Clinical trial NCT01784861
Conditions: Adenocarcinoma Pancreatic Neoplasms
Sponsor: Washington University School of Medicine
Start date: 2013-05-03; Completion date: 2020-08-19
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is to evaluate the combination of an investigational drug X-82 with everolimus in the treatment of pancreatic neuroendocrine tumors.

Detailed description:

Arms: arm 1: * X-82 100 mg by mouth once daily
* Everolimus 10mg by mouth once daily for each cycle
* Everolimus and X-82 should be taken at the same time every day
* 28 days =1 cycle arm 2: * X-82 150 mg by mouth once daily
* Everolimus 10mg by mouth once daily for each cycle
* Everolimus and X-82 should be taken at the same time every day
* 28 days =1 cycle arm 3: * X-82 200 mg by mouth once daily
* Everolimus 10mg by mouth once daily for each cycle
* Everolimus and X-82 should be taken at the same time every day
* 28 days =1 cycle arm 4: * X-82 (dose determined by Phase I portion to be 300 mg) mg by mouth once daily
* Everolimus 10mg by mouth once daily for each cycle
* 28 days =1 cycle arm 5: * X-82 300 mg by mouth once daily
* Everolimus 10mg by mouth once daily for each cycle
* Everolimus and X-82 should be taken at the same time every day
* 28 days =1 cycle arm 6: * Everolimus 10mg by mouth once daily for each cycle MUST BE TAKEN FIRST
* X-82 400 mg by mouth once daily 2 HOURS AFTER everolimus dose
* 28 days =1 cycle
Interventions: intervention 1: X-82 intervention 2: Everolimus
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Amendment 8: Version: 01/29/16 
 
Page 1 of 66 
 
 
A phase I/II study of X-82, an oral anti-VEGFR tyrosine kinase inhibitor, with everolimus 
for patients with pancreatic neuroendocrine tumors 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol#:  201303150 
Version Date: 01/29/16 
 
Principal Investigator: 
Benjamin R. Tan, M.D. 
Phone:  (314) 362-5740 
E-mail:  btan@dom.wustl.edu 
 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Andrea Wang-Gillam, M.D., Ph.D. 
Washington University  
Medical Oncology 
A. Craig Lockhart, M.D. 
 
Washington University  
Medical Oncology 
Michael Naughton, M.D. 
 
Washington University  
Medical Oncology 
Joel Picus, M.D. 
 
 
Washington University  
Medical Oncology 
Anna Roshal, M.D. 
 
 
Washington University  
Medical Oncology 
Bruce Roth, M.D. 
 
 
Washington University  
Medical Oncology 
Rama Suresh, M.D. 
 
 
Washington University  
Medical Oncology 
Tanya M. Wildes, M.D.  
 
Washington University  
Medical Oncology 
Kathryn Fowler, M.D.  
 
Washington University  
Radiology 
Feng Gao, Ph.D. 
 
 
Washington University  
Biostatistics 
Bert H. O’Neil, M.D. 
 
 
Indiana University 
 
Medical Oncology 
Emily Chan, M.D. 
 
 
Vanderbilt University 
 
Medical Oncology 
 
 
Study Drug(s): 
 
X-82 
Everolimus 
 
IND#: 
117888 
Clinical Trials.gov#: 
NCT01784861 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


Amendment 8: Version: 01/29/16 
 
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A phase I/II study of X-82, an oral anti-VEGFR tyrosine kinase inhibitor, with everolimus 
for patients with pancreatic neuroendocrine tumors 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
04/03/13 
Amendment #1 Version 
 
 
 
 
 
 
06/03/13 
Amendment #2 Version 
 
 
 
 
 
 
11/06/13 
Amendment #3 Version 
 
 
 
 
 
 
01/23/14 
Amendment #4 Version 
 
 
 
 
 
 
04/01/14 
Amendment #5 Version 
 
 
 
 
 
 
09/05/14 
Amendment #6 Version 
 
 
 
 
 
 
02/27/15 
Amendment #7 Version 
 
 
 
 
 
 
10/28/15 
Amendment #8 Version  
 
 
 
 
 
 
01/29/16 


Amendment 8: Version: 01/29/16 
 
Page 3 of 66 
A phase I/II study of X-82, an oral anti-VEGFR tyrosine kinase inhibitor, with everolimus 
for patients with pancreatic neuroendocrine tumors 
 
Principal Investigator Signature Page 
 
 
Principal Investigator: 
 
Benjamin R. Tan, M.D. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 4 of 66 
 
A phase I/II study of X-82, an oral anti-VEGFR tyrosine kinase inhibitor, with everolimus 
for patients with pancreatic neuroendocrine tumors 
 
SCHEMA 
 
 
Phase I 
 
Dose Escalation Schedule 
Dose Level 
X-82 Dose 
Everolimus Dose 
Level -1 
50 mg QD 
10 mg QD 
Level 0 (Starting Dose) 
100 mg QD 
10 mg QD 
Level 1 
150 mg QD 
10 mg QD 
Level 2 
200 mg QD 
10 mg QD 
Level 3 
300 mg QD 
10 mg QD 
Level 4 
400 mg QD 
10 mg QD 
 
Note: Enrollment to Phase II and the PK Expansion Cohort will take place simultaneously. 
 
Phase II 
 
X-82 will be given orally once daily at the recommended phase II dose.  Everolimus 10 mg will 
be given orally once daily.  These patients will be randomized to one of two groups: the first group 
will begin taking everolimus 3 weeks prior to initiating X-82, while the second group will begin 
taking X-82 3 weeks prior to initiating everolimus.  Cycle 1 Day 1 will be considered the day when 
both study drugs are taken together for the first time.  The lead-in period will be referred to as 
Cycle 0. 
 
 
PK Expansion Cohort for Renal Cell Carcinoma 
 
X-82 will be given orally once daily at the recommended phase II dose.  Everolimus 10 mg will 
be given orally once daily.  Three evaluable patients with renal cell carcinoma will be enrolled to 
each of the following groups: 
 
Group A: Will take everolimus first, followed by X-82 two hours later 
Group B: Will take everolimus first, followed by X-82 four hours later 
Group C: Will take X-82 and everolimus at the same time 
 
Blood will be drawn for pharmacokinetic testing on Cycle 1 Day 14. 
 
 


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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
AUC 
Area under the curve 
BP 
Blood pressure 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMP 
Complete metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DCE-MRI 
Dynamic contrast enhanced-magnetic resonance imaging 
DLTs 
Dose Limiting Toxicities 
DNA 
Deoxyribonucleic acid 
DOB 
Date of birth 
DSM 
Data and Safety Monitoring  
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FWA 
Federal wide assurance 
G-CSF 
Granulocyte colony stimulating factor, filgrastim (Neupogen) 
GI 
Gastrointestinal 
GPS@WU 
Genomic and Pathology Services at Washington University 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HHS 
Department of Health and Human Services’ 
HIV 
Human immunodeficiency virus 
HRPO 
Human Research Protection Office (IRB) 
HTN 
Hypertension 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LD 
Longest diameter 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 


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MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NET 
Neuroendocrine tumor 
NIH 
National Institutes of Health 
NSE 
Neuron-specific enolase 
NYHA 
New York Heart Association 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PIGF 
Placental growth factor 
PNET 
Pancreatic neuroendocrine tumors 
PO 
Per os (orally) 
PR 
Partial response 
PTEN 
Phosphatase and tensin homolog 
QASMC 
Quality Assurance and Safety Monitoring Committee 
QD 
Quaque die (every day) 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
TKI 
Tyrosine kinase inhibitor 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UPC 
Urine protein to creatinine ratio 
UPN 
Unique patient number 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
WU-CaMP 
Washington University Cancer Mutational Profile 
 
 


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Table of Contents 
 
SCHEMA ........................................................................................................................................ 4 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 9 
1.1 
Neuroendocrine Tumors ................................................................................................... 9 
1.2 
Tyrosine kinase inhibition and NETs ............................................................................... 9 
1.3 
mTOR inhibition and NETs ............................................................................................. 9 
1.4 
X-82 ................................................................................................................................ 10 
1.5 
Study Rationale .............................................................................................................. 11 
1.6 
Correlative Studies Background..................................................................................... 12 
2.0 
OBJECTIVES .................................................................................................................... 13 
2.1 
Primary Objectives ......................................................................................................... 13 
2.2 
Secondary Objectives (Phase II) .................................................................................... 13 
2.3 
Exploratory Objectives ................................................................................................... 13 
3.0 
PATIENT SELECTION .................................................................................................... 14 
3.1 
Phase I and PK Expansion Cohort Eligibility ................................................................ 14 
3.2 
Phase II Eligibility .......................................................................................................... 16 
3.3 
Inclusion of Women and Minorities............................................................................... 20 
4.0 
REGISTRATION PROCEDURES ................................................................................... 20 
4.1 
Confirmation of Patient Eligibility ................................................................................. 20 
4.2 
Patient Registration in the Siteman Cancer Center Database ........................................ 21 
4.3 
Assignment of UPN ....................................................................................................... 21 
4.4 
Phase II Randomization ................................................................................................. 21 
5.0 
TREATMENT PLAN ........................................................................................................ 21 
5.1 
Agent Administration ..................................................................................................... 21 
5.2 
Dose Escalation Schema ................................................................................................ 23 
5.3 
Phase II Treatment Plan ................................................................................................. 23 
5.4 
PK Expansion Cohort ..................................................................................................... 23 
5.5 
Definition of MTD, DLT, Dose Escalation Criteria, and Toxicity, Response, and DLT 
Evaluations ................................................................................................................................ 24 
5.6 
General Concomitant Medication and Supportive Care Guidelines .............................. 25 
5.7 
Women of Childbearing Potential .................................................................................. 27 
5.8 
Duration of Therapy ....................................................................................................... 27 
5.9 
Duration of Follow-up .................................................................................................... 28 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 28 
6.1 
X-82 Dose Modifications ............................................................................................... 28 
6.2 
Everolimus Dose Modifications ..................................................................................... 29 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 31 
7.1 
Adverse Events (AEs) .................................................................................................... 31 
7.2 
Unanticipated Problems ................................................................................................. 31 
7.3 
Noncompliance............................................................................................................... 32 
7.4 
Serious Noncompliance.................................................................................................. 32 
7.5 
Protocol Exceptions........................................................................................................ 32 
7.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality Assurance 
and Safety Monitoring Committee (QASMC) at Washington University ................................ 32 
7.7 
Reporting Requirements for Secondary Sites ................................................................ 33 


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7.8 
Reporting to Secondary Sites ......................................................................................... 33 
7.9 
Reporting to the FDA ..................................................................................................... 34 
7.10 Reporting to Tyrogenex ................................................................................................. 35 
7.11 Timeframe for Reporting Required Events .................................................................... 35 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 35 
8.1 
X-82 ................................................................................................................................ 35 
8.2 
Everolimus ..................................................................................................................... 36 
9.0 
CORRELATIVE STUDIES .............................................................................................. 39 
9.1 
Archived Tumor Tissue .................................................................................................. 39 
9.2 
Tumor Biopsy (Optional) ............................................................................................... 39 
9.3 
Blood Samples................................................................................................................ 40 
9.4 
DCE-MRI (Phase II Only - Optional) ............................................................................ 41 
9.5 
Blood for Pharmacokinetic Testing (PK Expansion Cohort Only) ................................ 41 
10.0 STUDY CALENDAR ....................................................................................................... 43 
10.1 Phase I and PK Expansion Cohort Study Calendar........................................................ 43 
10.2 Phase II Study Calendar ................................................................................................. 44 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 45 
12.0 MEASUREMENT OF EFFECT........................................................................................ 46 
12.1 Antitumor Effect – Solid Tumors................................................................................... 46 
12.2 Disease Parameters ......................................................................................................... 46 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 47 
12.4 Response Criteria ........................................................................................................... 48 
13.0 DATA AND SAFETY MONITORING ............................................................................ 51 
14.0 AUDITING ........................................................................................................................ 52 
15.0 STATISTICAL CONSIDERATIONS............................................................................... 53 
15.1 Primary Endpoints and Objectives ................................................................................. 53 
15.2 Study Design .................................................................................................................. 53 
15.3 Data Analysis of the Phase II Study ............................................................................... 54 
15.4 DCE-MRI Analyses ....................................................................................................... 54 
16.0 MULTICENTER REGULATORY REQUIREMENTS ................................................... 54 
17.0 REFERENCES .................................................................................................................. 56 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 59 
APPENDIX B: UPC Ratio Calculation ........................................................................................ 60 
APPENDIX C: NYHA Classification .......................................................................................... 61 
APPENDIX D: Patient’s Medication Diary – X-82 ..................................................................... 62 
APPENDIX E: Patient’s Medication Diary – Everolimus ........................................................... 63 
APPENDIX F: Drugs that Prolong QT Interval and/or Induce Torsades De Pointes .................. 64 
APPENDIX G: CYP2C9 Substrates ............................................................................................. 65 
APPENDIX H: CYP3A4 Moderate and Strong Inhibitors and Strong Inducers.......................... 66 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Neuroendocrine Tumors 
 
Neuroendocrine tumors (NETs) consist of a spectrum of malignancies arising from 
neuroendocrine cells in the body, the most common of which are carcinoid tumors and 
pancreatic neuroendocrine tumors. Carcinoid tumors most commonly arise in the 
gastrointestinal tract or the lungs or thymus1. Median survival for patients with carcinoid 
is 75 months. Well (G1) to moderately differentiated (G2) carcinoid tumors are associated 
with a much longer survival (124 and 64 months) compared to those with poorly 
differentiated (G3) or anaplastic (G4) types (10 months). Pancreatic neuroendocrine 
tumors (PNETs) represent 1-2% of all pancreatic neoplasms with an estimated incidence 
of 1 in 100,0002.  Clinically divided into functional or non-functional groups, NETs are 
generally classified by the World Health Organization as well differentiated tumor, well 
differentiated carcinoma or poorly differentiated carcinoma with 5- and 10-year survival 
rates of 64% and 44%, respectively3. 
 
