion of 
PTEN/MMAC1 in primary bladder cancers. Oncogene 16:3215-8, 1998 
43. 
Aveyard JS, Skilleter A, Habuchi T, et al: Somatic mutation of PTEN in bladder 
carcinoma. Br J Cancer 80:904-8, 1999 
44. 
Laugier P, Kuffer R, Olmos L, et al: [Cowden disease: report of 8 cases in 2 families 
(author's transl)]. Ann Dermatol Venereol 106:453-63, 1979 
45. 
Hauser H, Ody B, Plojoux O, et al: Radiological findings in multiple hamartoma 
syndrome (Cowden disease): a report of three cases. Radiology 137:317-23, 1980 
46. 
Chiong E, Lee I-L, Dadbin A, et al: Effects of mTOR Inhibitor everolimus (RAD001) 
on Bladder Cancer Cells. Clinical Cancer Research 17:2863-2873, 2011 
47.    Vasconcelos-Nóbrega C, Pinto-Leite R, Arantes-Rodrigues R, et al: In vivo and in vitro 
effects of RAD001 on bladder cancer. Urologic Oncology: Seminars and Original Investigations 
Epub, 2011 
48. 
Milowsky MI, Regazzi AM, Garcia-Grossman IR, et al: Final results of a phase II study 
of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium. 
ASCO Meeting Abstracts 29:4606, 2011 
49. 
Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, et al: Inactivation of p53 and Pten 
promotes invasive bladder cancer. Genes Dev 23:675-80, 2009 
50. 
O'Reilly T, Wood JM, Littlewood-Evans A, et al: Differential anti-vascular effects of 
mTOR or VEGFR pathway inhibition: A rational basis for combining RAD001 and 
PTK787/ZK222584. Proc Amer Assoc Cancer Res 2005:3038, 2005 
51. 
DePrimo S, Bello C, Smeraglia J, et al: Circulating protein biomarkers of 
pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: 
modulation of VEGF and VEGF-related proteins. Journal of Translational Medicine 5:32, 2007 
52. 
Wagle N, Emery C, Berger MF, et al: Dissecting Therapeutic Resistance to RAF 
Inhibition in Melanoma by Tumor Genomic Profiling. J Clin Oncol, 2011 
53. 
Wagle N, Berger MF, Davis MJ, et al: High-throughput detection of actionable genomic 
alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer 
discovery 2:82-93, 2012 


Everolimus-Pazopanib Phase I 
v. 11/3/16 
- 99 - 
 
 
 
 
54. 
Li H, Durbin R: Fast and accurate long-read alignment with Burrows-Wheeler 
transform. Bioinformatics 26:589-95, 2010 
55. 
DePristo MA, Banks E, Poplin R, et al: A framework for variation discovery and 
genotyping using next-generation DNA sequencing data. Nature genetics 43:491-8, 2011 
56. 
McKenna A, Hanna M, Banks E, et al: The Genome Analysis Toolkit: A MapReduce 
framework for analyzing next-generation DNA sequencing data. Genome Research 20:1297- 
1303, 2010 
57. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 


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17. APPENDICES Appendix A 
 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self- 
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self- 
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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Appendix B 
Pazopanib Blood Pharmacokinetic Collection and Handling 
 
Pharmacokinetic Sample Supplies 
 
GlaxoSmithKline will provide all tubes for blood collection, storage, and labels with the visit 
name and time of sample collection (tubes sent as bulk shipment with separate labels). 
 
Blood samples for the determination of plasma pazopanib concentrations will be collected into 
2mLEDTA vacutainers. The blood samples will be collected into tubes and immediately placed 
on ice. Samples will be centrifuged at 3000 RPM for 10 minutes under chilled conditions 
(approximately 4C).  Transfer no more than 750µL of the resultant plasma 
into 
appropriately labelled 1.4mL Matrix TrakMate polypropylene tubes and 
stored frozen (within 60 minutes of the sampling time) at -20C. 
 
PK Blood Collection Tubes Labels 
 
Please place labels on the tubes vertically, as they are found in the picture. 
Do 
not place them horizontally around the tube, resulting in a tag. 
 
