Conditions: Recurrent Malignant Solid Neoplasm Recurrent Melanoma Recurrent Primary Central Nervous System Neoplasm Recurrent Thyroid Gland Carcinoma Refractory Malignant Solid Neoplasm Refractory Primary Central Nervous System Neoplasm Thyroid Gland Medullary Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of cabozantinib S-malate in treating younger patients with solid tumors that have come back or no longer respond to treatment. Cabozantinib S-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of XL184 (cabozantinib) (cabozantinib S-malate) administered orally to children with refractory solid tumors including central nervous system (CNS) tumors.

II. To define and describe the toxicities of XL184 (cabozantinib) administered on this schedule.

III. To characterize the pharmacokinetics of XL184 (cabozantinib) in children with refractory solid tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of XL184 (cabozantinib) within the confines of a phase 1 study.

II. To assess the biologic activity of XL184 (cabozantinib). III. To assess the biomarker response (carcinoembryonic antigen \[CEA\] and calcitonin) in patients with medullary thyroid cancer treated with XL184.

IV. To evaluate overall survival from study entry through a five-year follow-up period.

OUTLINE: This is a dose-escalation study. (Complete as of 4/16/2014)

Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 6 months, and then annually for up to 60 months.

Arms:
arm 1: Patients receive cabozantinib S-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cabozantinib S-malate intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
Pediatric Early Phase Clinical Trial 
Network (PEP-CTN) and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
PEP-CTN and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
foxe@email.chop.edu 
 
PEP-CTN Operations  
Data & Statistics Center Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
PEP-CTN Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
PEP-CTN and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Children’s Oncology Group 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
PEP-CTN Operations Data & 
Statistics Center 
222 E. Huntington Drive 
Suite 100  
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
 
A National Cancer Institute  
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
  
 
i 
 
January 31, 2019 
 
 
Martha Kruhm, M.S., RAC 
Head, Protocol and Information Office (PIO)  
 
National Institutes of Health/NCI/DCTD/CTEP/OIB/PIO 
9609 Medical Center Drive, OIB MSC 9742, Room #5W246 
Bethesda, MD 20892-9742 
 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #10 for ADVL1211, A Phase 1 Study of XL184 
(Cabozantinib) in Children and Adolescents with Recurrent or Refractory Solid Tumors, 
including CNS Tumors. 
 
The protocol has been amended in response to the Request for Amendment from Dr. 
Malcolm Smith, dated December 20, 2018, in which COGC transitions to PEP-CTN. 
Additional administrative and editorial changes were included for consistency. 
 
 
 
Sincerely, 
 
Patrice Navrude, MS, Protocol Coordinator for 
Meredith Chuk, M.D., ADVL1211 Study Chair, and 
Brenda Weigel, M.D., PI, PEP-CTN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                             
 
ii 
 
SUMMARY OF CHANGES 
 
The following specific revisions have been made to the protocol and informed consent document. Additions 
are in boldfaced font and deletions in strikethrough font.  
 
SUMMARY OF CHANGES PROTOCOL DOCUMENT: 
# 
Section 
Comments 
1. 
General 
The version date and amendment number have been updated 
throughout the protocol. 
COGC has been replaced with PEP-CTN. 
PEP-CTN logo has been added throughout the protocol. 
2. 
Title Page 
PEP-CTN has replaced COGC as the lead organization. 
Supplemental COG sites have been removed. 
3. 
Study 
Committee 
Study Committee members contact information has been updated 
PEP-CTN Operations and Data/Statistics  
4. 
Certificate 
of 
Confidentiality 
“The Children’s Oncology Group has received This trial is covered 
by a Certificate of Confidentiality from the federal government…” 
5. 
13.3 
CTEPAERS@childrensoncologygroup.org. 
PEPCTNAERS@childrensoncologygroup.org 
6. 
14.4 
Developmental therapeutics has been replaced with COG PEP-
CTN to show that the study will be monitored in accordance with 
PEP-CTN polices for data and safety monitoring. 
7. 
Appx XVI 
CTEP and CTSU registration procedures have been added. 
 
SUMMARY OF CHANGES INFORMED CONSENT DOCUMENT: 
# 
Section 
Comments 
1. 
General 
The version date has been updated throughout. 
COGC and Phase I Consortium have been replaced with PEP-CTN. 
PEP-CTN logo has been added throughout. 
2. 
Certificate 
of 
Confidentiality 
The Children’s Oncology Group has received This trial is covered 
by a Certificate of Confidentiality from the federal government… 
 
 
 
 


 
 
 
 
 
ADVL1211 
 
Page 1 
 
 
Activated: 
October 15th, 2012 
Version Date: 
1/31/19 
Closed: 
February 27, 2015 
Amendment #: 
   10   
 
 
CHILDREN’S ONCOLOGY GROUP 
 
ADVL1211 
 
A PHASE 1 STUDY OF XL184 (CABOZANTINIB) IN CHILDREN AND ADOLESCENTS WITH 
RECURRENT OR REFRACTORY SOLID TUMORS, INCLUDING CNS TUMORS  
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
STUDY CHAIR 
Meredith Chuk, MD 
Mark O Hatfield-Warren Grant Magnuson Clinic 
Pediatric Oncology Branch, NCI, CCR 
10 Center Dr., MSC 1101   
Building 10, CRC, Room 1-5750  
Bethesda, MD 20892-1928 
Phone: (301) 796-5006 
Email: meredith.chuk@fda.hhs.gov 
 
 
For COG PEP-CTN Operations and Statistics & Data Center Contacts See: 
http://members.childrensoncologygroup.org 
 
 


                           
ADVL1211 
 
Page 2 
Version Date: 1/31/2019 
TABLE OF CONTENTS 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
2.0 
BACKGROUND 
8 
2.1 
Introduction/Rationale for Development 
8 
2.2 
Preclinical Studies 
9 
2.3 
Adult Studies 
9 
2.4 
Pediatric Studies 
12 
2.5 
Overview of Proposed Pediatric Study 
12 
2.6 
Amendment to Open PK Expansion (January 2014) 
13 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
14 
3.1 
Current Study Status 
14 
3.2 
IRB Approval 
14 
3.3 
Patient Registration 
15 
3.4 
Reservation and Contact Requirements 
15 
3.5 
Informed Consent/Assent 
15 
3.6 
Screening Procedures 
15 
3.7 
Eligibility Checklist 
15 
3.8 
Institutional Pathology Report 
15 
3.9 
Study Enrollment 
15 
3.10 
Dose Assignment 
16 
4.0 
PATIENT ELIGIBILITY 
16 
4.1 
Inclusion Criteria 
16 
4.2 
Exclusion Criteria 
19 
5.0 
TREATMENT PROGRAM 
21 
5.1 
Overview of Treatment Plan 
21 
5.2 
Criteria for Starting Subsequent Cycles 
21 
5.3 
Dose Escalation Schema 
22 
5.4 
Grading of Adverse Events 
22 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
23 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
25 
6.1 
Dose Modifications for Hematological Toxicity 
25 
6.2 
Dose Modifications for Non-Hematological Toxicity 
25 
6.3 
Dose Modifications for Proteinuria 
25 
6.4 
Dose Modifications for Hypertension 
26 
6.5 
Dose Modifications for DVT 
28 
6.6 
Dose Modifications for Liver Toxicity 
28 
6.7 
Dose Modifications for Pancreatic Toxicity 
29 
6.8 
Dose Modifications for Diarrhea 
29 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
29 
7.1 
Concurrent Anticancer Therapy 
29 


                           
ADVL1211 
 
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Version Date: 1/31/2019 
7.2 
Investigational Agents 
29 
7.3 
Supportive Care 
29 
7.4 
Growth Factors 
29 
7.5 
Concomitant Medications 
29 
7.6 
Surgery 
30 
7.7 
Concurrent Anti-Hypertensive Therapy 
30 
7.8 
Management of Hypothyroidism 
30 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
31 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
31 
8.2 
Monitoring for Specific Toxicities 
33 
8.3 
Radiology Studies 
33 
8.4 
Pharmacology COMPLETE 
34 
8.5 
Correlative Studies 
35 
9.0 
AGENT INFORMATION 
37 
9.1 
Cabozantinib 
37 
9.2 
Agent Ordering and Agent Accountability 
42 
9.3 
Clinical Drug Request 
42 
9.4 
Agent Inventory Records 
42 
9.4.1 
Useful Links and Contacts 
43 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
43 
10.1 
Criteria for Removal from Protocol Therapy 
43 
10.2 
Off Study Criteria 
44 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
45 
11.1 
Sample Size and Study Duration 
45 
11.2 
Definitions 
46 
11.3 
Dose Escalation and Determination of MTD:- COMPLETE 
46 
11.4 
Inclusion of Children, Women and Minorities 
47 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
48 
12.0 
EVALUATION CRITERIA 
49 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
49 
12.2 
Response Criteria for Patients with Solid Tumors 
49 
12.3 
Biomarker Response Criteria for Patients with MTC 
53 
12.4 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
54 
12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
55 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
56 
12.7 
Response Criteria for Patients with CNS Tumors 
57 
12.8 
Best Response 
59 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
62 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
62 
13.2 
When to Report an Event in an Expedited Manner 
64 
13.3 
Expedited Reporting Methods 
65 
13.4 
Definition of Onset and Resolution of Adverse Events 
65 
13.5 
Other Recipients of Adverse Event Reports 
66 
13.6 
Reporting Secondary AML/MDS 
66 
13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
67 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
69 


                           
ADVL1211 
 
Page 4 
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14.1 
Categories of Research Records 
69 
14.2 
CDUS 
69 
14.3 
CRADA/CTA/CSA 
69 
14.4 
Data and Safety Monitoring Plan 
71 
REFERENCES 
72 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
73 
APPENDIX IIA: XL184 DOSING NOMOGRAM 
74 
APPENDIX IIB: XL184 DOSING NOMOGRAM (AMENDMENT #5A) 
75 
APPENDIX III: XL184 PATIENT DIARY 
77 
APPENDIX IV: CORRELATIVE STUDIES GUIDE 
80 
APPENDIX V: PHARMACOKINETIC STUDY FORM   COMPLETE 
81 
APPENDIX VI: PREGNANCY INFORMATION FORM 
83 
APPENDIX VII:  URINE PROTEIN TO CREATININE (UPC) RATIO 
84 
APPENDIX VIII: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE 
85 
APPENDIX IX:  CYP3A4 INDUCERS AND INHIBITORS 
87 
APPENDIX X: PHARMACODYNAMIC/BIOMARKER STUDY FORM 
88 
APPENDIX XI:  TISSUE STUDY FORM 
89 
APPENDIX XII:  PACKAGING AND SHIPPING INSTRUCTIONS FOR PHARMACODYNAMIC 
AND ARCHIVAL TISSUE SAMPLES 
90 
APPENDIX XIII:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-
ENZYME INDUCING ANTICONVULSANTS 
91 
APPENDIX XIV:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
92 
APPENDIX XV:  MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
94 
 


                           
ADVL1211 
 
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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS  
Meredith Chuk, MD 
Mark O Hatfield-Warren Grant Magnuson Clinic 
Pediatric Oncology Branch, NCI, CCR 
10 Center Dr., MSC 1101   
Building 10, CRC, Room 1-5750  
Bethesda, MD 20892-1928 
Phone: (301) 796-5006 
Email: meredith.chuk@fda.hhs.gov 
 