1.2 
Tyrosine kinase inhibition and NETs 
 
Several reports have shown that vascular endothelial growth factor (VEGF) is key in the 
angiogenesis, carcinogenesis, and development of resistance in NETs4-6.   VEGFR2 and 
VEGFR3 as well as PDGFR are highly expressed in pancreatic neuroendocrine tumor 
cells6, 7. Bevacizumab, an anti-VEGF ligand antibody, resulted in an 18% response rate for 
patients with NET8.  Multi-targeted tyrosine kinase inhibitors have also been evaluated for 
NET. A multi-institutional Phase II study involving 66 patients with advanced PNET and 
41 patients with advanced carcinoid noted an overall response rate of 16.7% response in 
PNET patients and 2.4% for carcinoid patients9. Recently, sunitinib, an oral multi-target 
tyrosine kinase inhibitor, was approved by the Food and Drug Administration (FDA) for 
the treatment of patients with advanced unresectable pancreatic neuroendocrine tumors.  
Patients treated with sunitinib had a significantly longer median progression-free survival 
(PFS) duration of 11.4 months compared to 5.5 months for patients treated with placebo10.  
Response rate is only 9.3%. Approximately 17% of patients on sunitinib discontinued study 
treatment due to adverse events, including fatigue, diarrhea and congestive heart failure, 
compared to 8% in the placebo group.  Overall survival between the two groups was 
similar. Another tyrosine kinase inhibitor, sorafenib, has also been evaluated in patients 
with neuroendocrine tumors11. Reported response rates were 11% among 43 patients with 
PNET and 7% among the 50 carcinoid patients. 
 
1.3 
mTOR inhibition and NETs 
 
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase which regulates 
cell growth, proliferation, and apoptosis through the modulation of the cell cycle12. Exome 
sequencing and expression profiling of well differentiated PNET demonstrated that the 
mTOR pathway is frequently altered in this malignancy13, 14. Activation of the mTOR 
pathway via the insulin-like growth factor 1 leads to proliferation of neuroendocrine tumor 


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cells15. Rapamycin, an mTOR inhibitor, inhibited carcinoid tumor cell growth in vitro16. 
Temsirolimus has been evaluated in patients with neuroendocrine tumors with an-intent-to 
treat response rate of 5.6%17. Outcomes were similar between patients with carcinoid 
tumors and pancreatic neuroendocrine tumors.  Another phase II study treated 30 patients 
with carcinoid and 30 patients with PNET with everolimus with octreotide18. Carcinoid 
patients had a 17% response rate while PNET patients had a 27% response rate to 
everolimus.  The FDA approved the use of everolimus for patients with progressive PNETs 
based on a randomized Phase III study. A total of 410 patients with low to intermediate 
grade PNET were treated with either everolimus plus octreotide or placebo + octreotide. 
Progression free survival was significantly longer among patients treated with everolimus 
compared to those treated with placebo in the RADIANT-3 study (11 months v 4.6 months, 
p<0.001)19. The response rate with everolimus was only 5%. Toxicities included stomatitis, 
hyperglycemia and, rarely, pneumonitis, among others.  Another randomized Phase III 
study for patients with carcinoid tumors was also conducted (RADIANT2) involving 429 
patients. Compared to patients treated with placebo and octreotide, patients treated with 
everolimus plus octreotide improved PFS from 11.3 months to 16.4 months (hazard ratio 
0.77, one sided p= 0.026)20.  Adverse events were minimal and consisted mainly of 
stomatitis, rash and fatigue.  
 
1.4 
X-82 
 
X-82 is an oral multikinase inhibitor targeting VEGFR and PDGFR. Due to its smaller 
volume of distribution, shorter half-life (approximately 4 to 8 hrs) and limited tissue 
accumulation, X-82 could potentially minimize toxicities associated with other multikinase 
inhibitors such as sunitinib and sorafenib while still maintaining targeted efficacy. In a 
Phase 1 study, no dose limiting toxicities were noted at the 200 mg BID dose level with 
the capsules21.  Most toxicities were grade 1 or 2, the most common of which included 
fatigue, nausea/vomiting, diarrhea and hypertension.  One patient developed grade 3 
pancreatitis which resolved after discontinuation of drug.  One patient with pancreatic 
cancer had a complete response to therapy while 2 patients with carcinoid tumor had 
prolonged stable disease beyond 24 weeks. 
 
The current risk profile for X-82 is based primarily on safety data collected from completed 
nonclinical studies and available literature from similar products, including sunitinib 
(Sutent®), sorafenib (Nexavar®) and pazopanib (Votrient®); limited information is 
available to date based on clinical experience with X-82.  
 
The pathology findings from the toxicology studies for X-82 include adrenal cortical 
changes, lymphoid depletion, pancreatic changes, and bone marrow hypocellularity. 
Laboratory findings include changes in red blood cell counts, hemoglobin and hematocrit, 
lower white blood cell and absolute lymphocyte counts and calcium, and higher platelet 
counts, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, creatine kinase, and potassium.  
 
The toxicity studies also indicate increased toxicities in female rats compared with male 
rats, likely related to increased drug exposure. These findings were not observed in dogs. 


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A phototoxicity study in guinea pigs demonstrated sensitivity to light when exposed to X-
82.  
 
Approved TKIs have a well characterized adverse event profile. The cardiotoxic effects 
include a high incidence of hypertension, less frequent occurrence of impaired cardiac 
function (decreased left ventricular ejection fraction (LVEF) or congestive heart failure), 
QT prolongation/Torsades de Pointes and cardiac ischemia/infarction. Other warnings or 
precautions include hepatotoxic effects, including liver failure, thyroid dysfunction, 
hemorrhage and thrombosis/thrombotic events, hand foot syndrome, gastrointestinal 
perforation, and proteinuria.  
 
The most common adverse reactions (>20%) noted in at least one of the labels for the 
approved TKIs are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, 
vomiting, anorexia, weight loss, abdominal pain, constipation, hypertension, peripheral 
edema, rash/desquamation, hand-foot syndrome, skin discoloration, dry skin, hair color 
changes, alopecia, altered taste, headache, back ache, arthralgia, extremity pain, cough, 
dyspnea, and bleeding.  
 
The extent to which adverse events associated with related compounds or the non-
clinical toxicology findings noted with X-82 will be observed in the clinical trials is 
unknown. 
 
1.5 
Study Rationale 
 
Targeting both VEGFR and mTOR pathways in neuroendocrine tumors appear to be a 
reasonable treatment strategy. A recent abstract from the Mayo Clinic Consortium P2C 
study reported the interim analysis of the Phase II study combining bevacizumab, a VEGF 
inhibitor, and temsirolimus, an mTOR inhibitor22.  Confirmed responses were noted in 52% 
of the first 25 patients enrolled. Progression-free survival at 6 months was 84%.  Another 
study by Yao et al confirmed a 32% decreased tumor blood flow assessed by a CT perfusion 
scan in pancreatic neuroendocrine tumors treated with bevacizumab23.  The addition of 
everolimus to bevacizumab further decreased blood flow by another 15%.  There were 26% 
of patients treated with this combination achieving PRs and 69% of patients with stable 
disease.  Partial responses were associated with decreased tumor blood flow.  The Alliance 
Cooperative group recently completed accrual for the Phase III study randomizing patients 
with pancreatic neuroendocrine tumors to everolimus alone or with bevacizumab. 
 
When a multi-targeted TK inhibitor, sunitinib was combined with everolimus in a Phase I 
study for patients with renal cell carcinoma, daily doses of everolimus above 2.5 mg and 
sunitinib above 37.5 mg were not tolerated24.  Dose limiting toxicities for sunitinib 
combined with everolimus included mucositis, thrombocytopenia, febrile neutropenia, 
vomiting, pulmonary embolism and gastrointestinal hemorrhage. The drug X-82 may be a 
more tolerable oral multikinase inhibitor with which an mTOR inhibitor such as everolimus 
could be combined.  We therefore propose a Phase I/II study to determine the dose limiting 
toxicities and the maximum tolerated dose of X-82 in combination with everolimus.  The 
Phase I portion will be conducted in patients with solid tumors and will evaluate the dose 


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limiting toxicities and determine an appropriate dose of X-82 when combined with 
everolimus to be used in the Phase II portion.  The Phase II portion of the study will assess 
the response rate and PFS for this combination among patients with pancreatic 
neuroendocrine tumors. 
 
1.6 
Correlative Studies Background 
 
In patients with neuroendocrine tumors, serum chromogranin A and 24-hour urine 5 
hydroxyindoleacetic acid (5”-HIAA) level have been routinely measured to assess 
treatment response. Chromogranin A presents in the chromaffin granules of the 
neuroendocrine cells, and often becomes detectable in the plasma of patients with 
neuroendocrine tumors.  Worse clinical outcomes are seen in patients with neuroendocrine 
tumors who have elevated baseline chromogranin A level25.  Furthermore, declining 
chromogranin A was found to be predictive of treatment response26, 27. For example, based 
on a phase II study of oral everolimus in patients after failure of cytotoxic therapy, patients 
with early response of chromogranin A had a longer PFS compared with patients without 
an early response (13.3 months vs. 7.5 months; HR=0.25; p=0.00004)26 .  In addition, 
neuron-specific enolase (NSE) has also been shown to be a prognostic marker in PNET28 .  
Therefore, we propose to explore the prognostic and predictive value of chromogranin A 
and NSE in this study.  
 
The mTOR acts in downstream activation of PI3K/Akt, and it plays a key role in the 
signaling of malignant cell growth, proliferation, differentiation, migration, and survival 
29.  Everolimus is an mTOR inhibitor that has FDA approval in patients with PNET19.  A 
recent study reported that PIK3CA mutation or phosphatase and tensin homolog (PTEN) 
loss are linked to sensitivity to mTOR inhibition, but concurrent presence of either KRAS 
or BRAF mutation renders them treatment resistant30 . Therefore, we propose to evaluate 
the predictive significance of a panel of biomarkers including PIK3CA mutation, PTEN 
loss, KRAS mutation, and BRAF mutation in this trial. 
   
X-82 is an oral multikinase inhibitor mainly targeting VEGFR and PDGFR.   Preclinical 
evidence demonstrates the key role of VEGF in neuroendocrine tumors31, 32 ; moreover, the 
clinical benefit of sunitinib further proves the success of anti-angiogenesis strategy in 
PNET10.   At present, there have not been validated biomarkers that can predict response 
to angiogenesis inhibitors.  Interestingly, a recent study reported that patients with 
neuroendocrine tumors with higher serum level of placental growth factor (PIGF), a VEGF 
homolog, have shorter time to progression (TTP) compared with patients with lower 
PIGF33 .  In our study, we plan to explore the prognostic and predictive values of serum 
levels of PIGF along with other angiogenesis biomarkers such as angiopoietin-2, VEGF, 
FGF et al.  
 
Dynamic contrast enhanced (DCE)-MRI is a non-invasive imaging technique with 
potential to provide predictive or prognostic information for tumor response65.  DCE-MRI 
can be incorporated into clinical MRI examinations to quantitatively evaluate the passage 
and distribution of gadolinium contrast agents from the circulation to tumors over time.  
Quantitative perfusion parameters obtained from DCE-MRI were initially applied in the 
brain and for evaluation for antiangiogenic therapy in cancer treatment66, 67, but its use has 


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expanded to other cytotoxic agents and organs68.  There is growing consensus69 on which 
perfusion parameters should be used during the application of DCE-MRI: the transfer 
constant, Ktrans, describing the passage of gadolinium from the vascular space to the 
extravascular, extracellular space70, and the blood normalized Initial Area under the 
Gadolinium Curve (IAUGC)71. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. To determine the dose-limiting toxicities and assess the overall toxicities of X-82 in 
combination with everolimus in patients with solid malignancies (Phase I). 
 