 
DMPK Shipping Guide- Pazopanib 
 
Specific regulations exist for the shipment of biological specimens. The 
Department of Drug Metabolism and Pharmacokinetics (DMPK) requires 
the use of IATA/ICAO regulations when specimens are shipped on our 
behalf. 
It is the sender’s responsibility to abide by all regulations. 
Notification of Shipment 
Please remember to notify the department of DMPK as soon as possible, but at least two days 
in advance of any shipment. DO NOT leave a message on an answering machine. Please state 
protocol number, expected shipping date, carrier, estimated time of arrival and airway bill 
number if applicable. 
Frozen samples should be shipped on solid carbon dioxide. 
Shipping Days 
Please ship MONDAY through WEDNESDAY only 
Please ensure that wherever possible samples are transported so as to arrive between the hours of 
09:00 and 16:00. 
UM Sample Management Contact Details: 
The shipping boxes must be clearly labeled with the following address: 
GlaxoSmithKline 
Department of Drug Metabolism and PharmacoKinetics 
Mail Stop UW2710 
709 Swedeland Road 
King of Prussia, PA 19406 
USA 


Everolimus-Pazopanib Phase I 
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Attn: Kathleen Dolce/ Josh Albert 
 
Phone # 
Mail Code 
FAX 
Kathleen Dolce 
610-270-6757 
UW2710 
610-270-4971 
Josh Albert 
610-270-6549 
UW2710 
610-270-4971 
Michael Adamek 
610-270-4658 
UW2710 
610-270-4971 
 
Packaging instructions: 
 
NOTE: Do not let samples thaw while packaging! 
1.   Place individual tubes into Matrix 96 well rack. Place rack into a large bag with absorbent material. 
Place bags with racks in bottom of cooler. 
2.   Fill box completely with dry ice and put top on cooler. 
3.   Enclose a copy of the requisition forms, corresponding to the samples in that box, in a bag or 
envelope and place on the top of the cooler. 
4.   Close the flaps and tape shut. 
5.   Complete the airbill and shipping labels, according to the directions below. Affix airbill to top of 
shipping box. 
 
 
 
Example UPS Airbill 
 
 
 
*Please use one airbill per box 
You must enter on the airbill: 
• Your site’s address 


Everolimus-Pazopanib Phase I 
v. 11/3/16 
- 103 - 
 
 
 
 
• The weight of the package in lbs. 
• The weight of the dry ice in KG 
• Sender’s signature 
 
Shipping Box 
 
1.   Complete the following label found on the specimen shipping box: 
 
• 
Address/return address label (fill in blanks) 
 
• 
Carbon dioxide, solid [Dry Ice] UN1845 #KG (fill in blank). Note:  This weight 
should match the weight on the airbill. 
 
2.   Prior to shipping, notify the following individuals of the airbill number(s), the number of 
boxes shipped, the nature of the shipment (i.e.: medical specimens), and scheduled 
shipment/pick-up and arrival date. 
 
• 
UPS Office at 1-800-877-1497 and give them account# 301923. 
 
• 
GlaxoSmithKline DMPK via the FAX page located in the PK Sample Information and 
Shipping Notebook (Fax: 610-270-4971). 


Everolimus-Pazopanib Phase I 
v. 11/3/16 
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Cycle 1 shipping Form – Include with Pazopanib PK samples 
 
 
STUDY NUMBER 
Pazopanib Plasma Requisition Form 
A copy of this completed page must accompany the samples being shipped to GlaxoSmithKline. Please keep a 
copy for your records. Please use a new sheet for each subject/shipment. 
Subject Number:  
 
Cycle 1 
Day 
Time- 
point 
Time 
 if included in 
this shipment 
Comments 
Rec'd By 
1 
0h 
1 
1h 
1 
2h 
1 
4h 
1 
6h 
1 
24h 
1 
48h 
(If Applicable) 
15 
0h 
15 
1h 
15 
2h 
15 
4h 
15 
6h 
15 
24h 
15 
48h 
(If Applicable) 


Everolimus-Pazopanib Phase I 
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Cycle 2 Shipping Form – Include with Pazopanib PK samples 
 
 
 
 
STUDY NUMBER 
Pazopanib Plasma Requisition Form 
 
A copy of this completed page must accompany the samples being shipped to GlaxoSmithKline. Please keep a 
copy for your records. Please use a new sheet for each subject/shipment. 
 