STUDY VICE CHAIR  
Brigitte Widemann, MD 
Mark O Hatfield-Warren Grant Magnuson Clinic 
Pediatric Oncology Branch, NCI, CCR 
10 Center Dr., MSC 1101   
Building 10, CRC, Room 1-5750   
Bethesda, MD 20892-1928 
Phone: (301) 496-7387 
Fax:     (301) 480-8871 
Email: widemanb@mail.nih.gov 
 
SENIOR STATISTICIAN  
Charles Minard, PhD 
Baylor College of Medicine  
One Baylor Plaza, BCM 122 
Houston, TX 77030 
Phone:   (713) 798-2353 
Fax:  
 (713) 798-2816 
Email: minard@bcm.edu  
 
STATISTICIAN  
Xiaowei Liu 
Statistics 
Children's Oncology Group - Operations Center 
222 E. Huntington Drive, Suite 100 
Monrovia, CA  91016 
Phone: (626) 241-1535 
Fax: 
(626) 445-4334 
Email: xwliu@childrensoncologygroup.org  
 
STUDY PHARMACIST 
Brooke Bernhardt, PharmD 
Pharmacy 
Baylor College of Medicine 
6621 Fannin Street, MC 2-2510 
Houston, TX 77030 
Phone: (832) 824-5292 
Fax: 
(832) 825-5261 
Email: mbbernha@txch.org 
Brenda J. Weigel, MD 
Chair, Developmental Therapeutics 
Hematology/Oncology 
University of Minnesota Medical Center - Fairview 
Department of Pediatrics 
420 Delaware Street, SE  MMC 366 
Minneapolis, MN 55455 
Phone: (612) 626-5501 
Fax: 
(612) 624-3913 
Email: weige007@umn.edu 
 
Elizabeth Fox, MD 
Vice Chair, Developmental Therapeutics 
Children’s Hospital of Philadelphia 
Pediatrics/Division of Oncology 
3501 Civic Center Blvd. 
CTRB-4016 
Philadelphia, PA 19104 
Phone:   (267) 425-3010  
Fax:  
 (267) 425-0113  
Email: foxe@email.chop.edu  
 
Yaël P. Mossé, MD 
Division of Oncology 
Children’s Hospital of Philadelphia 
CTRB Room 3056 
3501 Civic Center Blvd. 
Philadelphia, PA 19104 
Phone: (215) 590-0965 
Fax: 
(267) 426-0685 
E-mail: mosse@chop.edu      
 
Maya Beth Lodish, MD 
Department of Pediatrics 
Division of Pediatric Endocrinology, Mission Hall  
550 16th Street 
4th Floor, Box 0434 
San Francisco, CA  94143 
Phone: (415) 476-3310 
Fax: (415) 476-5356 
Email: Maya.lodish@ucsf.edu 
 
AeRang Kim, MD 
Children’s National Medical Center 
111  Michigan Avenue, N.W. 
Washington, DC  20010 
Phone: (202) 476-4744 
Fax:     (202) 476-5685 
Email: aekim@childrensnational.org 


                           
ADVL1211 
 
Page 6 
Version Date: 1/31/2019 
STUDY COMMITTEE 
 
 
PROTOCOL COORDINATOR 
STUDY NURSE 
Patrice Navrude, MS 
Janet Gammon, RN, BSN 
Children’s Oncology Group – Operations Center 
Hospital for Sick Children 
222 E. Huntington Drive, Suite 100 
Hematology/Oncology 
Monrovia, CA  91016 
555 University Ave. 
Phone: (626) 241-1607 
Toronto, ON M5G 1X8 
Fax: 
(626) 445-4334 
Phone: (416) 813-5861 
E-mail: pnavrude@childrensoncologygroup.org  
Fax: 
(416) 813-5574 
 
E-mail: janet.gammon@sickkids.ca 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For PEP-CTN Operations and 
 
Data/Statistics contacts see: 
 
http:members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
Cabozantinib (XL184, NSC# 761968) 
 
 
 
Sponsor: CTEP 
 
SEE SECTION 8.4.6 FOR SPECIMEN SHIPPING ADDRESS 


                           
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THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Page 7 
Version Date: 1/31/2019 
This trial is covered by a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects.  The Certificate protects against the involuntary release of 
information about subjects collected during the course of our covered studies.  The researchers involved in 
the studies cannot be forced to disclose the identity or any information collected in the study in any legal 
proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or 
legislative proceedings.  However, the subject or the researcher may choose to voluntarily disclose the 
protected information under certain circumstances.  For example, if the subject or his/her guardian requests 
the release of information in writing, the Certificate does not protect against that voluntary disclosure.  
Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS 
request for information for an audit or program evaluation or an FDA request under the Food, Drug and 
Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
 
XL184 (cabozantinib) is an oral small molecule inhibitor of multiple tyrosine kinases including primarily 
MET, VEGFR2 and RET. Overexpression or dysregulation of these tyrosine kinases contribute to the 
pathogenesis of a number of pediatric and adult solid tumors. XL184 has been shown to inhibit these 
tyrosine kinases in vivo and has shown dose-dependent tumor suppression in a variety of xenograft models. 
Treatment with XL184 has also shown antitumor activity in clinical trials in adults assessing its activity in 
several tumor types. This is a limited dose-escalation study of XL184 in pediatric and adolescent patients 
with relapsed or refractory solid tumors including CNS tumors. We will evaluate the MTD or recommended 
phase 2 dose and toxicity of XL184 administered orally on a continuous dosing schedule in the pediatric 
population. We will also preliminarily define the antitumor effects of XL184 within the confines of a phase 
I study, with a particular focus on medullary thyroid cancer (MTC) given the activity of XL184 seen in 
adult patients with MTC. Pharmacokinetic and pharmacodynamic studies will be conducted to further 
define the properties of XL184 in pediatric and adolescent patients.   
 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Time 
Agent 
Days 1-28 
Oral XL184*  
*Refer to dosing nomogram in Appendix II for dosing schedule. 
 
Treatment will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy. Therapy may otherwise continue provided that the patient 
meets the criteria for starting subsequent cycles (Section 5.2) and does not meet any of the criteria for 
removal from protocol therapy or off study criteria (Section 10.0).  
 
 


                           
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Page 8 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose of XL184 (cabozantinib) administered orally to children with refractory 
solid tumors including CNS tumors. 
 
1.1.2 
To define and describe the toxicities of XL184 (cabozantanib) administered on 
this schedule. 
 
1.1.3 
To characterize the pharmacokinetics of XL184 (cabozantanib) in children with 
refractory solid tumors. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the antitumor activity of XL184 (cabozantanib) within 
the confines of a Phase 1 study. 
 
1.2.2 
To assess the biologic activity of XL184 (cabozantanib). 
 
1.2.3 
To assess the biomarker response (CEA and calcitonin) in patients with 
medullary thyroid cancer treated with XL184. 
 
1.2.4 
To evaluate overall survival from study entry through a five-year follow-up 
period. 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Overexpression or dysregulation of certain receptor tyrosine kinases (RTKs) including 
VEGFR, MET and RET have been implicated in the pathogenesis of a variety of tumors. 
Molecularly targeted therapy against these receptors can interrupt this signaling leading to 
tumor shrinkage and in some cases prolonged survival as seen in colorectal and renal 
cancers.1 These RTKs are overexpressed in a variety of pediatric cancers; VEGFR in 
pediatric sarcomas2 and MET in osteosarcoma, glioma, and papillary thyroid cancer3,4. 
Activating RET mutations are the driving force for the development of medullary thyroid 
cancer (MTC) in patients with MEN2, where tumors can appear early in childhood, 
particularly in MEN2B.5  
XL184 is a small molecule inhibitor of multiple tyrosine kinases including primarily MET, 
VEGFR2 and RET and to a lesser extent KIT and TIE-2. In vitro models also show that 
XL184 also inhibits AXL a RTK thought to be involved in gliomagenesis.6  
Selective inhibition of VEGFR2 may lead to increased invasiveness and metastasis.7 
Preclinical models suggest that inhibition of VEGFR2 together with c-MET may not only 
decrease tumor size, but decrease invasiveness and metastases.8,9  
 
 


                           
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2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity  
After treatment with XL184 in in vivo models, immunohistochemical analysis 
showed significant and sustained inhibition of MET, RET and VEGFR2 in solid 
tumors expressing high levels of these RTKs and inhibition of VEGFR2 and TIE-
2 in lung lysate.6  
XL184 has shown dose-dependent inhibition of tumor growth in a variety of 
xenograft models including human breast, lung and MTC, transgenic RIP-Tag2 
model of pancreatic cancer and rat glioma.6 In vivo models showed that plasma 
exposures of XL184 were similar across the models tested and that peak 
concentrations between 2 and 27 mcM were required for target inhibition and anti-
tumor activity. However, much lower trough concentrations (as low as 0.1mcM) 
were seen in these models suggesting that sustained elevated plasma levels of 
XL184 are not needed for efficacy.6   
XL184 has also been shown to block both osteoblastic and osteolytic progression 
of murine xenograft prostate tumors that express both MET and the VEGF co-
receptor NP-1. 7  
 
2.2.2 
Animal Toxicology 
Cardiovascular toxicology studies in beagle dogs showed no significant effects on 
systolic blood pressure, heart rate, left ventricular pressure or QT/QTc 
prolongation at doses of 150 mg/kg and 1000 mg/kg. There was a transient increase 
in diastolic blood pressure (22%) that led to a 12% increase in mean arterial 
pressure at the 1000 mg/kg dose.6  
In chronic dosing toxicity studies, XL184 was well tolerated in rats and dogs with 
daily dosing for 26 weeks.7 
 
2.2.3 
Preclinical Pharmacokinetic Studies 
Preclinical pharmacology showed that XL184 is metabolized by demethylation, 
oxidation and glucuronidation. It is an inhibitor of CYP2C8, CYP2C9*3 and 
CYP2C19 isoenzymes in vitro and is a substrate for CYP3A4 metabolism. 
CYP3A4 induction was seen in vitro in one of two studies with human hepatocytes 
but not with HEPG2 cell lines. XL184 is highly protein-bound (98%).6 
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
As of May 2011, there have been 1333 adult subjects treated with XL184 in a 
variety of clinical trials. In the initial phase I study in adults, 85 patients were 
treated at doses ranging from 0.08 to 11.52 mg/kg/day with subsequent cohorts 
receiving fixed doses of 175 mg, 250 mg and 265 mg daily. The MTD in this study 
was 175 mg po daily (salt form; equivalent to 140 mg freebase form). However, a 
significant percentage of patients receiving this dose required dose-reductions for 
toxicity and a dose of 125 mg (100 mg freebase form) was found to be better 
tolerated. Other studies with XL184 have also found that patients required 
significant dose-reductions with long-term treatment and based on tolerability and 
response data at doses of 40 mg per day10, starting doses as low as 60 mg per day 