2. To determine the recommended phase II dose for this combination (Phase I). 
 
3. To determine the objective response rate (complete response + partial response) for X-
82 in combination with everolimus in patients with pancreatic neuroendocrine tumors 
(PNETs) (Phase II). 
 
2.2 
Secondary Objectives (Phase II) 
 
1. To determine the disease stabilization rate of X-82 in combination with everolimus 
in patients with PNETs.  Disease stabilization rate is defined as the proportion of 
patients achieving a best overall response of complete response, partial response, or 
stable disease. 
 
2. To describe the PFS for patients with PNETs treated with X-82 in combination with 
everolimus. 
 
3. To assess the toxicities of this combination for patients with PNETs. 
 
4. To describe the 3-year overall survival rate of patients with PNET treated with this 
combination. 
 
5. To evaluate the value of dynamic contrast enhanced (DCE) MRI perfusion 
parameters as biomarkers of tumor response before and during the first course of 
treatment with X-82 in combination with everolimus. 
 
2.3 
Exploratory Objectives 
 
1. To determine the trough levels of everolimus when administered at the 
recommended dose of 10 mg daily when combined with X-82. 
 
2. To determine the trough levels of X-82 when combined with everolimus. 
 


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3. To determine chromogranin A levels and NSE as prognostic and predictive markers 
for response to the combination of everolimus and X-82 (Phase II). 
 
4. To assess the predictive values of genetic alterations such as PI3KCA, PTEN, 
KRAS, and BRAF (Phase II). 
 
5. To analyze the pharmacokinetics of X-82 and everolimus as relating to timing of 
administration in patients with renal cell carcinoma (PK Expansion Cohort). 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Phase I and PK Expansion Cohort Eligibility 
 
3.1.1 Inclusion Criteria 
 
1. Phase I Patients: Histologic documentation of a solid malignancy and who have 
exhausted available standard medical treatments or for whom no standard 
treatments are currently available.  This includes primary brain tumors. 
 
2. PK Expansion Patients: Histologic documentation of locally unresectable or 
metastatic renal cell carcinoma not currently amenable to surgery, radiation, or 
other therapy with curative intent. 
 
3. Measurable or nonmeasurable disease per RECIST 1.1 criteria. 
 
4. ECOG performance status of 0-1 (see Appendix A). 
 
5. At least 18 years of age. 
 
6. Normal bone marrow and organ function as defined below: 
a. Granulocytes > 1,500/mcL 
b. Platelets > 100,000/mcL 
c. Hemoglobin ≥9 g/dL 
d. Creatinine < 1.5 x ULN 
e. Bilirubin < 1.5 x ULN 
f. AST and ALT < 2.5 x ULN (< 5 x ULN if liver metastases are present) 
g. Urine protein < 1+ OR urine protein to creatinine ratio < 1; if UPC ratio is 
> 1 on urinalysis, then 24-hour urine collection for protein must be obtained 
and level must be < 1,000 mg for patient enrollment.  (See Appendix B.) 
 
7. QTcF < 450 ms. 
 
8. Normal LVEF. 
 
9. Recovery from any major or minor surgeries. 


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10. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to 
study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she must 
inform her treating physician immediately. 
 
11. Ability to swallow and retain oral medication. 
 
12. Able to understand and willing to sign written informed consent document. 
 
3.1.2 Exclusion Criteria 
 
1. Active or severe liver disease (acute or chronic hepatitis, cirrhosis). 
 
2. Patients currently receiving cancer therapy (i.e., chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or 
tumor embolization). 
 
3. Receiving any other investigational agent(s) within 21 days or 5 half-lives 
(whichever is shorter) prior to the first dose of study drug.  A minimum of 10 
days between termination of the investigational drug and administration of 
study drug is required. 
 
4. Any radiotherapy or immunotherapy within the last 3 weeks (limited palliative 
radiation is allowed ≥2 weeks).  Chemotherapy regimens with delayed toxicity 
within the last 4 weeks (or within the last 6 weeks for prior nitrosourea or 
mitomycin C).  Chemotherapy regimens given continuously or on a weekly 
basis with limited potential for delayed toxicity within the last 2 weeks. 
 
5. Major surgery within the last 4 weeks; minor surgery within the last 2 weeks. 
 
6. Immunization with any attenuated live vaccine within 1 week prior to 
registration. 
 
7. Concurrent condition resulting in immune compromise, including chronic 
treatment with corticosteroids or other immunosuppressive agents. 
 
8. History of allergic reactions attributed to, or intolerance of, or other significant 
toxicity with, compounds of similar chemical or biologic composition to X-82 
or everolimus. 
 
9. Patients with fasting serum cholesterol > 300 mg/dL OR > 7.75 mmol/L AND 
fasting triglycerides > 2.5 x ULN who would need to initiate lipid lowering 
medications.  
 


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10. Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades 
de Pointes, or patients with a history of risk factors for Torsades de Pointes 
(e.g., familial long QT syndrome, heart failure, left ventricular hypertrophy, 
slow heart rate (<45 beats per minute)). 
 
11. Concomitant use of herbal medications (i.e. St. John’s wort, Kava, ephedra (ma 
huang), ginkgo biloba) at least 7 days prior to the first dose of study drug and 
throughout participation in the trial. 
 
12. Concomitant use of any drug which is a moderate or strong CYP3A4 inhibitor 
or strong CYP3A4 inducer. 
 
13. Patients with known CNS metastases, unless metastases are treated and stable 
and the patients do not require systemic steroids. 
 
14. Treatment with therapeutic doses of coumarin-type anticoagulants (maximum 
daily dose of 1 mg allowed for port line patency permitted).  Low molecular 
weight heparin (LMWH) will be allowed. 
 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, inadequately controlled hypertension, uncontrolled diabetes mellitus, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or cerebrovascular accident or transient ischemic attack within 6 
months of starting study drugs, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
16. Presence of active gastrointestinal (GI) disease or other condition that will 
interfere significantly with the absorption, distribution, metabolism, or 
excretion of the study drugs. 
 
17. Inability or unwillingness to comply with study and/or follow-up procedures 
outlined in the protocol. 
 
18. Pregnant or breastfeeding. 
 
19. Known HIV-positivity on combination antiretroviral because of the potential 
for pharmacokinetic interactions with X-82 or everolimus. In addition, these 
patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. 
 
3.2 
Phase II Eligibility 
 
3.2.1 Inclusion Criteria 
 


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1. Histologic documentation of well differentiated or moderately differentiated 
locally unresectable or metastatic pancreatic neuroendocrine tumor from either 
a primary or metastatic site with documented disease progression  12 months 
prior to enrollment with whose disease is not currently amenable to surgery, 
radiation or modality therapy with curative intent.  If different histologic 
classification schemes are used, equivalent histologic classifications (for 
example “grade 1,” “low grade,” or “intermediate grade”) are allowed.  There 
must be histologic documentation of a pancreatic primary site or clinical 
evidence of a pancreatic neuroendocrine primary tumor as determined by the 
treating physician.  Documentation from a metastatic site is sufficient if there 
is clinical evidence of a pancreatic primary site.  In the case of discordant 
pathology, patient eligibility will be determined by the PI after review of 
available records.  Patients with neuroendocrine tumors (e.g., gastrinoma, 
VIPoma) in whom a pancreatic or peripancreatic primary site is strongly 
suspected are also eligible. 
 
2. Evidence of measurable disease per RECIST 1.1.  Measurable disease is defined 
as lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as > 2 cm with conventional techniques or as > 1 cm 
with spiral CT scan. 
 
3. There is no limit on the number of prior chemotherapy regimens allowed.  Any 
prior treatment (with the exception of lanreotide or octreotide) must be 
completed at least 4 weeks prior to initiation of treatment.  (See exclusion 
criterion #6.) 
 
4. Prior treatment with embolization or ablative therapies is allowed if measurable 
disease remains outside of the treated area or if there is definite progression of 
the treated lesions.  There is no limit on the number of prior procedures. 
 
5. ECOG performance status of 0-1 (see Appendix A). 
 
6. At least 18 years of age. 
 
7. Normal bone marrow and organ function as defined below: 
a. Granulocytes > 1,500/mcL 
b. Platelets > 100,000/mcL 
c. Hemoglobin ≥9 g/dL 
d. Creatinine < 1.5 x ULN 
e. Bilirubin < 1.5 x ULN 
f. ALT and AST < 2.5 x ULN (< 5 x ULN if liver metastases are present) 
g. Urine protein < 1+ OR urine protein to creatinine ratio < 1; if UPC ratio is 
> 1 on urinalysis, then 24-hour urine collection for protein must be obtained 
and level must be < 1,000 mg for patient enrollment.  (See Appendix B.) 
 
8. QTcF < 450 ms. 


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9. Normal LVEF. 
 
10. Patients with fasting serum cholesterol > 300 mg/dL OR > 7.75 mmol/L AND 
fasting triglycerides > 2.5 x ULN should initiate lipid lowering medications.  
 
11. Recovery from any major or minor surgeries.  Patient must be 4 weeks post-
major surgery and 2 weeks post-minor surgery. 
 
12. Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to 
study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she must 
inform her treating physician immediately. 
 
13. Ability to swallow and retain oral medication. 
 
14. Able to understand and willing to sign written informed consent document. 
 
3.2.2 Exclusion Criteria 
 
1. Poorly differentiated neuroendocrine carcinoma or small cell carcinoma. 
 
2. Prior treatment with everolimus, other mTOR inhibitors, or anti-VEGF drug 
(sunitinib, bevacizumab). 
 
3. Patients currently receiving cancer therapy (i.e., chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or 
tumor embolization). 
 
4. Major surgery < 4 weeks from the start of treatment. 
 
5. Minor surgery < 2 weeks from the start of treatment.  (Insertion of a vascular 
access device is not considered major or minor surgery.) 
 
6. Any radiotherapy or immunotherapy within the last 21 days (limited palliative 
radiation is allowed ≥2 weeks).  Chemotherapy regimens with delayed toxicity 
within the last 4 weeks.  Chemotherapy regimens given continuously or on a 
weekly basis with limited potential for delayed toxicity within the last 2 weeks. 
 
7. Immunization with any attenuated live vaccine within 1 week prior to 
registration. 
 
8. Concurrent condition resulting in immune compromise, including chronic 
treatment with corticosteroids or other immunosuppressive agents. 
 


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9. Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades 
de Pointes, or patients with a history of risk factors for Torsades de Pointes 
(e.g., familial long QT syndrome, heart failure, left ventricular hypertrophy, 
slow heart rate (<45 beats per minute)). 
 
10. Concomitant use of herbal medications (i.e. St. John’s wort, Kava, ephedra (ma 
huang), ginkgo biloba) at least 7 days prior to the first dose of study drug and 
throughout participation in the trial. 
 
11. Concomitant use of any drug which is a moderate or strong CYP3A4 inhibitor 
or strong CYP3A4 inducer. 
 
12. Active or severe liver disease (acute or chronic hepatitis, cirrhosis). 
 
13. Positive anti-HBV.  HBV seropositive patients (HBsAg positive) are eligible if 
they are closely monitored for evidence of active HBV infection by HBV DNA 
testing, and they must agree to receive suppressive therapy with lamivudine or 
other HBV-suppressive therapy until at least 4 weeks after the last dose of 
everolimus.  Patients who are anti-HCV positive are eligible provided that 
hepatitis C viral load (hepatitis C RNA) is undetectable. 
 
14. Clinical evidence of brain metastases or carcinomatous meningitis. 
 
15. History of GI perforation within 12 months prior to registration or presence of 
active gastrointestinal (GI) disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of the 
study drugs. 
 
16. History of clinically significant bleeding episodes. 
 
17. Current NYHA class II, III, or IV congestive heart failure (see Appendix C) or 
symptomatic heart failure within 60 days prior to the start of study drugs. 
 
18. Symptomatic arterial peripheral vascular disease. 
 
19. History of aortic aneurysm, aortic dissection, angina, myocardial infarction, 
stroke, transient ischemic attack, or other arterial thrombotic events within 6 
months of registration.  Patients on therapeutic non-coumarin anticoagulation 
are eligible provided that they are on a stable dose of anticoagulants. 
 
20. Uncontrolled diabetes mellitus or inadequately controlled hypertension. 
 
21. Receiving any other investigational agent(s) within 21 days or 5 half-lives 
(whichever is shorter) prior to the first dose of study drug.  A minimum of 10 
days between termination of the investigational drug and administration of 
study drug is required. 