 
 
Subject Number:  
 
Cycle 2, 4 
 
 
 
Cycle 
Day 
Time- 
point 
Time 
 if included in 
this shipment 
Comments 
Rec'd By 
2 
1 
0h 
4 
1 
0h 


Everolimus-Pazopanib Phase I 
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Sample Collection and Storage for Pazopanib 
At each of the sampling times, blood samples (2 mL) will be drawn into a K3 EDTA vacutainer, 
and centrifuged for 10 minutes to separate the plasma. The plasma will be transferred into pre- 
labeled storage tubes for analysis of paclitaxel and stored at approximately -20C. Sample 
handling from collection to storage should not exceed 60 minutes. A blood sample will be taken 
prior to the pazopanib dose, and at 0, 1, 2, 4, 6, and 24 hours.  If patients are treated on dose level 
-1, there will be a 48 hour blood draw (pre-dose) as well. 
 
 
All tubes must be frozen in an upright position to keep the plasma in the bottom of the tube. Until 
assayed, the samples must remain frozen in a freezer set at approximately -20°C or when shipping 
in a box with dry ice. Prior to collection, the collection tube and plasma storage tube must be 
labeled with the corresponding bar-coded labels provided by GSK.  The sample labels will 
include Protocol Number, Analyte, Subject Number, Relative Sample Time, Cycle and Dosing 
Day.  The labels must be placed along the length of the tube so the bar code can be easily read.  
Tape must not be used to secure the labels otherwise the tube will not fit into the autoanalyzer test 
tube rack. The labels are high quality and will not peel off of the tube even under extreme 
conditions. 
 
The sample will be centrifuged at approximately 1000 x g for 10 to 15 minutes. The resulting 
plasma will be transferred to the corresponding pre-labeled polypropylene storage tube (2mL). See 
shipping instructions with regard to packing the samples, enclosing a manifold with a sample 
inventory, and notification of the analytical sites prior to shipping. 


Everolimus-Pazopanib Phase I 
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APPENDIX C 
 
Instructions for Collecting, Processing, Storing, and Shipping 
Everolimus Pharmacokinetic Sample 
 
C.1 
Venous access 
 
Pharmacokinetic samples may be collected from a central catheter for this study because 
everolimus is given orally. 
 
For patients without a central catheter, place a large gauge peripheral catheter (e.g., 19 or 20 
gauge angiocath straight set with T-connector, or similar IV access device) in an arm vein 
for the collection of pharmacokinetic blood samples on days when multiple samples are to 
be collected. Maintain patency of the catheter between blood draws using either a heparin 
lock (e.g., 10 U/mL in normal saline) or a slow drip of Normal Saline for Injection, USP 
(e.g., 10 mL/hr). 
 
Blood may be obtained directly by venipuncture on days when only a single 
pharmacokinetic blood specimen is scheduled for collection. 
 
When sampling through a catheter, begin to clear the catheter approximately 1 min before 
the specified sample time by withdrawing the lock solution and approximately 0.5 mL of 
blood into a syringe. Remove and properly dispose the syringe used to clear the catheter. 
The catheter should be well-flushed after collecting each sample. 
 
C.2 
Timing 
 
A battery-powered digital timer/stopwatch programmed to operate continuously as a 24- 
hr clock will be used to accurately monitor drug administration and sample collection 
times.  The same timer must be allowed to run without interruption until the last blood 
specimen has been obtained from the subject during the first cycle of therapy. 
 
Timer readings will be noted at the precise time that the infusion is started and ended, as 
well as at the beginning and ending times of the blood sample collection intervals. 
 
Readings of the digital timer must be directly recorded on a copy of the appropriate 
DF/HCC Pharmacokinetic Dosing and Blood Collection Time Form' (see below). 
C.3 
Sample collection 
As indicated in section 8.1, two blood samples are to be collected in 2.0 mL Vacutainer 
plastic whole blood collection tube with spray-coated K2-EDTA (Becton-Dickinson, item 
no. 367863) at each and every time point. 
 
C.4 
Sample processing and storage 


Everolimus-Pazopanib Phase I 
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Promptly mix the blood collection tubes by gently inverting 6-times. 
 