                           
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are currently being studied in adults (personal communications Exelixis,11,12).  
DLTs in adult phase I studies were grade 3 lipase elevation, palmar-plantar 
erythrodysesthesia (PPE), and AST/ALT elevation at 11.25 mg/kg, grade 3 PPE 
and elevation of AST at 250 mg qd, and grade 2 and 3 mucositis at 265 mg per 
day. Other common but non dose-limiting toxicities seen with XL184 were fatigue, 
diarrhea, anorexia, nausea, constipation, vomiting, rash, hypertension, 
hypopigmentation of hair, and mucositis. Side effects associated with inhibition of 
VEGF signaling have also been seen including thrombotic events, hypertension, 
hemorrhage, and rare cases of GI perforation and rectal/perirectal abscess.6,11,12 
Thirty-seven patients with MTC were treated on the initial phase I study. 17/35 
(49%) had tumor shrinkage > 30% on at least one evaluation, 10 patients (29%) 
had a confirmed partial response and 15/37 (41%) had stable disease ≥ 6 months. 
Responses were seen in patients treated at doses between 75 and 175mg and in 
patients with and without RET mutations.  Patients with other tumor types 
experienced stable disease for at least 3 months including colorectal carcinoma 
(n=3), sarcoma (n=2), melanoma (n=2), carcinoid (n=2), and adenocyctic, 
follicular thyroid, papillary thyroid, parotid, appendiceal carcinoma, papillary 
renal cell carcinoma and mesothelioma.6,11-13 
 
2.3.2 
Phase 2 and 3 Studies 
In a phase II study in patients with relapsed glioblastoma multiforme (GBM), 
patients were treated with either 125 or 175 mg of XL184 on a daily schedule. 
Interim results from 124 patients revealed progression free survival at 6 months 
(PFS6) in the 175 mg cohort was 21% for all patients. Overall response rate (ORR) 
in patients without prior antiangiogenic therapy (n=34) was 21% and 8% in 
patients who had previously received antiangiogenic drugs. Median duration of 
response was 5.9 months (range 1.9-12.8). In the 125 mg cohort, ORR in patients 
who had not received prior antiangiogenic therapy (n=25) was 32% and mediation 
duration of response had not been met. The most frequent grade 3 /4 AEs were 
fatigue, diarrhea, transaminitis, headache, and PPE. Patients in the 125 mg cohort 
had fewer dose reductions and lower rates of drug discontinuation with similar 
signs of activity.14 
In a phase 2 randomized discontinuation study in patients with advanced solid 
tumors 531 patients have been enrolled as of August 2011. Forty patients (8%) 
have had a confirmed PR, 17 ovarian, 7 prostate, 6 NSCLC, 4 melanoma, 3 HCC, 
2 breast and 1 SCLC. Fifty four percent of patients experienced disease control 
(PR + SD) at week 12.6,15  
Data from an ongoing phase III study in adults with medullary thyroid carcinoma 
(MTC) showed an increase in progression free survival in the XL184 arm 
compared to placebo. In this study 330 patients (median age 55 yrs (67% male) 
with RET mutation status: pos 48%; negative 12%; unknown 39%) with 
unresectable, locally advanced or metastatic MTC were randomized 2:1 to receive 
either XL184 or placebo in a double-blind randomized fashion. Statistically 
significant PFS prolongation of 7.2 months was observed; median PFS for XL184 
was 11.2 mo vs. 4.9 months with placebo (p<0.0001).  The ORR was 28% for 
XL184 and 0% for placebo (p<0.0001).16 
Ongoing studies with XL184 in adults include phase II studies for various solid 


                           
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tumors including prostate cancer, neuroendocrine tumors, breast cancer and phase 
III studies in adults with MTC, and adults with prostate cancer.  
 
2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
Pharmacokinetic studies in adults show dose-proportional increases in maximal 
concentration (Cmax) and drug exposure (AUC) from 0.08 to 11.52 mg/kg. Steady-
state (Day 19) Cmax in the initial phase I study at the MTD of 175mg capsule daily 
(n=19) was 2,310 ng/ml and AUC was 41,600 ng∙h/ml. Steady-state Cmax for 
patients with GBM treated with single agent XL184 at a dose of 175mg/d was 1950 
± 1050 ng/ml (n=27) and 1350 ± 589 ng/ml for patients treated with 125mg/d 
(n=78). Half-life is reported to be between 58 and 136 hours.6,11,13  
Effect of Food on the Bioavailability of cabozantinib in Healthy Adult Subjects 
(Study XL184-004). Study XL184-004 is a Phase 1, open-label, randomized, 
single-dose, two-treatment, two way crossover study to assess the effect of food 
on the bioavailability of cabozantinib in healthy adult subjects. According to a 
randomization scheme, 56 subjects received single oral doses of the assigned 
treatment of Test (175 mg cabozantinib, dosed as one 100 mg capsule and three 25 
mg capsules 30 minutes after administration of a high fat breakfast) or Reference 
(175 mg cabozantinib, dosed as one 100 mg capsule and three 25 mg capsules 
under fasting conditions). Blood samples were collected up to 504 hours post dose 
for each subject after each treatment to assess plasma cabozantinib 
pharmacokinetics.  
Based on the preliminary PK data from 46 subjects who completed both 
treatments, a high fat meal did not appear to alter the terminal t1/2, z of 
cabozantinib [mean t1/2, z : 131 hours (fed) vs. 128 hours (fasted)]. The high fat 
meal significantly increased the median tmax to 6 hours from 4 hours (fasted). The 
high fat meal also significantly increased both the cabozantinib Cmax and AUC 
values by 39% and 56%, respectively. The geometric mean ratio of Cmax 
fed/fasted was 1.39 (90% CI: 1.16-1.67), and the geometric mean ratio of AUC0-
last fed/fasted was 1.56 (90% CI: 1.34-1.80). Based on this result, cabozantinib 
should be taken on an empty stomach (fasting is required 2 hours before and 1 hour 
after each cabozantinib dose). 
Preliminary results from a clinical pharmacology study, XL184-006, showed that 
concurrent administration of cabozantinib with the strong CYP3A4 inducer, 
rifampin, resulted in an approximately 80% reduction in cabozantinib exposure 
(AUC values) after a single dose of cabozantinib in healthy volunteers.  Co-
administration of cabozantinib with strong inducers of the CYP3A4 family (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib 
concentrations.  The chronic use of strong CYP3A4 inducers should be avoided.  
Other drugs that induce CYP3A4 should be used with caution because these drugs 
have the potential to decrease exposure (AUC) to cabozantinib (e.g., chronic use 
of modafinil) should be avoided because of its potential to reduce cabozantinib 
exposure.  Selection of alternate concomitant medications with no or minimal 
CYP3A4 enzyme induction potential is recommended.  In addition, caution must 
be used when discontinuing treatment with a strong CYP3A4 inducer in a subject 
who has been concurrently receiving a stable dose of cabozantinib, as this could 
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Preliminary results from a clinical pharmacology study, XL184-007, showed that 
concurrent administration of cabozantinib with the strong CYP3A4 inhibitor, 
ketoconazole, resulted in a 33-39% increase in the cabozantinib exposure (AUC 
values) after a single dose of cabozantinib in healthy volunteers.  Co-
administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g., 
ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations.  Grapefruit / grapefruit juice 
and Seville oranges may also increase plasma concentrations of cabozantinib.  
Strong CYP3A4 inhibitors and other drugs that inhibit CYP3A4 should be used 
with caution because these drugs have the potential to increase exposure (AUC) to 
cabozantinib. Selection of alternate concomitant medications with no or minimal 
CYP3A4 enzyme inhibition potential is recommended. 
Pharmacodynamic evaluation showed significantly increased PGF, VEGF-A, 
soluble MET and EPO and decreased sVEGFR2 in patient plasma after initiation 
of treatment with XL184.11 Preliminary analyses showed that baseline levels of 
Ang2, EPO and OPN significantly correlated with tumor response in a variety of 
tumor types (MTC, melanoma, colorectal carcinoma and others).6  Analysis of hair 
samples as surrogate markers revealed significant decreases in phosphorylated 
MET and downstream targets AKT and ERK (25-54%, 20-59% and 29-49% 
decrease from baseline, respectively).6  
 
2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
There is no prior experience with XL184 in the pediatric population.  
 
2.5 
Overview of Proposed Pediatric Study 
This is a phase 1 limited dose-escalation study of XL184 (cabozantinib) in pediatric and 
adolescent patients with recurrent or refractory solid tumors including CNS tumors. The 
primary objectives of this study are to identify a maximum tolerated dose (MTD) or 
recommended phase 2 dose (RP2D), characterize the toxicity profile and describe the 
pharmacokinetics of XL184 in pediatric and adolescent patients with solid tumors. 
 
Patients ages 2 to 18, inclusive, with refractory or recurrent solid tumors including CNS 
tumors will be eligible. Dosing will be based on body surface area (BSA) and rounded to 
nearest tablet to achieve the most accurate weekly doses. Doses on some days of the week 
may differ. Refer to dosing nomogram in Appendix II for details. XL184 will be 
administered orally at a starting dose of 30 mg/m2/day, which is roughly equivalent to the 
well tolerated 60 mg daily dose currently being evaluated in several adult studies. Doses 
will then be escalated to 40 mg/m2 and 55 mg/m2 in subsequent cohorts. One cycle will be 
28 days in length and dosing will be continuous. The dose will be escalated using a rolling 
six design. 
 
The maximum tolerated dose (MTD) will be determined from toxicities seen during the 
first cycle of therapy. The MTD will be the dose level immediately below the level in which 
≥ 2 out of 2 to 6 patients experience a DLT. To be eligible for the toxicity endpoint, patients 
must have received ≥ 85% of the prescribed study medication or have experienced a DLT 
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Doses will not be escalated beyond 55 mg/m2. If an MTD is not identified, a recommended 
dose will be established based on tolerability, pharmacokinetic parameters and response, if 
applicable. After the MTD or recommended phase 2 dose is determined in Part A, an 
additional 6 patients may be enrolled in an expansion phase and treated at this dose to gain 
additional PK and toxicity data in the pediatric population. Every attempt will be made to 
treat a minimum of 6 patients < 12 years of age and 6 patients ≥ 12 years of age at the MTD 
or recommended phase 2 dose. Given the activity seen in patients with medullary thyroid 
carcinoma (MTC), an additional cohort for MTC patients (Part B) will be open for 
enrollment if slots are filled for Part A, with the goal of enrolling at least four patients with 
MTC.  
 
Intra-patient dose-escalation will be allowed for patients with medullary thyroid carcinoma 
(MTC) remaining on study once an MTD or recommended dose is determined to allow 
patients who may be on study for extended periods of time, i.e. patients with MTC, the 
opportunity to receive the recommended dose.  
 
Pharmacokinetic sampling will be performed before drug administration, day 21-cycle 1 
for steady state parameters, pre C3, if possible at any time a patient experiences a DLT, pre 
C4 and with each disease evaluation for patients enrolled after Amendment #5A. 
Pharmacokinetic parameters including maximum concentration (Cmax) with the first dose 
and at steady state, area under the concentration time curve (AUC), apparent clearance and 
trough concentration will be measured or calculated. 
 
Given the antiangiogenic targeting of XL184 and concern for possible impact on growth 
in children, linear growth will be monitored and a baseline tibial x-ray for all patients, then 
prior to C2 and C5 and then 6 months later for patients with open growth plates remaining 
on study. MRIs will be obtained for patients with abnormal radiograph findings of the 
growth plate.   
 