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22. History of allergic reactions or intolerance of, or other significant toxicity with, 
attributed to compounds of similar chemical or biologic composition to X-82 
or everolimus. 
 
23. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
24. Inability or unwillingness to comply with study and/or follow-up procedures 
outlined in the protocol 
 
25. Pregnant or breastfeeding. 
 
26. Known HIV-positivity on combination antiretroviral because of the potential 
for pharmacokinetic interactions with X-82 or everolimus. In addition, these 
patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center database, the WUSM coordinator 
will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 


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1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT.  Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the WUSM research coordinator.  Registration will be confirmed by the WUSM 
research coordinator or by his/her delegate by email within one business day.  Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center database at 
Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
4.4 
Phase II Randomization 
 
Patients will be randomized in a 1:1 ratio to receive either everolimus three weeks prior to 
initiating X-82 or X-82 three weeks prior to initiating everolimus.  To better ensure the 
balance of potential risk factors across two groups, the assignment will be done in small 
blocks of 4 to 6 patients.  Randomization will be implemented through the WUSM 
REDCap (Research Electronic Data Capture).  REDCap is a secure, increasingly used web-
based application designed exclusively to support data capture for clinical research studies.  
Specifically, a randomization table will be generated by the study statistician using the SAS 
program PROC PLAN and uploaded to the WUSM REDCap website.  A REDCap account 
will be created and the study coordinator will be authorized to login for treatment 
assignment. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Agent Administration 


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X-82 is an oral drug which will be administered on an outpatient basis using the dosing 
schedule in Section 5.3 for patients in phase I and using the recommended phase II dose 
for patients in phase II and the PK expansion cohort.  X-82 will be taken daily on every 
day of each 28-day cycle.  Patients in Levels 0 through 3 should take X-82 at approximately 
the same time every day; patients in Level 4 should take everolimus first, wait 2 hours, and 
then take their X-82 dose.  Timing of X-82 and everolimus for the PK expansion cohort is 
described in Section 5.4.  If a patient misses a dose, the patient should take the dose as soon 
as possible, but not less than 12 hours before the next dose is due.  If the next dose is due 
in less than 12 hours, the patient should skip the missed dose and take the next dose as 
scheduled.  If vomiting occurs after taking the study medication, the patient should be 
instructed not to retake the dose, and should just take his/her next scheduled dose of X-82.  
Patients will be instructed to bring all unused tablets and their medication diary (see 
Appendix D) to each study visit for assessment of compliance. 
 
Update as of Amendment #8: The recommended phase II dose was determined to be 300 
mg QD due to concerns about the ability to maintain the 400 mg QD dosing level for 
multiple cycles without significant toxicity 
 
Everolimus is an oral drug which will be administered on an outpatient basis at a dose of 
10 mg daily on every day of each 28-day cycle.  All patients should take everolimus at the 
same time as X-82 with the exception of patients enrolled to Level 4 (who should take 
everolimus first, wait 2 hours and then take X-82) and the PK expansion cohort (See 
Section 5.4).  If a patient misses a dose, the patient should be instructed to take that dose 
up to 12 hours after the time that s/he would normally take it.  If more than 12 hours have 
elapsed, the patient should skip that dose for the day.  Patients should not take 2 doses to 
make up for the one that was missed. Patients will be instructed to bring all unused tablets 
and their medication diary (see Appendix E) to each study visit for assessment of 
compliance.   
 
 


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5.2 
Dose Escalation Schema 
 
Dose Level 
X-82 Dose  
Everolimus Dose 
Level -1 
50 mg QD 
10 mg QD 
Level 0 (Starting Dose) 
100 mg QD 
10 mg QD 
Level 1 
150 mg QD 
10 mg QD 
Level 2 
200 mg QD 
10 mg QD 
Level 3 
300 mg QD 
10 mg QD 
Level 4 
400 mg QD 
10 mg QD 
 
Dose escalation will not occur until all patients in the cohort have completed the first cycle 
and the Principal Investigator has been able to review all toxicities. 
 
If Level 4 is reached with no DLTs, additional dose escalation cohorts may be added at the 
discretion of the investigator and the sponsor. Expansion of cohorts (up to 12 patients) at 
doses lower than MTD may also be undertaken in order to better characterize the safety 
profile and thereby better define the recommended phase II dose.  Once an optimal dose is 
determined, this will be the recommended phase II dose. 
 
5.3 
Phase II Treatment Plan 
 
Once the MTD is determined, additional patients will be enrolled at the recommended 
phase II dose of X-82 for a goal of 29 evaluable patients.  These patients will be randomized 
to one of two groups: the first group will begin taking everolimus 3 weeks prior to initiating 
X-82, while the second group will begin taking X-82 3 weeks prior to initiating everolimus 
(see Section 4.4).  Cycle 1 Day 1 will be considered the day when both study drugs are 
taken together for the first time.  The lead-in period will be referred to as Cycle 0.  Timing 
of X-82 and everolimus will depend on which dose level is determined to be the 
recommended phase II dose.  Enrollment to phase II and to the PK Expansion cohort will 
take place simultaneously. 
 
5.4 
PK Expansion Cohort 
 
Once the MTD is determined, three patients with renal cell carcinoma will be enrolled at 
the recommended phase II dose of X-82 into each the following three groups (nine 
evaluable patients total): 
Group A: Will take everolimus first, followed by X-82 two hours later 
Group B: Will take everolimus first, followed by X-82 four hours later 
Group C: Will take X-82 and everolimus at the same time 
 
Patients enrolled in the PK expansion cohort will not participate in the lead-in period 
(Cycle 0) described in Section 5.3). 
 
Blood will be drawn from each patient for pharmacokinetic testing at several time points 
as described in Section 9.5. 


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Enrollment to phase II and to the PK Expansion cohort will take place simultaneously. 
 
5.5 
Definition of MTD, DLT, Dose Escalation Criteria, and Toxicity, Response, 
and DLT Evaluations 
 
5.5.1 Definition of Maximum Tolerated Dose (MTD) 
 
The maximum tolerated dose (MTD) is defined as the dose level immediately 
below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience 
dose-limiting toxicity during the first cycle.  Dose escalations in the phase I portion 
of the study will proceed until the MTD has been reached.  The recommended phase 
II dose is the dose to be received during phase II and the PK expansion portion of 
the study. 
 
5.5.2 Dose Limiting Toxicities (DLTs) 
 
Hematologic DLT is defined as any of the following that occur during the first cycle 
that are attributed as possibly, probably, or definitely related to the study treatment: 
 Grade 4 neutropenia (ANC < 500) > 5 days duration 
 Febrile neutropenia of any duration with temperature > 38.5 °C 
 Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with 
bleeding 
 
Non-hematologic DLT is defined as any possibly, probably, or definitely related 
grade 3 or grade 4 non-hematologic toxicity that occurs during the first cycle with 
the following specific exceptions: 
 Grade 3 rash if controlled with standard supportive care and lasting ≤ 48 
hours 
 Grade 3 diarrhea if controlled with standard supportive care and lasting ≤ 
48 hours 
 Grade 3 nausea if controlled with standard supportive care and lasting ≤ 48 
hours 
 Grade 3 vomiting if controlled with standard supportive care and lasting ≤ 
48 hours 
 Grade 3 hypertension if controlled with antihypertensive therapy within 48 
hours 
 
Treatment delay of > 14 days due to unresolved toxicity will also be considered a 
DLT. 
 
5.5.3 Dose Escalation Criteria 
 
Dose escalations will proceed as follows 
 


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Number of Patients 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  Three (3) additional 
patients will be entered at the next lowest dose level if only 
3 patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
If 0 of these additional patients experience DLT, proceed to 
the next dose level. 
If 1 or more of this additional group suffer DLT, then dose 
escalation is stopped.  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
<1 out of 6 at highest 
dose level below the 
maximally 
administered dose 
This or a lower dose is the recommended phase II dose. At 
least 6 patients must be entered at the recommended phase 
II dose during the phase I portion of the study. 
 
5.5.4 Toxicity, Response, and DLT Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients 
are evaluated from first receiving study treatment until a 30-day follow up after the 
conclusion of treatment or death. 
 
All patients in Phase II are evaluable for disease response, unless they come off 
study prior to completion of Cycle 3 and have not had any disease assessment. 
 
A patient is evaluable for DLT assessment only if s/he is enrolled in phase I of the 
trial, and only during Cycle 1 of treatment.  If the patient is not able to be treated 
on Day 1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and 
can experience a DLT.  Once the patient has been treated in Cycle 2, s/he will no 
longer be evaluated for DLTs in all subsequent cycles. 
 
In order for a patient in the PK expansion cohort to be considered evaluable for the 
PK endpoints, s/he must have taken the drugs as mandated by his/her group 
assignment and must have had blood drawn at each of the time points specified in 
Section 9.5.  If either of these criteria is not met, the patient will be considered 
inevaluable for the PK endpoints and will be replaced in that cohort.  S/he may still 
be evaluable for disease response and other endpoints. 
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
Standard use of octreotide or lanreotide for patients with neuroendocrine tumors is allowed. 
 
Use of erythropoietin replacement or bisphosphonates is considered supportive care and is 


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permitted if initiated > 2 weeks prior to start of treatment or after the completion of Cycle 
1. 
 
Prophylactic G-CSF is prohibited.  However, at the discretion of the treating physician, 
patients may receive therapeutic G-CSF if neutropenia occurs.  Therapeutic use of G-CSF 
should follow standard ASCO guidelines. 
 
Patients are permitted to receive palliative radiation therapy on study at the discretion of 
the treating physician. 
 
No routine prophylactic antiemetics will be given; however, antiemetics may be 
administered with nausea and vomiting when they occur, and may be given 
prophylactically afterwards. 
 
Patients will be instructed not to take any additional medications (including over-the-
counter products) during the course of the study without prior consultation with the 
research team.  At each visit, the investigator will ask the patient about any new 
medications s/he is taking or has taken after the start of study drugs. 
 
The following treatments are prohibited while on this study: 
 Chronic treatment with systemic steroids (dose > 10 mg daily of 
methylprednisolone or equivalent) or another immunosuppressive agent.  Topical 
or inhaled corticosteroids are allowed. 
 Anticoagulation with coumarin-derivatives will not be permitted.  However, a 
maximum daily dose of 1 mg will be permitted for port line patency.  Should a 
thrombotic event occur while the patient is receiving treatment, the patient may 
continue on study.  Low molecular weight heparin will be allowed. 
 Concomitant treatment with any medication which may cause QT prolongation or 
Torsades de Pointes is not allowed (See Appendix F).  If a patient, after study 
enrollment, requires use of any medication which may cause QT prolongation 
and/or Torsades de Pointes, the patient must be removed from study. 
 Herbal preparations and medications are not permitted throughout the trial.  Patients 
should stop using these herbal medications at least 7 days prior to the first dose of 
study drug. 
 Live vaccines and close contact with those who have received live vaccines are not 
permitted on study. 
 
The following drugs should be used with caution: 
Potent CYP2C9 substrates which have a narrow therapeutic index (see Appendix G) or 
potent CYP3A4 inhibitors and inducers (see Appendix H) should be avoided.  The co-
administration of these drugs with X-82 at high doses could result in increases/decreases 
in exposure of either the study medication or concomitant medication, and could therefore 
alter the safety and/or efficacy of these drugs.  In addition, due to significant increases in 
exposure of everolimus, co-administration with moderate or strong CYP3A4 inhibitors and 
strong CYP3A4 inducers should be prohibited (see Appendix H).  Alternative therapies 
should be used whenever available. 


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5.7 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum or urine pregnancy test within 7 days prior to the first dose of X-82.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 3 months following the last dose of X-82.  
 
If a patient is suspected to be pregnant, X-82 should be immediately discontinued.  In 
addition a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last dose of X-82, the investigator must be notified in order to 
facilitate outcome follow-up. 
 
5.8 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 
 Documented and confirmed disease progression 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 


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5.9 
Duration of Follow-up 
 
Patients will be followed for toxicity for 30 days following end of therapy, every 12 weeks 
for disease progression if patients discontinue for a reason other than disease progression, 
and every 12 weeks for 3 years for survival.  Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event.   
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS  
 
Any patients who require treatment delay of more than 3 weeks due to treatment-related toxicity 
will be discontinued from trial treatment unless the treating physician and PI agree that continued 
treatment at lower doses is in the best interest of the patient. 
 
6.1 
X-82 Dose Modifications 
 
Reduce current dose by 100 mg daily for each dose reduction.  Lowest dose allowed is 100 
mg QD.  Doses will not be re-escalated once reduced.  Dose reductions will not be allowed 
during Cycle 1 for patients enrolled in the phase I portion of this study. 
 