Transfer the whole blood from one tube collected at each time point directly into a 4.5 
mL self-standing polypropylene microcentrifuge cryogenic tube with external threads 
(Fisher Scientific, cat. no. 12-565-291). 
 
Centrifuge the other tube of blood collected at each time point at 1,300 x g for 10 min 
within 15 min after collection.  Separate the plasma from the blood cells using a pipette 
and transfer the plasma it into a polypropylene cryogenic storage vial with external 
threads. 
 
Affix a pre-printed labels (protocol number, patient entry no., sample no., scheduled 
sample time) to the cryotube, oriented lengthwise toward the upper part of the tube.  Do 
not place the label over the vial cap.  Hand-written information on sample tube labels is 
absolutely prohibited. 
 
Completely cover the label with protective cryogenic freezer tape (e.g., Fisher Scientific, 
cat. no. 11-867B). 
 
 
Place the tube on crushed dry-ice until stored in a freezer maintained at -70°C until 
packaged for shipment. 
 
C.5 
Time forms and sample tube/vial labels 
 
 
Computer files for dose administration and sample collection time forms and specimen 
tube labels will be placed in a subdirectory located on a secure network server 
(W:\PHASE1RD) maintained by Partners HealthCare System (PHS) Information 
Resources.   All members of the clinical, laboratory, and administrative staff involved 
with Phase I studies should have read-only access to this subdirectory, which may be 
obtained by contacting Susan Oliveira by email (see PHS Global e-mail directory). 
 
The files are placed under the following subdirectories:    PK_Time_Forms; 
PK_Tube_Labels. 
 
Files for the PK time forms are to be printed directly from the file stored on the network 
server for each subject study.  Since changes may be periodically made to these forms, 
they should not be copied onto user personal computers and staff members are instructed 
not to make photocopies of blank forms. 
 
The PK_Tube_Label files are templates that are intended to be copied and edited by 
replacing the word 'code' with the patient entry number using the MS Word edit/replace 
all function and printed on an Avery 5260 label sheet.   Hand-written information on 
sample tube labels is absolutely prohibited.  There are separate sets of labels for blood 
collection tubes and sample storage tubes. Blood collection tubes should be pre-labeled. 


Everolimus-Pazopanib Phase I 
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- 109 - 
 
 
 
 
 
C.6 
Sample shipment 
 
Contact 
Susan 
Oliveira 
(tel: 
617-726-5868 
or 
617-726-5854; 
e-mail: 
soliveira2@partners.org) or Dr. Jeffrey Supko (email: supko.jeffrey@mgh.harvard.edu) 
to arrange transportation of each complete set of samples to the DF/HCC Cancer 
Pharmacology Core at the Massachusetts General Hospital, 55 Fruit Street, Room 
GRJ1025, Boston, MA 02114. 


Everolimus-Pazopanib Phase I 
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- 110 - 
 
 
 
 
 
APPENDIX D 
 
 
 
Drug Supply Request Form 
 
 
PI: 
 
GSK Study Number: 
Title of Study: 
 
In order to facilitate your shipment for drug supply, please fill in the following information. If you have 
any questions regarding completing this form, please contact Kamal Bhatt, via telephone at (610)917- 
5768 or via email at Kamalnayan.H.Bhatt@gsk.com. 
 
 
The full shipping address for drug supply: 
 
Institution Name 
Full Street Address (with contact name/phone #) 
 
Specific dosage requested 
Amount Requested 
 
For CRT (investigator initiated) studies, the PI holds the IND and is therefore responsible for following 
CFR and GCP for labeling and dispensing (21 CFR 312.6). GSK will ship labeled pazopanib bottles in a 
sealed carton (68 tabs per bottle for pazopanib 400mg and 34 tabs/btl for pazopanib 200mg). A label 
will be affixed to each carton identifying the product, strength and number of bottles. In addition, a 
packing slip will be enclosed with the drug name, strength, lot/batch #, storage conditions, and 
expiration/retest date. 