Disease evaluations will be conducted after every other cycle starting after the end of cycle 
1 and then every third cycle if the patient has stable disease or better for 2 sets of restaging.  
 
Pharmacodynamic studies looking at markers of angiogenesis and components of the 
cMET pathway will be conducted. VEGF-A, soluble VEGFR2 (sVEGFR2), hepatocyte 
growth factor (HGF) and soluble MET (sMET) will be measured prior to and following 
XL184 dosing and expression of c-MET in archival tumor samples will be measured.  
 
2.6 
Amendment to Open PK Expansion (January 2014) 
As of January 2014, a total of 29 patients have been enrolled on ADVL1211: 6 patients at 
Dose Level 1, 11 patients at Dose Level 2 and 12 patients at Dose Level 3. During the dose 
escalation phase (Part A) during Cycle 1, dose-limiting toxicities (DLTs) occurred in 0/6 
patients at 30 and 40 mg/m2 and 1/6 patients at 55 mg/m2 (Grade 3 fatigue and headache).  
Other Cycle 1 DLTs in expansion cohorts included Grade 2 palmar plantar 
erythrodysesthesia (PPE) and oral mucositis in 1 patient at 40 mg/m2, Grade 3 proteinuria 
and Grade 2 hypertension (HTN) in 1 patient at 55 mg/m2, and Grade 3 HTN and reversible 
posterior leukoencephalopathy syndrome in 1 patient at 55mg/m2.  Later cycle DLTs 
occurred in 10 patients at all dose levels and included Grade 3 weight loss (n=2), Grade 3 
PPE (n=2), Grade 3 and 4 lipase increase (n=1 each), Grade 4 neutropenia (n=1),  Grade 2 
fatigue (n=1), Grade 2 arthralgia (n=1) and  Grade 3 anorexia, dyspnea, skin ulcer (n=1).  
 
Pharmacokinetic studies conducted in 18 patients during the dose-escalation phase showed 


                           
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that cabozantinib exposure was not dose proportional.  The mean ± SD steady state AUC0-
24h at 30 mg/m2 (n=6), 40 mg/m2 (n=6) and 55 mg/m2 (n=6) was 31.9 ± 7.8, 33.3 ± 11.3 and 
33.7 ± 15 µg•h/mL, respectively. Given the toxicities seen at Dose Level 3 and in later 
cycles and comparable exposure of cabozantinib, the recommended Phase 2 dose for 
further evaluation in pediatric patients with solid tumors is 40 mg/m2 (Dose Level 2) and 
enrollment will be expanded at this dose level to gain additional pharmacokinetic and 
safety information in at least 6 patients under the age of 12 and 6 patients between 12 and 
18 years of age. We will also collect trough levels with each disease evaluation in all 
patients enrolled after Amendment #5A to gain additional information about steady state 
pharmacokinetics.-COMPLETE 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
3.1 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual.  If the study is listed as active, investigators should then access the page 
CTSU OPEN (Oncology Patient Enrollment Network) to ensure that a reservation for the 
study is available. To access the Slot Availability page:  
1.  Log in to https://open.ctsu.org/open/  
2.  From the home page, select Create New Registration. The ENROLL Create 
New page appears.  
3.  Select the Protocol Number and Click the Slot Availability link. The Slot 
Availability window will open. 
 
3.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. 
Sites must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) 
Regulatory Office and allow 3 business days for processing. The submission must include 
a fax coversheet (or optional CTSU IRB Transmittal Sheet) and the IRB approval 
document(s). The CTSU IRB Certification Form may be submitted in lieu of the signed 
IRB approval letter.  All CTSU forms can be located on the CTSU web page 
(www.ctsu.org). Any other regulatory documents needed for access to the study enrollment 
screens will be listed for the study on the CTSU Member’s Website under the RSS Tab.   
 
IRB/REB approval documents may be faxed (1-215-569-0206),  
Emailed (CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.   
 
When a site has a pending patient enrollment within the next 24 hours, this is considered a 
“Time of Need” registration. For Time of Need registrations, in addition to marking your 
submissions as ‘URGENT’ and faxing the regulatory documents, call the CTSU 
Regulatory Helpdesk at: 1-866-651-CTSU. For general (non-regulatory) questions, call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
 


                           
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3.3 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry system once authorization for the release of 
protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made following the steps in 
Section 3.1 above and the Study Chair or Vice Chair should be notified. (The patient will 
need a COG patient ID number in order to obtain a reservation). Patients must be enrolled 
within 7 calendar days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website.  
 
3.5 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent. This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment.  
 
3.8 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report must 
include the associated study number and COG patient registration and accession numbers. 
Personal identifiers, including the patient’s name and initials must be removed from the 
institutional pathology report prior to submission. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by CTSU OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org/open/. For questions, please contact the CTSU OPEN helpdesk at 
https://www.ctsu.org/CTSUCOntact.aspx. Patients must be enrolled before treatment 
begins.  The date protocol therapy is projected to start must be no later than five (5) calendar 
days after the date of study enrollment. Patients must not receive any protocol therapy 
prior to enrollment. 


                           
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3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
4.0 
PATIENT ELIGIBILITY  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies must be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging 
if necessary).  
  
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:  Patients must be ≥ 2 and  18 years of age at the time of study enrollment. 
 
4.1.2 
Body Surface Area (BSA): Patients must have a body surface area ≥ 0.44 m2 
when enrolling on dose level -1. Patients must have a body surface area ≥ 0.35 
m2 when enrolling on dose levels 1, 2, or 3.   
 
4.1.3 
Diagnosis:  
Part A: Patients with relapsed or refractory solid tumors (excluding medullary 
thyroid cancer) including CNS tumors and malignant melanoma are 
eligible. Patients must have had histologic verification of malignancy at 
original diagnosis or relapse except in patients with intrinsic brain stem 
tumors, optic pathway gliomas, or patients with pineal tumors and 
elevations of CSF or serum tumor markers including alpha-fetoprotein or 
beta-HCG.  
 
Part B:  Patients with medullary thyroid cancer (MTC), with or without bone 
marrow involvement, will be eligible for Part B. These patients will be 
enrolled at Dose Level 2, the recommended Phase 2 Dose determined in 
the dose escalation part of the study.  
 
 


                           
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4.1.4 
Disease Status:  
Patients must have either measurable or evaluable disease (see Sections 12.2 and 
12.3 for definitions).  
 
4.1.5 
Therapeutic Options: Patient’s current disease state must be one for which there 
is no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
  
4.1.6 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I).  Note:  Neurologic deficits 
in patients with CNS tumors must have been relatively stable for at least 7 days 
prior to study enrollment.  Patients who are unable to walk because of paralysis, 
but who are up in a wheelchair, will be considered ambulatory for the purpose of 
assessing the performance score. 
 
4.1.7 
Prior Therapy 
 
4.1.7.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer chemotherapy. 
 
a. Myelosuppressive chemotherapy:   
At least 21 days after the last dose of myelosuppressive chemotherapy 
(42 days if prior nitrosourea).  
b. Hematopoietic growth factors: At least 14 days after the last dose of a 
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting 
growth factor.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair.  
c. Biologic (anti-neoplastic agent):  At least 7 days after the last dose of 
a biologic agent.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair. 
d. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
e. Monoclonal antibodies: At least 3 half-lives of the antibody after the 
last dose of a monoclonal antibody. (See table on DVL homepage 
listing monoclonal antibody half-lives.) 
f. XRT: At least 14 days after local palliative XRT (small port); At least 
150 days must have elapsed if prior TBI, craniospinal XRT or if  50% 
radiation of pelvis; At least 42 days must have elapsed if other 
substantial BM radiation. 
g. Stem Cell Infusion without TBI:  No evidence of active graft vs. host 
disease and at least 56 days must have elapsed after transplant or stem 
cell infusion. 
 
 


                           
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4.1.8 
Organ Function Requirements 
 
4.1.8.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
• 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
• 
Platelet count  100,000/mm3 (transfusion independent, 
defined as not receiving platelet transfusions for at least 7 
days prior to enrollment) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.8.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity. At least 5 of every 
cohort of 6 patients with a solid tumor must be evaluable for 
hematologic toxicity in the dose-escalation part of the study. If 
dose-limiting hematologic toxicity is observed, all subsequent 
patients enrolled must be evaluable for hematologic toxicity. 
 
4.1.8.2 Adequate Renal Function Defined as: 
• Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
• A serum creatinine based on age/gender as follows: 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
• Urine protein: ≤ 30 mg/dl in urinalysis or ≤ 1+ on dipstick, unless 
quantitative protein is < 1000 mg in a 24 h urine sample. 
 
4.1.8.3 Adequate Liver Function Defined as: 
• Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
• SGPT (ALT)  110 U/L.  For the purpose of this study, the ULN for 
SGPT is 45 U/L.  
• Serum albumin  2.8 g/dL. 
 
4.1.8.4 Adequate coagulation status Defined As: 
• PT and INR ≤ 1.5x ULN 
 
4.1.8.5 Adequate Pancreatic Function Defined As: 
• Serum amylase ≤ 1.5 x ULN and 
• Serum lipase ≤ 1.5 x ULN 
 
 


                           
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4.1.8.6 Adequate Blood Pressure Control defined as: 
A blood pressure (BP) ≤ the 95th percentile for age, height, and gender 
(Appendix VIII) measured as described in Section 6.4, and not receiving 
medication for treatment of hypertension. Please note that 3 serial blood 
pressures should be obtained and averaged to determine baseline BP (See 
Section 6.4). 
 
4.1.8.7 Central Nervous System Function Defined as: 
Patients with seizure disorder may be enrolled if receiving non-enzyme 
inducing anticonvulsants and well controlled. See Appendix XIII for a list 
of recommended non-enzyme inducing anticonvulsants. 
 
4.1.8.8 Adequate Cardiac Function Defined As: 
• No history of congenital prolonged QTc syndrome, NYHA Class III 
or IV congestive heart failure (CHF) 
• No clinically significant cardiac arrhythmias, stroke or myocardial 
infarction within 6 months prior to enrollment 
• QTc ≤ 480 msec. Note: Patients with Grade 1 prolonged QTc (450-
480 msec) at the time of study enrollment should have correctable 
causes of prolonged QTc addressed if possible (i.e. electrolytes, 
medications). See Appendix XV for a list of drugs that prolong QTc. 
 
4.1.9 
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
4.1.10 Archival tumor tissue slides from either initial diagnosis or relapse must be sent 
per Section 8.5.1.2 and Appendix XI. If tumor tissue is unavailable, the study 
chair must be notified prior to enrollment. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy 
tests must be obtained in girls who are post-menarchal. Males or females of 
reproductive potential may not participate unless they have agreed to use two 
methods of birth control- a medically accepted barrier method of contraceptive 
method (e.g., male or female condom) and a second effective method of birth 
control- during protocol therapy and for at least 4 months after the last dose of 
XL184. Abstinence is an acceptable method of birth control. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. 
 
4.2.2.2 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
 


                           
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4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible  
 
4.2.2.4 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.2.5 CYP3A4 active agents: Patients must not be receiving any of the following 
potent CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, 
ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John’s 
wort. A list of other known CYP3A4 inducers and inhibitors that should 
be discontinued prior to initiation of protocol therapy and should be 
avoided during study therapy if reasonable alternatives exist is included in 
Appendix IX. 
 