6.1.1 Dose Modifications Due to Hematologic Toxicity  
 
If hematologic toxicity occurs, treatment with X-82 should be held (see Table 2), 
and re-evaluated in at least 1 week. ANC and platelets should be monitored at least 
weekly until recovery. If ANC and/or platelets do not recover within 3 weeks, the 
patient will be discontinued from the trial unless the treating physician and PI agree 
that continued treatment at lower doses is in the best interest of the patient.  
 
Event  
X-82 Dose 
Neutropenia (ANC)  
Grade 4  
Hold dose until recovery to ≤ grade 2, then resume X-82 
at one lower dose level.  
Recurrent grade 4  
Hold dose until recovery to ≤ grade 2, then resume X-82 
at one lower dose level.  
Thrombocytopenia  
Grade 3  
Hold dose until improvement to platelets ≥ 75 x 109/L  
• If resolved in ≤ 5 days, then resume without a dose 
reduction.  
• If resolved in > 5 days but < 3 weeks, then resume X-82 
at one lower dose level.  
 
6.1.2 Dose Modifications Due to Non-Hematologic Toxicities  
 
If a grade 3 non-hematologic toxicity that is expected to be manageable and 
reversible with dose reduction occurs, treatment with X-82 should be held until the 
toxicity resolves to ≤ grade 1. If the grade 3 non-hematologic toxicity lasts longer 


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than 7 days, study drug will be discontinued. Patients with grade 3 non-hematologic 
toxicity lasting ≤ 7 days that does not resolve to ≤ grade 1 within 3 weeks should 
also be removed from the trial, unless the treating physician and PI agree that 
continued treatment at lower doses is in the best interest of the patient. If a grade 4 
non-hematologic toxicity occurs, study drug will be discontinued. 
  
Specific Recommendations for Rash, Nausea, Vomiting and Diarrhea:  
For patients with grade 3 rash, nausea, vomiting, and/or diarrhea, X-82, should be 
held and supportive care initiated. If the grade 3 toxicity lasts ≤ 7 days, patients 
may restart X-82 at a reduced dose when toxicity returns to ≤ grade 1. If the patient 
has recurrent grade 3 toxicity despite supportive care, the patient will restart X-82 
at the next lower dose level once toxicity has resolved to ≤ grade 1. 
  
Specific Recommendations for Liver Function Test Abnormalities:  
For patients with grade 3 liver enzyme elevations (AST/ALT), X-82 should be held 
until the values recover to ≤ grade 1. Patients with an elevation of ALT ≥ 3 x ULN 
in conjunction with a bilirubin ≥ 2 x ULN may remain in the study if a correctable, 
non-drug related cause of the liver test evaluations can be documented; otherwise, 
the patient must be discontinued from the trial. 
 
Specific Recommendations for the Treatment of Hypertension:  
Medication recommendations for the treatment of hypertension should be applied 
based on the patient and clinical status. General recommendations on initial 
management of hypertension are:  
 
For persistent HTN (recommend initiation of treatment at consistent BP readings 
of over 140/90) - initiate treatment with an ACE inhibitor (e.g. benazepril, 
lisonopril), angiotensin II receptor blocker (ARB) (e.g. - losartan), thiazide diuretic 
(e.g. - HCTZ), or dihydropyrimidine calcium channel blocker (e.g. - amlodipine). 
Titrate to BP control with dose escalation of the chosen drug, or if additional agents 
are needed, choose a second agent from the recommended list.  
 
For patients whose HTN is over 160/90, initiation of combination therapy with an 
ACE inhibitor and dihydropyrimidine calcium channel blocker is recommended.  
 
6.2 
Everolimus Dose Modifications 
 
Doses will not be re-escalated once reduced. 
 
No dose reduction below Dose Level -2 is allowed (see Section 6.2.1). 
 
If more than one dose modification applies, use the most stringent (i.e., the greatest dose 
reduction). 
 
Patients who do not tolerate treatment with lanreotide or octreotide may discontinue 
lanreotide/octreotide therapy, but may continue with X-82 and everolimus. 


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6.2.1 Everolimus Dose Levels 
 
Dose Level 
Everolimus 
0 
10 mg daily 
-1 
5 mg daily 
-2 
5 mg every other day 
 
6.2.2 Hematologic Toxicities 
 
For ANC <1000/μL, interrupt everolimus until ANC ≥1000/μL, then resume with 
one dose level reduction of everolimus. If everolimus is interrupted for ≥3 weeks 
for ANC, discontinue everolimus unless the treating physician and PI agree that 
continued treatment at lower doses is in the best interest of the patient. 
 
For platelets <50,000/μL, interrupt everolimus until platelets ≥50,000/μL, then 
resume with one dose level reduction of everolimus. If everolimus is interrupted 
for ≥ 3 weeks, discontinue everolimus unless the treating physician and PI agree 
that continued treatment at lower doses is in the best interest of the patient. 
 
6.2.3 Oral Mucositis  
 
For grade ≥ 2 oral mucositis, interrupt everolimus until mucositis improves to ≤ 
grade 1, then resume everolimus with 1 dose level reduction. 
 
If everolimus is interrupted for mucositis for ≥ 3 weeks, discontinue everolimus 
unless the treating physician and PI agree that continued treatment at lower doses 
is in the best interest of the patient. 
 
6.2.4 Hepatotoxicity  
 
Reactivation of hepatitis B in patients already receiving antiviral therapy is defined 
as an increase of 1 log in HBV DNA over baseline or the appearance of new 
measurable HBV DNA and ALT > 5 x ULN. 
 
For reactivation of hepatitis B in patients already receiving antiviral therapy, 
interrupt everolimus until ALT improves to less than or equal to grade 1, and HBV 
DNA improves to less than or equal to baseline level, and add a second antiviral. 
When ALT and HBV DNA improve, resume everolimus with one dose level 
reduction. 
 
Reactivation of hepatitis B in patients not receiving antiviral therapy is defined as 
new appearance of measurable HBV DNA. 
 
For reactivation of hepatitis B in patients not receiving antiviral therapy, interrupt 
everolimus until HBV DNA improves to less than or equal to baseline level, and 


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add lamuvidine (or other HBV-suppressive therapy). When HBV DNA improves, 
resume everolimus with one dose level reduction. 
 
If everolimus is interrupted for ≥3 weeks, discontinue everolimus unless the 
treating physician and PI agree that continued treatment at lower doses is in the best 
interest of the patient. 
 
Reactivation of hepatitis C is defined as ALT > 5 x ULN (in patients with detectable 
HCV RNA at baseline) or new appearance of detectable HCV RNA (in patients 
with knowledge of past hepatitis C infection but no detectable HCV RNA at 
baseline). 
 
For reactivation of hepatitis C in any patient, discontinue everolimus. 
 
Reactivation of hepatitis B or C is considered a grade 3 (or in the case of a life-
threatening event, grade 4) event.  
 
6.2.5 Dose Reductions for other Non-Hematologic Toxicities 
 
For other grade 3 or 4 non-hematologic toxicity (except nausea, vomiting, and 
fatigue) considered at least possibly due to treatment with everolimus, interrupt 
everolimus until toxicity resolves to < grade 1. If toxicity improves to < grade 1 
within 3 weeks, resume treatment with one dose level reduction of everolimus.  
Standard supportive measures for the treatment of nausea, vomiting, or fatigue are 
encouraged, at the discretion of the treating physician. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.1 
Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can 
be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.2 
Unanticipated Problems 


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Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the 
research); and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
7.3 
Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human 
subjects 
research 
or 
failure 
to 
follow 
the 
determinations 
of 
the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 
7.4 
Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 
 
7.5 
Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the event.  For 
secondary sites, the Washington University PI will issue approval of the exception, but it 
must also be submitted to the local IRB with documentation of approval forwarded to 
Washington University.  HRPO approval is not required for protocol exceptions occurring 
at secondary sites.  
 
 
7.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 


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at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.7 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 7.6) 
within 1 working day of the occurrence of the event or notification of the secondary site’s 
PI of the event.  This notification may take place via email if there is not yet enough 
information for a formal written report (using either an FDA MedWatch form if required 
or an institutional SAE reporting form if not).  A formal written report must be sent to the 
Washington University PI and research coordinator within 10 working days of the 
occurrence of the event or notification of the secondary site’s PI of the event.  The death 
of a research participant that qualifies as a reportable event should be reported within 1 
working day of the occurrence of the event or notification of the secondary site’s PI of the 
event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines. 
 
7.8 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary 
site of all reportable events that have occurred at other sites (as described in Section 7.6) 
within 10 working days of the occurrence of the event or notification of the PI of the event.  
This includes events that take place both at Washington University and at other secondary 
sites, if applicable. 
 
 


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7.9 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
 Report any unexpected fatal or life-threatening adverse experiences associated with 
use of the drug (i.e., there is a reasonable possibility that the experience may have 
been caused by the drug) by telephone or fax no later than 7 calendar days after 
initial receipt of the information.  A life-threatening adverse experience is defined 
as any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 Report any serious, unexpected adverse experiences associated with the use of the 
drug, as well as results from animal studies that suggest significant clinical risk 
within 15 calendar days after initial receipt of this information.  A serious adverse 
drug experience is defined as any adverse drug experience occurring at any dose 
that results in any of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
An unexpected adverse drug experience is defined as any adverse drug experience, 
the specificity or severity of which is not consistent with the current labeling or 
investigator brochure (or risk information, if an IB is not required or available). 
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
Secondary sites must submit a completed MedWatch form to the Washington University 


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PI and research coordinator within 4 calendar days (for fatal or life-threatening adverse 
experiences) or 11 calendar days (for serious, unexpected adverse experiences).  The 
Washington University PI will be responsible for submitting all MedWatch forms from 
secondary sites to the FDA within the timeframes specified above. 
 
7.10 
Reporting to Tyrogenex 
 
Tyrogenex or designee is responsible for reporting relevant SAEs to participating 
investigators in other trials using X-82, in accordance with ICH guidelines, FDA 
regulations, and/or local regulatory requirements. 
 
Any death while on study or within 30 days of study or any reportable death (considered 
possibly related to study drug) more than 30 days after end of study will be reported to 
Tyrogenex within 24 hours.  Any reportable adverse events as described in Sections 7.1 
and 7.2 and 7.7 will be reported to Tyrogenex within 24 hours.  A safety report will be 
provided to the Tyrogenex on a monthly basis, including all serious adverse events.  All 
noncompliance and serious noncompliance described in Sections 7.3 and 7.4 will be 
reported to Tyrogenex within 10 days.   
 
All reports should be sent to the Tyrogenex at the following email address or by fax: 
                X82-CLI-102@tyrogenex.com 
                FAX: 1-561-828-0228 
 
7.11 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment.  For the purposes of this study, abnormal lab values will only be considered 
adverse events if they are clinically significant. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
X-82 
 
8.1.1 X-82 Description 
 
X-82 is a small molecule indolinone inhibitor of a family of type III and type V 
receptor tyrosine kinases characterized by an extracellular domain containing 
several immunoglobulin-like domains, a membrane spanning region, and a 
cytoplasmic split kinase domain. 
 
Additional information may be found in the X-82 investigator’s brochure. 
 
 


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8.1.2 Clinical Pharmacology 
 
Clinical pharmacology studies have not been performed to date. 
 
8.1.3 Supplier(s) 
 
X-82 will be provided free of charge by Tyrogenex.   
 
8.1.4 Dosage Form and Preparation 
 
X-82 will be supplied in 100 mg tablets. 
 
8.1.5 Storage and Stability 
 
X-82 tablets (100 mg) are stored in 60cc wide mouth round HDPE bottles with one 
Sorbit ½ gram desiccant canister.  Thirty tablets are included in each bottle. 
 
X-82 should be stored at room temperature (15ºC-30ºC/59ºF- 86ºF). 
 
8.1.6 Administration 
 
X-82 is an oral tablet intended to be taken at the same time every day.  If a patient 
misses a dose, the patient should take the dose as soon as possible, but not less than 
12 hours before the next dose is due.  If the next dose is due in less than 12 hours, 
the patient should skip the missed dose and take the next dose as scheduled.  If 
vomiting occurs after taking the study medication, the patient should be instructed 
not to retake the dose, and should just take his/her next scheduled dose of X-82. 
 
8.2 
Everolimus 
 
8.2.1 Everolimus Description 
 
Everolimus, an inhibitor of mTOR, is an antineoplastic agent.  It is FDA approved 
for adults with progressive neuroendocrine tumors of pancreatic origin that are 
unresectable, locally advanced, or metastatic. 
 
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-dimethoxy15,17,21,23,29,35-
hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-
tetraene-2,3,10,14,20pentaone.  
 