 
 
 
Appendix E: Genes in NGS sequencing assay 
 
ABL1 
BCL6 
CDK8 
DNMT3A 
ERBB3 
FLT3 
HRAS 
KDM6A 
MET 
NFKB1 
PHOX2B 
PTPN11 
SMARCA4 
TOP1 
ABL2 
BCOR 
CDKN1A 
DNMT3B 
ERBB4 
FLT4 
HSP90AA1 
KDR 
MITF 
NFKB2 
PIK3C2G 
PTPRD 
SMARCB1 
TP53 
AKT1 
BIRC2 
CDKN2A 
E2F3 
ERG 
FOXL2 
IDH1 
KEAP1 
MLH1 
NKX2‐1 
PIK3CA 
PTPRS 
SMO 
TP63 
AKT2 
BRAF 
CDKN2B 
EGFR 
ESR1 
FUBP1 
IDH2 
KIT 
MLL 
NOTCH1 
PIK3CB 
PTPRT 
SOCS1 
TSC1 
AKT3 
BRCA1 
CDKN2C 
EIF4EBP1 
ETV1 
GATA1 
IGF1R 
KLF6 
MLL2 
NOTCH2 
PIK3CD 
RAF1 
SOX2 
TSC2 
ALK 
BRCA2 
CEBPA 
EP300 
ETV6 
GATA2 
IGFBP7 
KRAS 
MLL3 
NOTCH3 
PIK3CG 
RARA 
SPOP 
TSHR 
ALOX12B 
BUB1B 
CHEK1 
EPHA10 
EZH2 
GATA3 
IKBKE 
LDHA 
MLST8 
NOTCH4 
PIK3R1 
RB1 
SRC 
U2AF1 
APC 
CARD11 
CHEK2 
EPHA2 
FAM123B 
GLI1 
IKZF1 
LGR6 
MPL 
NPM1 
PIK3R2 
REL 
SRSF2 
VHL 
AR 
CBL 
CIC 
EPHA3 
FAM46C 
GLI3 
IL7R 
LMO1 
MSH2 
NRAS 
PIK3R3 
RET 
STAG2 
WAS 
ARAF 
CBLB 
CREBBP 
EPHA4 
FAS 
GNA11 
INPP4A 
MAGI2 
MSH6 
NTRK1 
PKM2 
RICTOR 
STK11 
WNK1 
ARHGAP26 
CCND1 
CRKL 
EPHA5 
FAT1 
GNAQ 
INPP4B 
MAP2K1 
MTOR 
NTRK2 
PLK2 
RNF43 
SUFU 
WT1 
ARID1A 
CCNE1 
CRLF2 
EPHA6 
FBXO11 
GNAS 
INSR 
MAP2K2 
MYB 
NTRK3 
PNRC1 
ROR2 
TBK1 
XPO1 
ARID2 
CD79B 
CSF1R 
EPHA7 
FBXW7 
GOLPH3 
IRS1 
MAP2K4 
MYC 
PAK7 
PPP2R1A 
ROS1 
TEK 
YAP1 
ASXL1 
CDC42EP2 
CTNNB1 
EPHA8 
FGFR1 
GRIN2A 
IRS2 
MAP3K8 
MYCL1 
PALB2 
PRDM1 
RPTOR 
TERT 
YES1 
ATM 
CDC73 
CYLD 
EPHB1 
FGFR2 
GRM3 
JAK1 
MCL1 
MYCN 
PARK2 
PREX2 
RUNX1 
TET1 
ZRSR2 
ATRX 
CDH1 
DAXX 
EPHB2 
FGFR3 
GSK3B 
JAK2 
MDM2 
MYD88 
PARP1 
PRKAA2 
SDHB 
TET2 
AURKA 
CDH11 
DDR2 
EPHB3 
FGFR4 
HDAC2 
JAK3 
MDM4 
NCOA2 
PAX5 
PRKAR1A 
SETD2 
TGFBR2 
BAP1 
CDK12 
DICER1 
EPHB4 
FH 
HIF1A 
JUN 
MED12 
NF1 
PBRM1 
PRKCI 
SF3B1 
TMPRSS2 
BCL2L1 
CDK4 
DIS3 
EPHB6 
FLCN 
HMGA2 
KCNJ5 
MEF2B 
NF2 
PDGFRA 
PTCH1 
SHQ1 
TNFAIP3 
BCL2L11 
CDK6 
DNMT1 
ERBB2 
FLT1 
HNF1A 
KDM5C 
MEN1 
NFE2L2 
PDGFRB 
PTEN 
SMAD4 
TNFRSF14