4.2.2.6 Patients who are receiving systemic treatment anticoagulation are not 
eligible. Patients receiving prophylactic systemic anticoagulation will be 
allowed as long as eligibility PT/INR requirements are met (See Section 
4.1.8.4).   
 
4.2.2.7 Enzyme-inducing Anticonvulsants: Patients must not have received 
enzyme–inducing anticonvulsants within 14 days prior to enrollment (See 
Appendix XIII for a list of unacceptable enzyme inducing 
anticonvulsants). 
 
4.2.2.8 QTc Agents: Patients who are receiving drugs that prolong QTc are not 
eligible (See Appendix XV for a list of agents). 
 
4.2.3 
Patients must be able to swallow intact tablets. Patients who cannot swallow 
intact tablets are not eligible. 
 
4.2.4 
Patients with active bleeding are not eligible. Specifically, no clinically 
significant GI bleeding, GI perforation, intra-abdominal abcess or fistula for 6 
months prior to enrollment, no hemoptysis or other signs of pulmonary 
hemorrhage for 3 months prior to enrollment. 
 
4.2.5 
Patients with evidence of an acute intracranial or intratumoral hemorrhage on CT 
or MRI are not eligible (patients with evidence of resolving hemorrhage will be 
eligible). 
 
4.2.6 
Surgery: Patients who have had or are planning to have the following invasive 
procedures are not eligible: 
• 
Major surgical procedure, laparoscopic procedure, open biopsy or 
significant traumatic injury within 28 days prior to enrollment.  
• 
Central line placement or subcutaneous port placement is not considered 
major surgery but must be placed at least 3 days prior to enrollment for 
external lines (e.g. Hickman or Broviac) and at least 7 days prior to 
enrollment for subcutaneous port.   
• 
Core biopsy within 7 days prior to enrollment. 
• 
Fine needle aspirate within 7 days prior to enrollment. 


                           
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• 
Surgical or other wounds must be adequately healed prior to enrollment 
 
4.2.7 
Patients on antihypertensive therapy for control of blood pressure at the time of 
enrollment are not eligible.  
 
4.2.8 
Patients with any medical or surgical conditions that would interfere with 
gastrointestinal absorption of this oral agent are not eligible.  
 
4.2.9 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.10 Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.11 Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
Treatment Schedule Table 
Time 
Agent 
Days 1-28 
Oral XL184*  
*Refer to dosing nomogram in Appendix II for dosing schedule. 
 
XL184 will be administered orally at approximately the same time as prescribed. XL184 
should be taken on an empty stomach; patients should fast 2 hours before and 1 hour after 
taking the drug. Tablets should not be crushed or chewed; tablets should be swallowed whole. 
See also Section 9.1.6 for medications and foods to be avoided. 
 
A cycle of therapy is considered to be 28 days.   
 
Drug doses should be adjusted based on the BSA calculated from height and actual body 
weight measured within 7 days prior to the beginning of each cycle, and according to the 
dosing nomogram (see Appendix II).  Sites will fill out the number of prescribed tablets 
per day in the patient diary (see Appendix III). Patients must complete the patient diary 
with the date, time and number of XL184 tablets taken each day. The patient diary should 
be reviewed after completion of each treatment cycle. 
 
If a patient vomits after the dose of XL184 is administered, the dose should not be repeated. 
 
If a dose of XL184 is missed and less than 6 hours have passed since the scheduled dosing 
time, the dose should be taken immediately. If more than 6 hours have passed since the 
scheduled dosing time, the patient should not take the missed dose but should wait and take 
the next regularly scheduled dose. 
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease, has again 
met laboratory parameters as defined in the eligibility sections 4.1.8.1- 4.1.8.3 and 4.1.8.5, 
and has not experienced study-drug related adverse events warranting permanent 
discontinuation. 
 


                           
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Patients who have a delay in starting subsequent cycles for resolution of toxicity should 
also have the required observations in Section 8.1 until the start of the next cycle.   
 
5.3 
Dose Escalation Schema 
 
5.3.1 
Inter-Patient Escalation- (Part A) COMPLETE 
The starting dose will be 30 mg/m2 (Dose Level 1) with dose levels for 
subsequent groups of patients as follows. 
 
Dose Level 
XL184 Dose (mg/m2 po daily) 
-1 
23 
   1* 
30 
 2 
40 
 3 
55 
* Starting Dose Level 
 
There will be no escalations beyond dose level 3 (55 mg/m2). 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort of 
patients will be treated at a dose of 23 mg/m2 (Dose Level -1).  
 
With Amendment #5A, patients enrolled onto Part A of the study will be treated 
at the recommended Phase 2 dose, which has been determined to be Dose Level 
2 (40 mg/m2). 
 
5.3.2 
Part B: Patients with medullary thyroid cancer (MTC) can be accrued to a 
separate stratum if there are no available slots on Part A. These patients will be 
enrolled at one dose level below the dose level at which patients on Part A are 
actively enrolling, or at the starting dose level (Dose Level 1) if dose escalation 
has not yet occurred.    COMPLETE 
 
With Amendment #5A, patients enrolled onto Part B of the study will be treated 
at the recommended Phase 2 dose, which has been determined to be Dose Level 
2 (40 mg/m2). 
 
5.3.3 
Intra-Patient Escalation (Patients with MTC only) 
Intra-patient dose escalation will be allowed for patients with MTC remaining on 
study in cycles of therapy subsequent to Cycle 1, once an MTD or recommended 
Phase 2 dose is identified, if the patient has not experienced dose-limiting toxicity 
at the dose at which they began therapy. Patients who are one dose level below the 
MTD can escalate to the MTD. Patients who are more than one dose level below 
the MTD can escalate one dose level per cycle until they reach the MTD as long 
as they do not experience a DLT when escalating. Sites have to confirm with the 
Study Chair and the COG Phase 1 Operations office that their patient may proceed 
with an intra-patient dose escalation following the completion of Cycle 1 or 
subsequent cycles.   COMPLETE 
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or 
confirmed dose-limiting toxicity should be reported immediately (within 24 hours) to the 


                           
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Study Chair. 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to XL184. The DLT observation period for the purposes of dose-escalation will 
be the first cycle of therapy. Any drug-related toxicity that requires a dose reduction in 
Cycle 1 will also be considered a DLT. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
 
5.5.1 
Non-Hematological Dose-Limiting Toxicity 
 
5.5.1.1 Any Grade 3 or Grade 4 non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
• 
Grade 3 nausea and vomiting of < 3 days duration 
• 
Grade 3 diarrhea ≤ 3 days duration 
• 
Grade 3 liver enzyme elevation, including ALT/AST/GGT/bilirubin, 
that return to levels that meet initial eligibility criteria or baseline 
within 7 days of study drug interruption and that does not recur upon 
re-challenge with XL184. Note: For the purposes of this study the 
ULN for ALT is defined as 45 U/L. See section 6.6 for dose 
modifications for liver toxicity. 
• 
Grade 3 or 4 fever < 5 days duration. 
• 
Grade 3 infection < 5 days duration. 
• 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to supplementation 
• 
Grade 3 asymptomatic amylase or lipase elevation that resolves to ≤ 
Grade 1 within 7 days of study drug interruption and that does not 
recur upon re-challenge with XL184.  See section 6.7 for dose 
modifications for pancreatic toxicity. 
• 
Grade 3 proteinuria (urine protein/creatinine (P/C) ratio > 1.9) unless 
it is confirmed with a second measurement within 72 hours.  
 
5.5.1.2 Dose-limiting hypertension 
• 
Any Grade 4 hypertension 
• 
A blood pressure >25 mmHg above the 95th percentile for age, 
height, and gender (Appendix VIII) confirmed by repeated 
measurement is dose limiting. 
• 
In patients who begin antihypertensive therapy a blood pressure > 10 
mmHg but ≤ 25 mmHg above the 95th percentile for age, height, and 
gender (Appendix VIII) for > 14 days is dose limiting. 
 
5.5.1.3 QTc prolongation > 500 ms that persists despite correction of serum 
electrolyte abnormalities will be considered dose limiting. 
 
5.5.1.4 Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
 
5.5.1.5 Any toxicity requiring interruption of study drug during a cycle of therapy 


                           
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for ≥ 7 days or which recurs upon drug challenge. 
 
5.5.1.6 Note: Allergic reactions that necessitate discontinuation of study drug will 
not be considered a dose-limiting toxicity. 
 
5.5.2 
Hematological dose limiting toxicity  
 
5.5.2.1 Hematological dose limiting toxicity is defined as: 
 
• 
In patients evaluable for hematological toxicity (see Section 
4.1.8.1), Grade 4 thrombocytopenia (platelet count < 25,000/mm3) 
or Grade 4 neutropenia (see Section 6.1), not due to malignant 
infiltration. 
• 
Myelosuppression that causes a delay of > 14 days between 
treatment cycles.  
• 
In patients with CNS tumors, requirement of platelet 
transfusion(s) for platelets ≤ 50,000/mm3 on more than one 
occasion during a cycle will be considered a DLT. I.e. If a patient 
with a CNS tumor requires more than one platelet transfusion to 
achieve a count > 50,000/mm3 (poor initial response, etc.) on one 
occasion this is not a DLT, but if it occurs again during the cycle, 
it will be dose limiting.  
 
 


                           
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6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. If a patient’s dose is reduced due to toxicity, any future XL184 total weekly dose 
should not exceed a previously un-tolerated dose. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
If a patient experiences dose-limiting Grade 4 neutropenia or thrombocytopenia, 
the treatment will be withheld. Counts should be checked every 3 - 4 days for 
thrombocytopenia and every other day for neutropenia during this time. If the 
toxicity resolves to meet eligibility parameters within 14 days of drug 
discontinuation, the patient may resume treatment at the next lower dose level 
(See Appendix IIB). Doses reduced for toxicity will not be re-escalated, even if 
there is minimal or no toxicity with the reduced dose.  
 
6.1.2 
If dose-limiting toxicity does not resolve to meet eligibility or baseline 
parameters within 14 days of drug discontinuation, the patient must be removed 
from protocol therapy. 
 
6.1.3 
Two dose reductions will be allowed for toxicity. If a patient experiences a dose-
limiting toxicity after two dose reductions, they must be removed from protocol 
therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.5.1, the treatment will be withheld. If the toxicity resolves to meet 
eligibility or baseline parameters within 14 days of drug discontinuation, the 
patient may resume treatment at the next lower dose level (See Appendix IIB). 
Doses reduced for toxicity will not be re-escalated, even if there is minimal or no 
toxicity with the reduced dose. 
 
6.2.2 
If dose-limiting toxicity does not resolve to meet eligibility or baseline 
parameters within 14 days of drug discontinuation, the patient must be removed 
from protocol therapy.  
 
6.2.2.1 The exception to this is Grade 3 weight loss as it is unlikely that the patient 
would return to baseline within 14 days. Patients who experience Grade 3 
weight loss may resume study medication after 14 days with a dose-
reduction (see Appendix II-B) if the patient is deriving benefit from 
therapy, the weight loss has stabilized and the treating physician feels it is 
in the best interest of the patient. Patients should be removed from protocol 
therapy if their weight loss is ≥ 20% from baseline and persists for ≥ 28 
days after the introduction of supplemental NG/G tube feeding or TPN. 
 