The molecular formula is C53H83NO14 and the molecular weight is 958.2. The 
structural formula is: 


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8.2.2 Clinical Pharmacology 
 
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-
threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is 
dysregulated in several human cancers. Everolimus binds to an intracellular 
protein, FKBP-12, resulting in an inhibitory complex formation with mTOR 
complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus 
reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic 
elongation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, 
involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates 
the activation domain 1 of the estrogen receptor which results in ligand-
independent activation of the receptor. In addition, everolimus inhibited the 
expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of 
vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus 
has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in 
in vitro and/or in vivo studies.  
 
Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to 
endocrine resistance in breast cancer. In vitro studies show that estrogen-
dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of 
everolimus, and that combination treatment with everolimus and Akt, HER2, or 
aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic 
manner.  
 
Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-
sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or 
TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, 
inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma 
formation throughout the body. 
 
 


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8.2.3 Pharmacokinetics and Drug Metabolism 
 
Absorption  
In patients with advanced solid tumors, peak everolimus concentrations are reached 
1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. 
Following single doses, Cmax is dose-proportional between 5 mg and 10 mg. At 
doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, 
however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. 
Steady-state was achieved within 2 weeks following once-daily dosing.  
 
Food effect: In healthy subjects, high fat meals reduced systemic exposure to 
everolimus 10 mg tablet (as measured by AUC) by 22% and the peak blood 
concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 
42%. Food, however, had no apparent effect on the post absorption phase 
concentration-time profile.  
 
Distribution  
The blood-to-plasma ratio of everolimus, which is concentration-dependent over 
the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined 
to the plasma is approximately 20% at blood concentrations observed in cancer 
patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% 
both in healthy subjects and in patients with moderate hepatic impairment.  
 
Metabolism  
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, 
everolimus is the main circulating component in human blood. Six main 
metabolites of everolimus have been detected in human blood, including three 
monohydroxylated metabolites, two hydrolytic ring-opened products, and a 
phosphatidylcholine conjugate of everolimus. 
 
These metabolites were also identified in animal species used in toxicity studies, 
and showed approximately 100-times less activity than everolimus itself.  
 
In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a 
mixed inhibitor of the CYP2D6 substrate dextromethorphan.  
 
Excretion  
No specific excretion studies have been undertaken in cancer patients. Following 
the administration of a 3 mg single dose of radiolabeled everolimus in patients who 
were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, 
while 5% was excreted in the urine. The parent substance was not detected in urine 
or feces. The mean elimination half-life of everolimus is approximately 30 hours. 
 
 


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8.2.4 Supplier(s) 
 
Everolimus is commercially available. 
 
8.2.5 Dosage Form and Preparation 
 
For this study, everolimus will be available commercially at 5 or 10 mg. 
 
8.2.6 Storage and Stability 
 
Store everolimus at room temperature, away from light. 
 
8.2.7 Administration 
 
Everolimus is an oral drug which will be administered on an outpatient basis at a 
dose of 10 mg daily on every day of each 28-day cycle.  Patients should take 
everolimus at the same time as X-82.  If a patient misses a dose, the patient should 
be instructed to take that dose up to 12 hours after the time that s/he would normally 
take it.  If more than 12 hours have elapsed, the patient should skip that dose for 
the day.  Patients should not take 2 doses to make up for the one that was missed. 
Patients will be instructed to bring all unused tablets and their medication diary (see 
Appendix E) to each study visit for assessment of compliance. 
 
8.2.8 Special Handling Instructions 
 
None. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Archived Tumor Tissue 
 
FFPE samples from previous diagnostic or therapeutic procedures will be requested. Tissue 
blocks are preferable; however, if the tissue block cannot be obtained, 20 unstained slides 
sectioned at 5 microns will be required.  Archival tumor tissue will be analyzed by the 
Genomic and Pathology Service at Washington University using the Washington 
University Cancer Mutational Profile (WU-CaMP), which was designed to perform full 
gene sequencing on a panel of 28 genes which include PI3KCA, KRAS, BRAF and PTEN. 
The Wu-CaMP assay subjects DNA extracted from paraffin-embedded tumor specimens 
or fresh tumor biopsy to next-generation sequencing technology for mutation analysis.  Ki-
67 proliferation index will be collected as well. 
 
9.2 
Tumor Biopsy (Optional) 
 
Fresh tumor biopsy samples will be obtained where feasible by CT or ultrasound-guided 


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core biopsy. Some areas that are considered feasible are chest wall lesions, skin lesions, 
palpable lymph nodes, liver lesions, lung lesions, or other areas deemed feasible by the 
treating physician or study PI.  Samples will be obtained at baseline (up to 28 days before 
Cycle 1 Day 1).  These samples will be snap frozen for future comprehensive genomic 
analysis.  
 
Accrued biopsy samples will be identified through HRPO number and protocol number, 
patient’s entry number, and sample collection date and time, and this information will be 
securely affixed by means of pre-made labels.  Samples will be released for laboratory 
analysis by specimen ID only.   
 
All biopsy samples will be processed and stored by the Siteman Cancer Center Tissue 
Bank.  The address and contact information are provided below. 
 
Siteman Cancer Center Tissue Procurement Facility 
BJC Institute of Health 
425 S. Euclid Ave., Room 5120 
St. Louis, MO  63110 
Phone: 314-454-7615 
 
9.3 
Blood Samples  
 
All samples will be taken to Siteman Cancer Center’s Tissue Procurement Core (BJCIH 
5th fl) after they are drawn.  No special processing need take place before delivery.  Please 
use the shipping address in provided in Section 9.2. 
 
9.3.1 Blood for Trough Levels 
 
Blood (10 mL) will be collected in 2 lavender top tubes (5 mL K2 EDTA tubes) on 
Cycle 2 Day 1 prior to dosing for evaluation of trough levels of everolimus and X-
82. 
 
9.3.2 Blood for Chromogranin A, Neuron-specific Enolases (NSE), and 
Angiogenesis Biomarker (Phase II Only) 
 
Blood (10 mL) will be collected in 1 lavender top tube (5 mL K2 EDTA tube) and 
1 red top tube (5 mL) for evaluation of chromogranin A, neuron-specific enolases 
(NSE), and angiogenesis biomarker.  Serum and plasma samples will be collected 
at the following time points: 
 
 Baseline  
 Pre-dose on Day 1 of every cycle beginning with Cycle 2 
 
Please note that if chromogranin A and NSE at baseline are less than upper limit of 
normal, there will not be further collection of both biomarkers during subsequent 
cycles.   


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Evaluation of chromogranin A is a standard care for patients with NETs; therefore, 
the test will be carried out by the Barnes-Jewish Laboratory.  NSE will be analyzed 
by Quest Diagnostic by using a solid-phase, noncompetitive enzyme immunoassay 
(Yao et al 2011).  
 
To evaluate the angiogenesis biomarkers, plasma samples will be analyzed by 
commercially available enzyme linked immunosorbent system (ELISA) kit which 
will determine the expression levels of a panel of angiogenesis biomarkers 
including angiopoietin-2, endothelin-1, EGF, FGF, TNFα, HGF, IL-8, Leptin, 
PIGF, VEGF and HB-EGF.   
 
9.4 
DCE-MRI (Phase II Only - Optional)  
 
Patients must have ≥3 cm target lesion in order to be eligible for the DCE-MRI. 
 
 
The schedule of evaluation with DCE-MRI is as follows: 
1. Before initiation of either study drug (baseline) 
2. 21 +/- 3 days after initiation of the first study drug (patients will be randomized to 
one of two groups: one group will begin taking everolimus 3 weeks prior to X-82,  
and the other group will begin taking X-82 3 weeks prior to everolimus) 
3. 21 +/- 3 days after initiation of the second study drug 
 
DCE-MRI will be performed following injection of contrast at a rate of 2 ml/s, with a delay 
of 6 s, followed by 20 ml of saline flush using an automatic injector.  Gadobenate 
dimeglumine (Gd-BOPTA, MultiHance, Bracco Diagnostics, Inc., Princeton, NJ) will be 
used at a standard concentration of 0.1 mmol/kg.  A series of images will be acquired over 
a time period of 4-5 min with a temporal resolution of approximately 8 s.  Oblique coronal 
images covering the tumor and including the abdominal aorta will be performed under the 
guidance of pre-contrast T1 and T2 weighted images.  The nominal parameters for the 
DCE-MRI, 3D spoiled gradient echo sequence (SPGR) are: TE = 1 ms, TR = 4 ms, flip 
angle 30 degrees, slice thickness 5 mm (with zero-filling), matrix size = 256x128, 12 slices, 
FOV = 320x320 mm, bandwidth = 23.8 kHz, NEx = 1.0, and number of phases = 30.  A 
3D SPGR sequence with the same parameters above will be performed for T1 mapping of 
the liver, using multiple flip angles (e.g., FA = 2, 5, 10, 15, 20, 25, 30 degrees) in the same 
acquisition plane. 
 
9.5 
Blood for Pharmacokinetic Testing (PK Expansion Cohort Only) 
 
2.5 mL of blood will be drawn from patients enrolled in the PK expansion cohort at the 
following time points on Cycle 1 Day 14: 
 Pre-administration of everolimus 
 1 hour post-administration of everolimus 
 2 hours post-administration of everolimus (prior to X-82 dosing for Group A) 
 3 hours post-administration of everolimus 


Amendment 8: Version: 01/29/16 
 
Page 42 of 66 
 4 hours post-administration of everolimus (prior to X-82 dosing for Group B) 
 5 hours post-administration of everolimus (for Groups A and B only) 
 6 hours post-administration of everolimus 
 7 hours post-administration of everolimus (for Group B only) 
 8 hours post-administration of everolimus 
 10 hours post-administration of everolimus (for Groups A and B only) 
 12 hours post-administration of everolimus (for Group B only) 
 
Collect blood sample using one 10 mL lavender-top K2 EDTA collection tube at the time 
points specified. After obtaining the blood sample, invert the tubes 8 times (process within 
30 minutes of blood collection). Centrifuge at 3000rpm for 10 minutes at 4°C temperature 
in swing-bucket centrifuge. Carefully aspirate plasma supernatant without disturbing the 
buffy coat layer. Transfer duplicate plasma aliquots of approximately equal volume, using 
standard laboratory technique, into 2 appropriately-labeled 2 mL cryovial tubes. Ensure 
that the white labels are completed with pertinent study and patient information and affix 
one label to each 2mL cryovial tube. Immediately store both plasma aliquot samples in a 
freezer set to maintain a temperature of -70°C. Complete the shipping manifest 
electronically with all the required specimen information.  A shipping manifest MUST BE 
sent to Covance prior to shipment to ensure accurate processing of the patient 
samples.  Print two copies of the manifest, one copy to be included in the sample shipment 
and one copy to be included in the site files. Ship the samples to Covance for analysis: 
Attention: Amber LaFayette 
Sample Management—Bioanalytical (Rm 1S 160)  
Covance Laboratory Inc.  
3301 Kinsman Boulevard  
Madison, WI 53704-2523 
 
Phone:  608-395-3750 
 
Send the electronic copy of the sample inventory form in .xls format (shipping manifest) 
to: Madison.SA@covance.com AND amber.lafayette@covance.com. 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 43 of 66 
10.0 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days +/- 2 days prior to start of protocol therapy.  
Scans and x-rays must be done no more than 28 days +/- 2 days prior to the start of the protocol 
therapy. 
 
10.1 
Phase I and PK Expansion Cohort Study Calendar 
 
 
Baseline 
Day 1 of 
each cycle 
End of every 
third cycle 
Follow-
upk 
Informed consent 
X 
 
 
 
Medical history 
X 
 
 
 
Physical exam, incl. weight, PS 
X 
X 
 
X 
CBCa 
X 
Xn 
 
 
CMPb (fasting) 
X 
Xn 
 
 
Fasting serum cholesterol and 
triglycerides 
X 
 
X 
 
Serum or urine pregnancy testc 
X 
 
 
 
Urinalysis 
X 
 
 
 
Hepatitis B test 
X 
 
 
 
EKG 
X 
Xg 
 
 
Echocardiogram or MUGAd 
X 
 
 
 
CT or MRI or PET/CT 
Xe 
 
X 
 
Archival tissue for WU-CaMP assay 
X 
 
 
 
OPTIONAL biopsye 
X 
 
 
 
Blood for trough levels of everolimus 
and X-82 
 
Xj 
 
 
Blood for PKs 
 
Xo 
 
 
X-82f 
 
X -------------------- X 
 
Everolimusf 
 
X -------------------- X 
 
Adverse event assessment 
X --------------------------------------------- Xm 
Concomitant medications 
X --------------------------------------------- X 
a: CBC parameters are hemoglobin, hematocrit, RBC, WBC, platelets 
b: CMP parameters are glucose, calcium, albumin, total protein, sodium, potassium, carbon dioxide, chloride, 
BUN, creatinine, alkaline phosphatase, ALT/SGPT, AST/SGOT, bilirubin 
c: Women of childbearing potential only; must be performed no more than 7 days before first dose of X-82 
d: At baseline and thereafter as clinically indicated 
e: May take place up to 28 days before C1D1 
f: To be taken daily 
g: Day 1 of every even-numbered cycle 
h: Will not be drawn on C1D1; will be repeated only if above ULN at baseline 
j: Drawn on C2D1 only  
k: Follow-up to take place every 12 weeks for 3 years. 
m: To 30 days after end of therapy; note that abnormal lab values will be considered AEs and will be captured 
in the CRFs only if they are clinically significant. 
n: Labs will also be drawn on C1D15. 
o: For patients in the PK expansion cohort only.  Drawn on Cycle 1 Day 14.  Refer to Section 9.5 for timing. 
 