6.2.3 
Two dose reductions will be allowed for toxicity. If a patient experiences a dose-
limiting toxicity after two dose reductions, they must be removed from protocol 
therapy. 
 
 
6.3 
Dose Modifications for Proteinuria 


                           
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• If urinalysis shows ≥ trace protein then obtain UPC.   
• If the urine protein/creatinine (P/C) ratio ≤ 1.9 continue XL184. If patient has 
Grade 3 proteinuria (urine protein/creatinine (P/C) ratio > 1.9), a second 
measurement should be obtained within 72 hours. A second confirmation of 
Grade 3 proteinuria will be considered a DLT. 
• If the second measurement confirms Grade 3 proteinuria (urine 
protein/creatinine (P/C) ratio > 1.9), then interrupt XL184 treatment and re-
assess weekly.   
• If XL184 is held for ≥ 14 days then remove from protocol therapy.  If the urine 
protein/creatinine (P/C) ratio decreases to ≤ 1.9 in < 14 days then resume 
XL184 at a lower dose as outlined in Section 6.2.1.  
• Monitor the UPC weekly for 2 consecutive weeks once protocol therapy 
resumes.   
 
6.4 
Dose Modifications for Hypertension 
 
• Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained as 
follows: 1) Obtain 3 serial blood pressures from the same extremity with the 
patient in the same position at rest with an appropriately sized cuff that are 
separated by at least 5 minutes. Avoid using the lower extremity if possible. 2) 
Average the systolic blood pressure from the 2nd and 3rd measurements. 3) 
Average the diastolic blood pressure from the 2nd and 3rd measurements. 4) The 
baseline BP is the average of the systolic over the average of the diastolic 
measurements. 
• Elevation in either the systolic or diastolic blood pressure should be considered 
when following the algorithm below. 
• The upper limit of normal (ULN) is defined as a BP equal to the 95th 
percentile for age, height, and gender. See Appendix VIII. 
• The NCI CTCAE will be utilized to determine the grade of hypertension for 
reporting purposes. 
• Elevated BP measurements should be repeated on the same day to confirm the 
elevation. If confirmed, patients with elevated BP should have BP 
measurements performed at least twice weekly until BP is ≤ ULN. 
• The algorithm below will be used to manage XL184- related hypertension. 
• Hypertension should be managed with appropriate anti-hypertensive agent(s) 
as clinically indicated. It is strongly recommended that nephrology or 
cardiology be consulted in the evaluation and management of hypertension. 
 


                           
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Arm 1 of algorithm: 
• 
If blood pressure (BP) ≤ 95% for age, height, and gender, continue XL184 at the same 
dose. 
 
Arm 2 of algorithm: 
• 
If BP ≤ 10 mm Hg above the ULN for age, height, and gender, continue XL184 at the 
same dose and recheck the BP within 72 hours. 
o If the BP is ≤ ULN on recheck, continue XL184 at the same dose. 
o If the BP remains above the ULN on recheck, then start antihypertensive therapy 
(Section 7.7) and follow Arm 3 of the algorithm from the point that anti-
hypertensive therapy is started. 
 
Arm 3 of algorithm: 
• 
If BP is 11 to 25 mm Hg above the 95% for age, height, and gender on ≥ 2 of 3 
measurements or > 35 mmHg above baseline on ≥ 2 of 3 measurements, start anti-
hypertensive therapy (see Section 7.7), continue XL184 at the same dose, and monitor 
BP at least twice weekly. 
o If the BP returns to ≤ ULN within 14 days, continue XL184 at the same dose and 
continue anti-hypertensive therapy. 


                           
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o If the BP remains elevated ≤ 25 mm Hg above the 95% or > 35 mm Hg above 
baseline for more than 14 days after the institution of anti-hypertensive therapy, 
hold XL184, monitor BP at least every 3 days, and follow Arm 4 of the algorithm 
from the point that XL184 is held. The antihypertensive therapy should be 
continued until the BP is less than the ULN. 
▪ 
If the BP returns to ≤ ULN within 14 days, restart XL184 at a reduced dose 
(Section 6.1.1). 
▪ 
If the BP remains > ULN for more than 14 days, patient is Off Protocol 
Therapy. 
o  If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive 
therapy, hold XL184, but continue the anti-hypertensive agent(s). Monitor the BP 
as clinically indicated and follow Arm 4 of the algorithm from the point that 
XL184 is held. 
▪ 
If the BP is ≤ ULN within 14 days, XL184 may be restarted at a reduced dose 
(Section 6.2.2). 
▪ 
If the BP is > ULN for > 14 days, the patient is Off Protocol Therapy (Section 
10.1). 
 
Arm 4 of algorithm: 
• 
If BP is > 25 mm Hg above the 95% for age, height, and gender hold XL184, monitor 
BP and administer anti-hypertensive therapy as clinically indicated. 
o If the BP returns to ≤ ULN within 14 days, XL184 may be restarted at a reduced 
dose (Section 6.2.2). 
o If the BP is > ULN for >14 days, the patient is Off Protocol Therapy (Section 10.1). 
 
Arm 5 of algorithm: 
• 
If the participant develops Grade 4 hypertension, discontinue XL184, monitor BP and 
administer anti-hypertensive therapy as clinically indicated. The patient is Off Protocol 
Therapy (Section 10.1). 
 
 
6.5 
Dose Modifications for DVT  
If a patient develops a DVT while on study, XL184 should be held until adequate 
anticoagulation is established. Full dose anticoagulation with warfarin is not permitted.  
Heparins should be used for anticoagulation. The drug may be resumed with a dose 
reduction if the DVT is dose-limiting (i.e. ≥ grade 3) and if the patient is deriving clinical 
benefit. 
 
6.6 
Dose Modifications for Liver Toxicity 
XL184 should be held for grade 3 elevation of ALT, AST or bilirubin. Note: For the 
purposes of this trial the ULN for ALT is defined as 45 U/L. XL184 may be re-administered 
at the same dose if levels of ALT, AST and bilirubin meet eligibility criteria or baseline 
within 7 days of drug discontinuation. Elevated laboratory parameters should be checked 
at least twice weekly until eligibility criteria is met.  
 
If lab values do not resolve to initial eligibility criteria or baseline within 7 days of 
interruption or if toxicity recurs with re-challenge, then this will be considered dose-
limiting per section 5.5.1.  XL184 will then be dose-reduced according to Section 6.2.1 
when eligibility criteria is met. 
 
 


                           
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6.7 
Dose Modifications for Pancreatic Toxicity 
XL184 should be held if patient experiences Grade 3 asymptomatic amylase or lipase 
elevation. Elevated laboratory parameters should be checked at least twice weekly until ≤ 
Grade 1. 
 
If lab values do not resolve to ≤ 1 Grade within 7 days of interruption or if toxicity recurs 
with re-challenge, then this will be considered dose-limiting per section 5.5.1. XL184 will 
then be dose-reduced according to Section 6.2.1 when eligibility criteria is met. 
 
6.8 
Dose Modifications for Diarrhea 
See Appendix XIV for specific guidelines for supportive care measures for patients who 
develop therapy-associated diarrhea.  
• 
If dose-limiting Grade 3 (> 3 days) or Grade 4 therapy-associated diarrhea is 
experienced by a patient despite maximal use of anti-diarrheal medications, the 
dose of XL184 should be reduced per Appendix IIB.  
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Section 7.5 for drugs that should not be used 
concomitantly due to potential interactions with XL184. 
 
Diarrhea is a common side effect of XL184. Loperamide should be used at the first sign of 
significant diarrhea (See Appendix XIV).  
 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome) is a 
common side effect of XL184. Careful attention should be paid to skin exams and supportive 
care instituted early if any swelling or erythematous skin changes or symptoms of pain or 
burning/tingling are noted. Patients should be instructed to apply moisturizing creams, avoid 
any trauma, harsh chemicals and limit hot water exposure. Topical steroid creams may be used 
and consider early dermatology referral.   
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
7.5 
Concomitant Medications 
Proton pump inhibitors (PPIs) and H2-antagonists should be avoided if possible (See Section 
9.1.6).  
 
Medications that are strong inhibitors or inducers of CYP3A4 should be avoided (see 


                           
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Appendix IX). Corticosteroids may induce CYP3A4 and are therefore not routinely 
recommended on study unless deemed absolutely necessary or when used in stable or 
decreasing doses from the time of study enrollment. 
 
The use of enzyme inducing anticonvulsants is not permitted. See Appendix XIII for a list 
of 
unacceptable 
enzyme 
inducing 
and 
recommended 
non-enzyme 
inducing 
anticonvulsants. 
 
XL184 has been associated with prolonged QTc, so medications that prolong QTc are 
prohibited and medications that may prolong QTc should be avoided when possible (see 
Appendix XV). 
 
7.6 
Surgery 
Patients should not have elective surgical procedures while on therapy. For patients who 
require emergent or urgent procedures, therapy may not be restarted until 28 days after 
major procedures and 7 days after minor procedures such as line replacement (3 days for 
external lines [e.g. Hickman or Broviac]), as detailed in section 4.2.6. 
 
7.7 
Concurrent Anti-Hypertensive Therapy 
The algorithm in Section 6.4 will be used to grade and manage XL184 related hypertension. 
Should initiation of anti-hypertensive therapy be required, single agent therapy (commonly 
including the calcium channel blockers amlodipine or nifedipine, which are permissible 
without discussion with the study chair) should be started and the blood pressure should be 
monitored at least twice weekly until BP is within the 95th percentile for age, height, and 
gender per Section 6.4. 
 
 
7.8 
Management of Hypothyroidism 
Patients with Grade 2 hypothyroidism adequately managed with thyroid hormone 
replacement may continue on protocol therapy. Patients with Grade 3 or greater 
hypothyroidism will be considered to have had a dose-limiting toxicity. These patients 
should be managed according to Section 6.2 and should also be evaluated by an 
endocrinologist for further management. Patients who enter the study on thyroid 
replacement should have their medication adjusted to maintain TSH in the normal range.  


                               
 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. 
Laboratory values used to assess eligibility (see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory tests 
need not be repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory evaluations must be re-checked within 48 
hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) and serum  creatinine.  If the recheck is outside the limits of 
eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy. Imaging studies must be obtained within 
14 days prior to start of protocol therapy (repeat the tumor imaging if necessary). 
STUDIES TO BE OBTAINED 
Pre-
Study 
During 
Cycle 1 
During Cycles 2 & 
3 
Prior to 
Subsequent 
Cycles^ 
30 days, 6 months, 
and annually up 
to 60 months ^^ 
History 
X 
Weekly 
 
X15 
X 
Physical Exam  with vital signs 
X 
Weekly 
 
X15 
X 
Blood pressure1 
X 
Weekly 
Every other week 
(Cycle 2) 
X15 
 
Height, weight, BSA 
X 
 
 
X15 
X 
Performance Status 
X 
 
 
 
 
Pregnancy Test2 
X 
 
 
X15 
 
CBC, differential, platelets 
X 
   Weekly3,4 
Every other week 
X3,4,15 
 
Urinalysis 5 
X 
Weekly 
 
X15 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
Every other week 
X15 
 
Creatinine, ALT, bilirubin 
X 
Weekly 
Every other week 
X15 
 
Albumin 
X 
 
 
X15 
 
Amylase, lipase 
X 
Weekly 
Every other week 
X15 
 
PT and INR 
X 
 
 
 
 
TSH 6 
X 
Once mid-
cycle (days 
15-22) 
 
X15 
 
RET mutation status (germline and tumor) for 
patients with MTC (if available) 
X 
 
 
 
 
CEA and calcitonin for patients with MTC7 
X 
End of Cycle 
1 
 
Every other cycle 
x 2 then q 3 cycles 
 


                               
 
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STUDIES TO BE OBTAINED 
Pre-
Study 
During 
Cycle 1 
During Cycles 2 & 
3 
Prior to 
Subsequent 
Cycles^ 
30 days, 6 months, 
and annually up 
to 60 months ^^ 
Tumor Disease Evaluation8, 14 
X 
End of Cycle 
1 
 
Every other cycle 
x 2 then q 3 cycles 
8, 14 
 
EKG (including QTc interval) 13 
X 
End of Cycle 
1 
End of Cycle 2 
Every other cycle 
x 2 then q 3 cycles 
13  
 
Plain radiograph tibial growth plate9 
X 
 
 
X9 
 
Patient Diary10 
 
Weekly 
 
X 
 
Pharmacokinetics11                                           COMPLETE 
X 
X 
X 
X  
 
Pharmacodynamics12 
X 
X 
 
 
 
Tissue Studies12 
X 
 
 
 
 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
^^    Required observations beginning 30 days, 6 months (± 14 days), and annually (± 30 days) following the last dose of investigational agent until patient is off 
study (see Section 10.2). 
1 
Blood pressure will be measured with an appropriate sized cuff at rest. Please note that 3 serial blood pressures should be obtained and averaged to determine 
baseline BP (See Section 6.4). Blood pressure measurement will be repeated within the same day if the blood pressure (BP) is elevated (> 95th percentile for 
age, height, and gender). If both BP measurements are > 95th percentile for age, height, and gender, follow the guidelines in Section 6.4. Patients with 
confirmed elevated BP at any time should have BP measurements performed at least twice weekly until BP is within the 95th percentile for age, height, and 
gender (See Appendix VIII). 
2 
Males or females of reproductive potential may not participate unless they have agreed to use both a medically accepted barrier method of contraceptive 
method (e.g., male or female condom) and a second effective method of birth control during protocol therapy and for at least 4 months after the last dose of 
XL184.  Abstinence is an acceptable method of birth control. 
3 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day (see Section 6.1). 
4 
If patients develop Grade 4 thrombocytopenia then CBCs should be checked every 3 to 4 days (see Section 6.1). 
5 
See Appendix VII for UPC rationale and calculation and Section 6.3 for dose modifications if UPC > 1.9. If patient is being followed for prior proteinuria 
and UPC is obtained, urinalysis is not required.  If 24 hour urine for protein is obtained, both urinalysis and UPC are not required. If patient has Grade 3 
proteinuria (urine protein/creatinine (P/C) ratio >1.9), a second measurement should be obtained within 72 hours.  
6 
Patients found to have an abnormal TSH level should have a free T4 level measured.  
7 
Calcitonin measurements should be obtained in the fasting state.  
8 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation of either a PR or CR. Please note that for solid 
tumor patients, if the institutional investigator determines that the patient has progressed based on clinical or laboratory evidence, he/she may opt not to 
confirm this finding radiographically. 
9 
Plain radiographs of at least one tibial growth plate should be obtained in all patients prior to first dose of protocol therapy. In patients with open growth 
plates, follow-up plain radiographs of the same growth plate(s) should be obtained according to Section 8.2.1. 


                                
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10 
Patient diary (see Appendix III) should be reviewed and uploaded into RAVE weekly during Cycle 1, 
and then after completion of each treatment cycle. 
11 
See Section 8.4 and Appendix V for timing of PK studies. COMPLETE 
12 
See Section 8.5 for timing of Pharmacodynamic/Biomarker studies and details regarding tumor tissue 
submission. Archival tumor tissue should be submitted for all patients.  If a patient does not have tissue 
available, the study chair must be notified prior to enrollment. 
13 
Patients with prolonged QTc should have correctable causes of prolonged QTc addressed if possible, 
including medications (See Appx. XV) and correction of electrolyte abnormalities (incl. Ca++ and 
Mg++). If there is no evidence of QTc prolongation after completion of 6 cycles of therapy, further EKGs 
are not required. 
14 
Patients currently enrolled on Part B of the study should be evaluated every 6 months. 
15 
Patients currently enrolled on Part B of the study should be evaluated/have this test performed every 
other cycle. 
 
8.2 
Monitoring for Specific Toxicities 
 
8.2.1 
Growth Plate Toxicity 
Patients will have a plain AP radiograph of a single proximal tibial growth plate 
obtained prior to the first dose of protocol therapy.  
a. If patients are found to have a closed tibial growth plate, no further radiographs 
will be required.  
b. If patients are found to have an open tibial growth plate, then repeat plain AP 
radiographs of the same tibial growth plate will be obtained prior to cycles 2, 
5 and then every 6 months until off protocol therapy. 
• 
Patients with evidence of growth plate thickening or other changes should 
have a knee MRI performed to further assess the degree of physeal 
pathology and undergo more frequent x-ray follow up. MRI should be 
performed without contrast. 
• 
Patients with knee MRI changes should be managed in an individualized 
manner. Decisions regarding continuation of XL184 should be made after 
discussion with the Study Chair or Study Vice-Chair and DVL Leadership, 
taking into account the presence of any symptoms referable to the knee as 
well as the patient’s response to XL184. Consultation with an orthopedic 
surgeon may also be indicated. Plans for follow-up imaging will also be 
made on an individualized basis, taking into account the presence of 
symptoms at the knee or other joints as well as the decision to continue 
XL184 or not. 
 
8.2.2 
Thyroid Toxicity 
Patients will have a TSH level measured prior to initial treatment, once mid-cycle 
of Cycle 1 (Day 15-22), and prior to subsequent cycles. Patients found to have an 
abnormal TSH level should have a free T4 level measured. Thyroid toxicity will 
be handled like any other non-hematological toxicity. Guidance on the 
management of patients who develop hypothyroidism is included in Section 7.8. 
 
8.3 
Radiology Studies 
 
8.3.1 
Bone Age/ Knee MRI 
All tibial radiographs and knee MRIs (if obtained) should be submitted for Central 
Review. 
 
8.3.2 
Central Radiology Review for Response:   


                                
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Patients who respond (CR, PR) to therapy or have long term stable disease (SD) 
(≥ 6 cycles) on protocol therapy will be centrally reviewed. COG Operations 
Center will notify the Imaging Center of any patient requiring central review. The 
Imaging Center will then request that the treating institution forward the requested 
images for central review. The central image evaluation results will be entered into 
RAVE for review by the COG Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the grid.   
 
COG institutions that are not connected to the grid can send the images on hard 
copy film, CD ROM, or by FTP.  Submitted imaging studies should be clearly 
marked with the COG patient ID, study number (ADVL1211) and date and shipped 
to Syed Aamer at the address below: 
 
Syed Aamer 
Imaging Research Center 
Data Administrator  
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone: (323) 361-3898 
Fax: 
(323) 361-3054 
E-mail: saamer@chla.usc.edu 
 
8.4 
Pharmacology COMPLETE 
 
8.4.1 
Description of Studies and Assay 
Plasma samples will be collected for the purpose of determining XL184 
concentrations for pharmacokinetic analysis of XL184 and/or metabolite 
concentrations. 
 
8.4.2 
Sampling Schedule (See Appendix IV and V) 
Blood samples will be obtained at the following time points:  
 
• 
Required from all patients:  
o Cycle 1 Day 1 (pre, 4 hours after the first dose)  
o Cycle 1 Day 21 (± 2) (pre, 2, 4, 8 and 24 hours after dose)  
o Cycle 3 Day 1 (pre) for patients remaining on study 
 
• 
Required from patients enrolled after Amendment #5A:  
o Cycle 4 Day 1 (pre) for patients remaining on study 
o With each disease evaluation  (beyond Cycle 4; pre-Day 1 dose) for 
patients remaining on study 
 
• 
Recommended from all patients: 
o If possible any time a patient experiences a DLT.  
 
8.4.3 
Sample Collection and Handling Instructions 
Blood samples (3 ml) will be collected in 3-mL K2-EDTA Vacutainer tubes 
(lavender top) tubes for pharmacokinetic evaluation. Record the exact time and 


                                
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date the sample is drawn. During Cycle 1, record the exact time the drug is 
administered. Record the actual date and time the last dose of drug was 
administered prior to the collection of trough samples (pre-Cycle 3, pre-Cycle 4 
and pre-Day 1 dose with each disease evaluation). 
 
8.4.4 
Sample Processing Instructions 
Tubes should be chilled on wet ice or in a refrigerator prior to collection. 
Immediately after blood collection, blood tubes should be inverted several times 
and then kept on wet ice until centrifuged. Within 30 minutes of blood collection, 
samples should be separated by centrifugation for 10 minutes (1000 - 1200 g) at 
approximately 4°C. The resultant plasma should be withdrawn in approximately 
equal volumes into two (2) appropriately labeled polypropylene tubes for PK assay 
and stored (within 1 hour of the blood sampling time) at -70°C or lower until 
shipment. The analyst should attempt to transfer the maximum amount of plasma 
without disturbing the barrier between the red blood cells (bottom layer) and the 
plasma (top layer). One tube is the primary sample; the other tube is the back-up 
sample. Refer to PK Manual provided by Exelixis for additional sample processing 
instructions. 
 
8.4.5 
Sample Labeling 
Each tube must be labeled with the patient’s I.D. and accession number, the 
study I.D. (ADVL1211), and the date and time the sample was drawn.  Data 
should be recorded on the Pharmacokinetic Study Form, which must accompany 
the sample(s). 
 
8.4.6 
Sample Shipping Instructions 
The primary samples collected for each subject should be shipped to Alturas Inc, 
on sufficient dry ice in an insulated container. Samples should be shipped between 
Monday and Wednesday for overnight delivery to ensure delivery to Alturas 
Analytics, Inc, before Friday. The back-up samples should be shipped to Alturas, 
Inc after confirmation of receipt of the primary samples. 
 
Samples should be shipped to the following address: 
Jennifer Zimmer, Ph.D. 
Senior Scientist 
Alturas Analytics, Inc. 
1324 Alturas Dr. 
Moscow, ID 83843 
Phone: (208) 883-3400 
Fax: (208) 882-9246 
 
Refer to PK Manual provided by Exelixis for additional sample shipping 
instructions. 
 
8.5 
Correlative Studies 
 
8.5.1 
Description of Studies 
8.5.1.1 Pharmacodynamic Biomarkers  
Blood samples will be collected for all subjects for potential analyses of 
cabozantinib mechanism of action based biomarkers (e.g. VEGF-A, PlGF, 
sVEGFR2, sKIT) and/or other disease specific markers such as circulating 


                                
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tumor cells. Markers of bone homeostasis (eg serum bone-specific ALP, 
NTx, and CTx) may be monitored to assess the effects of cabozantinib on 
bone metabolism. Additional exploratory studies may be performed to 
characterize disease subtypes and potential biomarkers of response or 
resistance. Analyses may include but are not limited to quantification and 
genotyping of circulating plasma DNA, evaluation of micro RNAs, and 
analyses of additional soluble markers.   
 