Amendment 8: Version: 01/29/16 
 
Page 44 of 66 
10.2 
Phase II Study Calendar 
 
 
Baseline C0
D1 
C0D21 
to 28 
Day 1 of 
each cycle 
End of every 
third cycle 
Follow-
upm 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical exam, incl. weight, PS 
X 
 
 
X 
 
X 
CBCa 
X 
 
 
X 
 
 
CMPb (fasting) 
X 
 
 
X 
 
 
Fasting serum cholesterol and 
triglycerides 
X 
 
 
 
X 
 
Serum or urine pregnancy testc 
X 
 
 
 
 
 
Hepatitis B test 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
EKG 
X 
 
 
Xh 
 
 
Echocardiogram or MUGAd 
X 
 
 
 
 
 
CT or MRI or PET/CT 
Xf 
 
 
 
X 
 
OPTIONAL DCE-MRI e 
X 
 
X 
Xe 
 
 
Archival tissue for WU-CaMP 
assay 
X 
 
 
 
 
 
OPTIONAL biopsyf 
X 
 
 
 
 
 
Blood for chromogranin A, 
NSE, and angiogenesis 
biomarkers 
X 
 
 
Xj 
 
 
Blood for trough levels of 
everolimus and X-82 
 
 
 
Xk 
 
 
X-82g 
 
X ------------------------------------- X 
 
Everolimusg 
 
X ------------------------------------- X 
 
Adverse event assessment 
X --------------------------------------------------------------- Xn 
Concomitant medications 
X --------------------------------------------------------------- X 
a: CBC parameters are hemoglobin, hematocrit, RBC, WBC, platelets 
b: CMP parameters are glucose, calcium, albumin, total protein, sodium, potassium, carbon dioxide, chloride, BUN, 
creatinine, alkaline phosphatase, ALT/SGPT, AST/SGOT, bilirubin 
c: Women of childbearing potential only; must be performed no more than 7 days before first dose of X-82 
d: At baseline and thereafter as clinically indicated 
e: DCE-MRI will be performed at baseline, 21 +/- 3 days after initiation of the first study drug (~C0D21), and then again 
21 +/- 3 days after initiation of the second study drug (C1D21). 
f: May take place up to 28 days before C1D1 
g: To be taken daily; patients in Phase II will be randomized so that half begin taking everolimus 3 weeks prior to starting 
X-82, while the other half begin taking X-82 3 weeks prior to starting everolimus.  Please note that Cycle 1 Day 1 is 
considered to be the first day when both drugs are taken. 
h: Day 1 of every even-numbered cycle 
j: Will not be drawn on C1D1; will be repeated only if above ULN at baseline 
k: Drawn on C2D1 only 
m: Follow-up to take place every 12 weeks for 3 years. 
n: To 30 days after end of therapy; note that abnormal lab values will be considered AEs and will be captured in the 
CRFs only if they are clinically significant. 
 
 


Amendment 8: Version: 01/29/16 
 
Page 45 of 66 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Electronic data management systems will be used in this trial in collaboration with the Center for 
Biomedical Informatics core at Washington University.   
 
ClinPortal is a web-based clinical studies data management system that will be used for capture of 
clinical data from this trial.  The case report forms developed for this trial will be transformed to 
electronic format. An electronic study calendar will drive the study’s data collection workflow.  An 
Oracle database securely stores PHI in compliance with HIPAA and IRB regulations. 
 
Identical study databases will be created in ClinPortal for each participating center; each center 
has access only to data from its own participants.  Washington University, as the data coordinating 
center, has access to data from all sites. 
 
Training in entering data in ClinPortal is required before a participating center will be given access 
to its site’s database.  The Center for Biomedical Informatics at Washington University offers 
monthly web-based training for external users; the scheduled may be found at the following URL: 
http://cbmi.wustl.edu/?q=clinportal-training-details.  Users must RSVP at least 3 days prior to the 
training session. 
 
In addition, a participating center must have IRB approval of this protocol prior to initiation of 
ClinPortal data entry training, which must be completed prior to study activation. 
 
 


Amendment 8: Version: 01/29/16 
 
Page 46 of 66 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Tissue Collection Form 
Research Blood Form 
Treatment Assignment Form 
Prior to starting treatment 
Treatment Form 
Research Blood Form 
Every cycle 
Toxicity Form 
Concomitant Medications Form 
Continuous 
DCE-MRI Form (Phase II only) 
Baseline 
Cycle 0 Day 21 +/- 3  
Cycle 1 Day 21 +/- 3  
PK Form (PK Expansion Cohort only) Cycle 1 Day 14 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 12 weeks for 3 years 
Tumor Measurement Form 
Baseline, end of every third cycle, and end of treatment 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 12 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained 4-8 weeks (not 
less than 4) weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1).  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used 
in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 


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Page 47 of 66 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  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 >15 mm 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. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
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), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 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, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 


Amendment 8: Version: 01/29/16 
 
Page 48 of 66 
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 unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
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:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. 
   
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 


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Page 49 of 66 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.4.3 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 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 


Amendment 8: Version: 01/29/16 
 
Page 50 of 66 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
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 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
12.4.4 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 recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  


Amendment 8: Version: 01/29/16 
 
Page 51 of 66 
 
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, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
12.4.6 Overall Survival 
 
OS is defined as the duration of time from diagnosis to time of death from any 
cause. 
 
12.4.7 Response Review 
 
Response rate is the primary efficacy endpoint.  All responses will be reviewed by 
an expert(s) independent of the study at the study’s completion.   
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark).  
The Data and Safety Monitoring Committee (DSMC) will meet to review toxicity data at least 
every 6 months following the activation of the first secondary site. 
 
During the phase I dose escalation, the Principal Investigator will review all patient data at least 
monthly (or before each dose-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC).  During the 
phase II, the Principal Investigator will review all patient data at least every six months, and 
provide a semi-annual report to the QASMC. This report will include: 
 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 


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Page 52 of 66 
 Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
 Protocol activation date at each participating site 
 Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
 Expected accrual end date, accrual by site, and accrual by cohort 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy  
 Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
 Summary of toxicities at all participating sites separated by cohorts with the number of 
dose-limiting toxicities indicated 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study  
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to 
be prepared by the study team will be submitted to the QASM Committee beginning 6 months 
after study activation at Washington University.  The study principal investigator and Research 
Patient Coordinator will monitor for serious toxicities on an ongoing basis. Once the principal 
investigator or Research Patient Coordinator becomes aware of an adverse event, the AE will be 
reported to the HRPO and QASMC according to institutional guidelines. 
 
A DSMC will consist of no fewer than 3 members including 2 clinical investigators and a 
biostatistician.  Like investigators, DSMC members are subject to the Washington University 
School of Medicine policies regarding standards of conduct. Individuals invited to serve on the 
DSMC will disclose any potential conflicts of interest to the trial principal investigator and/or 
appropriate university officials, in accordance with institution policies. Potential conflicts that 
develop during a trial or a member’s tenure on a DSMC must also be disclosed.  
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources/
Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurcance.pdf 
 
 
14.0 
AUDITING 
 
Since Washington University is the coordinating center, each site will be audited annually by 
Siteman Cancer Center personnel (QASMC) unless the outside institution has an auditing 
mechanism in place and can provide a report. The outside sites will be asked to send copies of all 
audit materials, including source documentation.  The audit notification will be sent to the 
Washington University Research Patient Coordinator, who will obtain the audit materials from the 
participating institution. 
 


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Page 53 of 66 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Additional details regarding the Auditing Policies and procedures can be found at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources/
Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurcance.pdf  
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Primary Endpoints and Objectives 
 
The primary objective of the Phase I portion is to determine the dose-limiting toxicities of 
X-82 in combination with everolimus in patients with solid malignancies and to determine 
the recommended phase II dose for this combination. 
 
The primary objective of the Phase II portion is to determine the preliminary efficacy (as 
measured by complete response and partial response) for X-82 in combination with 
everolimus in patients with pancreatic neuroendocrine tumor. 
 
15.2 
Study Design 
 
The Phase I portion will be conducted using a standard 3+3 design.  The definition of DLT 
as well as the procedures of dose escalation have been detailed in Section 5.4.   Depending 
on the dose level identified as the MTD, up to a maximum of 30 subjects may be required 
to determine the MTD (5 dose levels with a maximum of 6 patients per level) according to 
the 3+3 design.  
 
A total of 29 evaluable patients will be enrolled for the Phase II portion. The patients 
enrolled at the recommended phase II dose in the Phase I portion will not be counted as 
Phase II participants.  We assume a null hypothesis of 5% overall response rate. We 
hypothesize that an overall response rate of 20% or higher warrants further investigation. 
Based on Simon’s optimal two-stage design with 80% power at a 0.05 significance level, 
10 patients will be enrolled in the first stage.  If 1 or more responses are observed during 
the first stage, then 19 additional patients will be enrolled in stage II.  If 4 or more responses 
are observed by the end of the trial, we would conclude that preliminary evidence for 
efficacy exists and that further investigation of the drug is warranted.  Note, however, that 
an assessment of all of the efficacy and biomarker data, not just response rate, will 
ultimately be used to make this determination.  A total of 32 patients will be enrolled 
assuming 10% of cases will be inevaluable. 
 
Finally, 9 additional patients with renal cell carcinoma will be enrolled to the PK expansion 
cohort.  


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Page 54 of 66 
 
15.3 
Data Analysis of the Phase II Study 
 
Demographic and clinical characteristics of the sample, as well as response, toxicity by 
grade, and loss to follow up will be summarized using descriptive statistics. The overall 
response rate and disease stabilization rate, as well as their 95% confidence intervals, will 
be calculated. The toxicities by grade will also be tabulated. Kaplan-Meier product limit 
estimator will be used to describe the distribution of overall survival (OS) and progression-
free survival (PFS). The median OS and PFS and their 95% confidence intervals will be 
estimated. 
 
In the correlative studies, the association between clinical outcomes (response, PFS, and 
OS) and biomarkers (including chromogranin A, neuron-specific enolase, the mutation 
status of PIK3CA, PTEN loss, KRAS and BRAF, as well as serum level of PIGF, 
angiopoietin-2, VEGF, FGF et al.) will be assessed using Wilcoxon-Mann-Whitney rank-
sum tests, log-rank tests or univariate Cox proportional hazards models as appropriate.  
 
15.4 
DCE-MRI Analyses 
 
The DCE imaging will be evaluated for changes in Ktrans and initial area under the curve, 
which are parameters reflecting the passage of Gadolinium contrast agent from the vascular 
space to the extravascular, extracellular space.  The kinetic parameters and ADC values 
will be correlated with objective tumor response based upon RECIST 1.1 guidelines.  The 
tumor measurements will be performed by a reference radiologist using MRI, CT, or 
PET/CT.  Phase II patients will be randomized into two groups: one group will start taking 
everolimus 3 weeks prior to initiation of X-82, and the other group will start taking X-82 
3 weeks prior to initiation of everolimus.  Tumor DCE kinetic parameters and ADC 
measurement will be evaluated at baseline, 21 +/- 3 days after the initiation of the first 
study drug, and then 21 +/- 3 days after the initiation of the second study drug.  The ADC 
values and kinetic parameters will be correlated with overall survival and progression-free 
survival once this data is available at the termination of the study. 
 
Changes in tumor perfusion parameters and ADC values through Cycle 1 Day 21 +/- 3 will 
be correlated with objective response as determined by anatomic measurements on follow-
up MRI, CT, or PET/CT using guidelines from RECIST 1.1.  Changes in DCE-MRI 
parameters will be compared between the first and second scan using a signed-rank test.  
The change of DCE-MRI values over time will be described using two-way ANOVA for 
repeated measurement data, followed by post-hoc comparisons for between-time or 
between-group differences of interest.  The association between these changes and patient 
outcome (RECIST response and progression-free survival) will be explored using Cox 
regression (for PFS) and logistic regression (for response).  With at least 29 evaluable 
patients we will have approximately 80% power at a 1-sided 0.05 significance level to 
detect changes from baseline that are 50% of the standard deviation of the change score. 
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 


Amendment 8: Version: 01/29/16 
 
Page 55 of 66 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Each participating institution must have the following documents on file at Washington University 
prior to first subject enrollment: 
 Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
 Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including the 
Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 
 Documentation of FWA, signed FDA Form 1572, and signed and dated CVs of all 
participating investigators. 
 Documentation of training in protection of human subjects by all participating 
investigators. 
 Protocol signature page signed and dated by the investigator at each participating site. 
 
The Principal Investigator is responsible for disseminating to the participating sites all study 
updates, amendments, reportable adverse events, etc.  There will be one current version of the 
protocol document at any given time and each participating institution will utilize that document.  
Protocol/consent modifications and IB updates will be forwarded electronically to the secondary 
sites within 2 weeks of obtaining Washington University IRB approval with acknowledgement of 
receipt requested.  Secondary sites are to submit protocol/consent/IB modifications to their local 
IRBs within 4 weeks of receipt, and confirmation of submission must be forwarded to the 
appropriate contact person on the Washington University study team at the time of submission.  
Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the 
Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 


Amendment 8: Version: 01/29/16 
 
Page 56 of 66 
 
17.0 
REFERENCES 
 
1. 
Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of 
and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J 
Clin Oncol. Jun 20 2008;26(18):3063-3072. 
2. 
Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine 
tumors. Gastroenterology. Nov 2008;135(5):1469-1492. 
3. 
Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival 
in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer 
Res. Dec 1 2008;14(23):7798-7803. 
4. 
Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D. VEGF-A has a critical, 
nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer 
Cell. Mar 2002;1(2):193-202. 
5. 
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of 
antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer 
Cell. Oct 2005;8(4):299-309. 
6. 
Hansel DE, Rahman A, Hermans J, et al. Liver metastases arising from well-differentiated 
pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Mod Pathol. 
Jul 2003;16(7):652-659. 
7. 
Fjallskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET. Expression of 
molecular targets for tyrosine kinase receptor antagonists in malignant endocrine 
pancreatic tumors. Clin Cancer Res. Apr 2003;9(4):1469-1473. 
8. 
Yao JC, Phan A, Hoff PM, et al. Targeting vascular endothelial growth factor in advanced 
carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab 
and pegylated interferon alpha-2b. J Clin Oncol. Mar 10 2008;26(8):1316-1323. 
9. 
Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced 
neuroendocrine tumors. J Clin Oncol. Jul 10 2008;26(20):3403-3410. 
10. 
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic 
neuroendocrine tumors. N Engl J Med. Feb 10;364(6):501-513. 
11. 
Hobday TJ, Rubin J, Holen K. A Phase II trial of sorafenib in patients with metastatic 
neuroendocrine tumors: a phase II consortium study. J Clin Oncol. 2007;suppl(Abst 4504). 
12. 
Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with 
rapamycin derivatives. Ann Oncol. Apr 2005;16(4):525-537. 
13. 
Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are 
frequently altered in pancreatic neuroendocrine tumors. Science. Mar 4;331(6021):1199-
1203. 
14. 
Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling 
evidences a role for AKT-mTOR pathway. J Clin Oncol. Jan 10;28(2):245-255. 
15. 
von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine 
regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. 
Cancer Res. Aug 15 2000;60(16):4573-4581. 
16. 
Moreno A, Akcakanat A, Munsell MF, Soni A, Yao JC, Meric-Bernstam F. Antitumor 
activity of rapamycin and octreotide as single agents or in combination in neuroendocrine 
tumors. Endocr Relat Cancer. Mar 2008;15(1):257-266. 


Amendment 8: Version: 01/29/16 
 
Page 57 of 66 
17. 
Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of 
temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. Nov 6 
2006;95(9):1148-1154. 
18. 
Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR 
in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. 
J Clin Oncol. Sep 10 2008;26(26):4311-4318. 
19. 
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. 
N Engl J Med. Feb 10;364(6):514-523. 
20. 
Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting 
repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid 
syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. Dec 
10;378(9808):2005-2012. 
21. 
Moore KN, Jones SF, Kurkijian C, et al. A Phase I first in human trial of an oral VEGFR 
tyrosine kinase inhibitor, X-82, in patients with advanced solid tumors. J Clin Oncol. 
2012;30(155):Abstr 3041. 
22. 
Hobday TJ, Qin R, Reidy L, Ehrlichman C. Multicenter phase II trial of temsirolimus 
(TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET): Results of a 
planned interim efficacy analysis J Clin Oncol. 2012;30(suppl):abst 4047. 
23. 
Yao JC, Phan AT, Fogleman D, Hess KR. Randomized run-in study of bevacizumab (B) 
and everolimus (E) in low- to intermediate-grade neuroendocrine tumors (LGNETs) using 
perfusion CT as functional biomarker.. J Clin Oncol. 2010;28(15s):abst 4002. 
24. 
Kroog GS, Feldman DR, Motzer RJ. Phase I trial of RAD001 (everolimus) plus sunitinib 
in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(15s):abst 5037. 
25. 
Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors: analysis of prognostic 
factors and survival in 301 patients from a referral center. Ann Oncol. Jul 1997;8(7):685-
690. 
26. 
Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with 
metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a 
phase II trial. J Clin Oncol. Jan 1;28(1):69-76. 
27. 
Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the 
treatment of patients with locally advanced and metastatic pancreatic endocrine 
carcinomas. J Clin Oncol. Dec 1 2004;22(23):4762-4771. 
28. 
Yao JC, Pavel M, Phan AT, et al. Chromogranin A and neuron-specific enolase as 
prognostic markers in patients with advanced pNET treated with everolimus. J Clin 
Endocrinol Metab. Dec;96(12):3741-3749. 
29. 
Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase 
pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett. 
2005;10(3):479-498. 
30. 
Di Nicolantonio F, Arena S, Tabernero J, et al. Deregulation of the PI3K and KRAS 
signaling pathways in human cancer cells determines their response to everolimus. J Clin 
Invest. Aug;120(8):2858-2866. 
31. 
Zhang J, Jia Z, Li Q, et al. Elevated expression of vascular endothelial growth factor 
correlates with increased angiogenesis and decreased progression-free survival among 
patients with low-grade neuroendocrine tumors. Cancer. Apr 15 2007;109(8):1478-1486. 
32. 
Terris B, Scoazec JY, Rubbia L, et al. Expression of vascular endothelial growth factor in 
digestive neuroendocrine tumours. Histopathology. Feb 1998;32(2):133-138. 


Amendment 8: Version: 01/29/16 
 
Page 58 of 66 
33. 
Fischer C, Pape U, T N. Prognostic relevance of circulating PIGF levels in patients with 
neuroendocrine tumors. J Clin Oncol. 2012;30 suppl:abst 4128. 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 59 of 66 
 
APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 60 of 66 
APPENDIX B: UPC Ratio Calculation 
 
The UPC (urine protein to creatinine) ratio directly correlates with the grams of protein found in 
a 24-hour urine collection.  The UPC ratio can be used in the place of a 24-hour urine collection. 
 
Procedure for Obtaining a UPC Ratio: 
 
1. Obtain at least 4 mL of a random urine sample in a sterile container (does not have to be 
a 24-hour urine sample). 
2. Determine protein concentration (mg/dL). 
3. Determine creatinine concentration (mg/dL). 
4. Divide protein concentration by creatinine concentration. 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 61 of 66 
APPENDIX C: NYHA Classification 
 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, e.g., shortness of breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20-100 m).  Comfortable only at rest. 
IV 
Severe limitations.  Experiences symptoms even while at rest.  Mostly 
bedbound. 
 
 


Amendment 8: Version: 01/29/16 
 
Page 62 of 66 
APPENDIX D: Patient’s Medication Diary – X-82 
 
Today’s Date:    
 
 
 
 
Agent:  X-82  
Cycle:    
 
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID#:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___tablets) of X-82 daily at the same time each day. Take 
it with a glass of water and drink the glass of water in as little time as possible.  Swallow the tablets whole and do 
not chew them.  Your doctor will let you know when you should take X-82 relative to everolimus. 
2. Record the date, the number of tablets taken, and when you took them. 
3. If you forget to take X-82 before 6:00PM, then do not take a dose that day.  Restart taking it the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return this form to your physician or study coordinator when you go to your next appointment.  Bring your 
unused study medications and empty bottles with you to each clinic visit so that a pill count can be done. 
6. Avoid St. John’s Wort or any herbal medications, Seville oranges, grapefruit, grapefruit juice, grapefruit hybrids, 
pomelos, and exotic citrus fruits from 7 days before you start taking X-82 and throughout the entire study.   
Day 
Date 
What time was 
dose taken? 
# of tablets 
taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 63 of 66 
APPENDIX E: Patient’s Medication Diary – Everolimus 
 
Today’s Date:    
 
 
 
 
Agent:  Everolimus  
Cycle:    
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID#:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take 10 mg (1 tablet) of everolimus daily at the same time each day. Take 
it with a glass of water.  Your doctor will let you know when you should take everolimus relative to X-82. 
2. Record the date, the number of tablets taken, and when you took them. 
3. If you forget to take everolimus before 6:00PM, then do not take a dose that day.  Restart taking it the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return this form to your physician or study coordinator when you go to your next appointment.  Bring your 
unused study medications and empty bottles with you to each clinic visit so that a pill count can be done. 
6. Avoid St. John’s Wort or any herbal medications, Seville oranges, grapefruit or its juice or hybrids, pomelos, and 
exotic citrus fruits from 7 days before you start taking everolimus and throughout the entire study.   
Day 
Date 
What time was 
dose taken? 
# of tablets 
taken 
 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 64 of 66 
 
APPENDIX F: Drugs that Prolong QT Interval and/or Induce Torsades De Pointes 
 
This is not a comprehensive list.  A complete list may be found and updated at the following web 
address: http://qtdrugs/org/medical-pros/drug-lists/drug-lists.htm 
 
Antiarrhythmics 
Amiodarone 
Disopyramide 
Dofetilide 
Ibutilide 
Procainamide 
Quinidine 
Sotalol 
 
Antibiotics 
Clarithromycin 
Erythromycin 
Gatifloxacin 
Moxifloxacin 
Sparfloxacin 
 
Antipsychotics 
Chlorpromazine 
Haloperidol 
Mesoridazine 
Pimozide 
Risperidone 
Thioridazine 
Ziprasidone 
 
 
 
 
 
 
Antidepressants 
Amitriptyline 
Desipramine 
Doxepin 
Imipramine 
Maprotiline 
Venlafaxine 
 
Antifungals 
Keotconazole 
Itraconazole 
 
Antimalarials 
Chloroqine 
Halofantrine 
 
Antiemetics 
Dolasetron 
Domperidone 
Droperidol 
Ondandsetron 
Tropisetron 
 
Miscellaneous 
Arsenic trioxide 
Bepridil 
Methadone 
Pentamidine 
Cisapride 
Tacrolimus 
 
 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 65 of 66 
 
APPENDIX G: CYP2C9 Substrates 
 
The following list describes medications and foods which are common inhibitors, inducers, and 
substrates of CYP2C9.  This list should not be considered all-inclusive.  Consult individual drug 
labels for specific information on a compound’s propensity to inhibit or induce CYP2C9. 
 
CYP2C9 Substrates 
Major 
Celecoxib 
Lmoxicam 
Diclofenac 
Ibuprofen 
Piroxicam 
Meloxicam 
Phenytoin 
Fluvastatin 
Sulfonylurea 
Glibenclamide 
Glimepiride 
Glipizide 
Tolbutamide 
Irbesartan 
Losartan 
Warfarin 
Minor 
Amitriptyline 
Omeprazole 
Miconazole 
Pitavastatin 
Pheylbutazone 
Rosiglitazone 
Sertraline 
Sildenafil 
Sulfinpyrazone 
Tamoxifen 
THC 
 
 
 
 
 


Amendment 8: Version: 01/29/16 
 
Page 66 of 66 
 
APPENDIX H: CYP3A4 Moderate and Strong Inhibitors and Strong Inducers 
 
The following list describes medications and foods which are common strong inhibitors of 
CYP3A4.  This list should not be considered all-inclusive.  Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A4. 
 
Boceprevir 
Conivaptan 
Grapefruit juice 
Lopinavir 
Mibefradil 
Posaconazole 
Telaprevir 
Voriconazole 
Ritonavir 
Indinavir 
Nelfinavir 
Saquinavir 
Clarithromycin 
Telithromycin 
Chloramphenicol 
Ketoconazole 
Itraconazole 
Nefazodone 
Amprenavir 
Aprepitant 
Atazanavir 
Ciprofloxacin 
Darunavir 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir 
Imatinib 
Verapamil 
Avasimibe 
Carbamazepine 
Phenytoin 
Rifampin 
St. John’s wort