 
8.5.1.2 Tumor Tissue Banking 
Archival tumor tissue slides should be submitted. If a patient does not 
have tissue available, the study chair must be notified prior to 
enrollment. Tumor analyses may involve evaluation of the signaling 
pathways related to cabozantinib targets (eg, VEGFR, MET, KIT, RET) 
and include methods such as genotyping, fluorescence in situ 
hybridization (FISH) and/or immunohistochemistry (IHC). Broader 
genome-wide copy number and mutation profiling may also be conducted. 
See Appendix XI for details. 
 
8.5.2 
Sampling Schedule (See Appendix  IV and X) 
 
 
 
Blood samples will be collected as outlined in Appendix X. 
 
8.5.3 
Sample Collection and Handling Instructions 
Refer to Appendix XII and Pharmacodynamic Lab Manual provided by Exelixis 
for detailed instructions regarding collection and storage of these specimens. 
 
8.5.4 
Sample Processing and Shipping Instructions 
Refer to Appendix XII and Pharmacodynamic Lab Manual provided by Exelixis 
for detailed instructions regarding processing and shipment of these specimens. 
 
8.5.5 
Sample Labeling 
Each tube must be labeled with the patient’s I.D. and accession number, the study 
I.D. (ADVL1211), and the date and time the sample was drawn.  Data should be 
recorded on the Correlative Study Form (Appendix X), which must accompany 
the sample(s). 
 
 


                                
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9.0 
AGENT INFORMATION 
 
9.1 
Cabozantinib 
(XL-184, Cabozantinib s-malate, EXEL-7184, EXEL-02977184) NSC# 761968    
  
9.1.1 
Structure and molecular weight  
The chemical name of cabozantinib is N-(4-[(6,7-dimethoxyquinolin-4-
yl)oxy]phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, 
(2S)-
hydroxybutanedioate.  The molecular formula is C28H24FN3O5C4H6O5 and the 
molecular weight is 635.6.   
 
9.1.2 
Supplied by:  
Cabozantinib is supplied by Exelixis and distributed by the DCTD, NCI.   
 
9.1.3 
Formulation 
Cabozantinib is available in 20 mg and 60 mg tablets.  The yellow, film-coated tablets 
contain cabozantinib malate equivalent to 20 mg or 60 mg of cabozantinib.  The 20 
mg tablets have a round shape and the 60 mg tablets have an oval shape.    In active 
ingredients include the following: microcrystalline cellulose (Avicel PH-102), 
lactose anhydrous (60M), hydroxypropyl cellulose (EXF), croscarmellose sodium 
(Ac-Di-Sol), colloidal silicon dioxide, and magnesium stearate.  Inactive 
components of the yellow film coating include HPMC 2910/hypromellose 6 cp, 
titanium dioxide, triacetin, and iron oxide yellow.   
 
9.1.4 
Storage 
Store intact bottles at controlled room temperature, 20° to 25°C. 
 
9.1.5 
Stability 
Stability testing of the intact bottles is on-going. Cabozantinib (XL184) should be 
dispensed in its original container. Cabozantinib (XL184) tablets are stable up to 24 
hours when dispensed in an open container, such as in a pill cup, and are stable for up 
to 7 days when dispensed in a closed container, such as a pharmacy dispensing bottle 
(i.e., one other than the original container).  
 
9.1.6 
Administration 
Take cabozantinib on an empty stomach; patients should fast 2 hours before and 1 
hour after taking the drug.  Do not crush or chew the tablets; tablets should be 
swallowed whole.  
 
Cabozantinib is a substrate of CYP3A4.  Coadministration of cabozantinib with 
medications that are strong inhibitors/inducers of CYP3A4 should be avoided. 
Examples of strong CYP3A4 inducers are rifampin, dexamethasone, phenytoin, 
carbamazepine, rifabutin, rifampentin, Phenobarbital, and St. John’s Wort. Strong 
CYP3A4 inhibitors are ketoconazole, itraconazole, clarithromycin, indinavir, 
nefazodone, nelfinavir, and ritonavir. Refer to Section 7.5 regarding use of 
corticosteroids. Use alternative medications. Avoid grapefruit/ grapefruit juice, 
star fruit and Seville oranges while participating in this trial. Refer to Appendix 
IX for additional details. 
 
Cabozantinib is highly protein bound (99.9%).  Use caution when coadministering 
cabozantinib with medications that are highly protein-bound (e.g., diazepam, 


                                
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furosemide, dicloxacillin, and propranolol).  Avoid administration of warfarin with 
cabozantinib as warfarin is highly protein-bound and has a very narrow therapeutic 
index. 
 
Avoid concomitant use of cabozantinib with proton pump inhibitors (PPIs) and H2 -
antagonists if possible. The PPIs and H2 –antagonists may decrease cabozantinib 
plasma exposure levels and its effectiveness in humans. Examples of PPIs are 
omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole; examples of 
H2 –antagonists are ranitidine, famotidine, and nizatidine.  Cimetidine is a moderate 
CYP3A4 inhibitor.  Avoid using cimetidine with cabozatinib.  If needed, antacids are 
recommended for the initial treatment of dyspepsia or indigestion.  If antacids are not 
adequate, the use of H2 blockers (other than cimetidine) is preferred over PPIs. If 
antacids, H2 blockers, or PPIs are needed, take them at least 2 hours (preferably 4 
hours) after taking cabozantinib but at least 14 hours before the next dose of 
cabozantinib if possible. 
   
9.1.7 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). 
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2438 patients. 
Below is the CAEPR for XL184 (Cabozantinib s-malate). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
      Version 2.3, October 4, 20161 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 


                                
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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal hemorrhage3   
 
 
Gastrointestinal perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Musculoskeletal and 
connective tissue disorders - 
Other (muscle spasms) 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  


                                
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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Dyspnea 
 
  
 
 
 Pneumothorax6 
  
 
 
 Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
Voice alteration 
 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 3) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (hair color 
changes) 
 
 Skin and subcutaneous tissue 
disorders - Other (hair color 
changes) (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating 
patients with relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases.  
 
7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
 


                                
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8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC.  
 
9Thromboembolic event includes pulmonary embolism which may be life-threatening. 
 
 
Adverse events reported on XL184 (Cabozantinib s-malate) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that XL184 (Cabozantinib 
s-malate) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Febrile neutropenia; Hemolytic uremic syndrome 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac arrest; Chest pain - 
cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Myocarditis; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - 
Other (hypopituitarism); Endocrine disorders - Other (thyroiditis); Endocrine disorders - Other 
(thyrotoxicosis); Hyperthyroidism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Anal ulcer; Cheilitis; Colitis; 
Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; Esophagitis; Flatulence; 
Gastric ulcer; Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other 
(gastroenteritis); Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other 
(pneumoperitoneum); Hemorrhoids; Ileus; Pancreatitis; Rectal pain; Rectal ulcer 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Fever; Gait 
disturbance; General disorders and administration site conditions - Other (implant site inflammation); 
Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other 
(cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other 
(hepatitis toxic); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - 
Other (tendon injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Cardiac 
troponin I increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Investigations - Other (blood lactate dehydrogenase increased); Investigations - Other (D-
dimer); Investigations - Other (eosinophil count increased); Investigations - Other (glucose urine present); 
Investigations - Other (urine ketone body present); Lymphocyte count decreased; Neutrophil count 
decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders 
- Other (failure to thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Flank pain; 
Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorders - Other (muscle hemorrhage); Musculoskeletal and connective tissue disorders - Other 
(osteonecrosis); Musculoskeletal and connective tissue disorders - Other (rhabdomyolysis); Myalgia; 
Neck pain; Osteoporosis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity cancer); 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor 
pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory 


                                
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impairment; Nervous system disorders - Other (cerebral hematoma); Nervous system disorders - Other 
(hemiparesis); Nervous system disorders - Other (spinal cord compression); Nervous system disorders - 
Other (vocal cord paralysis); Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; 
Seizure; Somnolence; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; 
Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Renal and urinary disorders - 
Other (azotemia); Renal and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - 
Other (scrotal ulcer/erythema/edema); Vaginal fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Aspiration; Atelectasis; Hypoxia; Laryngeal edema; Pharyngeal mucositis; Pleural 
effusion; Pneumonitis; Productive cough; Pulmonary hypertension; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (nasal septum perforation); Respiratory, thoracic and 
mediastinal disorders - Other (oropharyngeal pain); Respiratory, thoracic and mediastinal disorders - 
Other (pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Pruritus; Rash acneiform; 
Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and erythema); Skin and 
subcutaneous tissue disorders - Other (psoriasis); Skin and subcutaneous tissue disorders - Other 
(splinter hemorrhages); Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders 
- Other (bleeding varicose vein); Vasculitis 
 
Note: XL184 (Cabozantinib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
9.2 
Agent Ordering and Agent Accountability 
NCI supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained.) The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
9.3 
Clinical Drug Request 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password. For questions about drug orders, transfers, returns, 
or accountability, call or email PMB any time. Refer to the PMB’s website for specific 
policies and guidelines related to agent management. 
 
9.4 
Agent Inventory Records 


                                
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The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
9.4.1 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: 
http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: 
PMBRegPend@ctep.nci.nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• 
PMB Online Agent Order Processing (OAOP) application: 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx 
• 
CTEP Identity and Access Management (IAM) account: 
https://eapps-ctep.nci.nih.gov/iam/ 
• 
CTEP Associate Registration and IAM account help: 
ctepreghelp@ctep.nci.nih.gov  
• 
PMB email: 
PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: 
(240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6). 
c) 
Refusal of further protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Physician determines it is not in the patient’s best interest. 
f) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of XL184 (See Section 8.1). 
g) 
Study is terminated by Sponsor. 
h) 
Pregnancy 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 


                                
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consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed beginning 30 days, 6 months, and 
annually (± 30 days) following the last dose of investigational agent until they meet the 
criteria for Off Study (see Section 10.2). Ongoing adverse events, or adverse events 
attributed to protocol therapy that emerge during the follow up period after the patient is 
removed from protocol therapy must be followed and reported via RAVE and CTEP-AERS 
(if applicable).  Follow-up data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Withdrawal of consent for any further required observations or data submission. 
d) 
The fifth anniversary of study entry. 
 
 
 


                                
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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Parts of the Study: 
Part A: Patients with relapsed or refractory solid tumors including CNS tumors and 
excluding patients with medullary thyroid cancer 
Part B:  Patients with medullary thyroid cancer (MTC)       
 
A minimum of 2 evaluable patients will be entered at each dose level for determination of 
MTD or recommended Phase 2 dose (RP2D) in Part A. Once the MTD or RP2D has been 
defined, up to 6 additional patients with relapsed/refractory solid tumors without heme 
restrictions may be enrolled to acquire PK data in a representative number of young 
patients (i.e. patients < 12 years old).  Review of the enrollment rate into previous COG 
new agent studies indicates that 1-2 patients per month are available, which will permit 
enrollment and determination of the MTD or RP2D within 15-29 months if all dose levels 
are studied with six evaluable patients. A maximum of 51 patients is anticipated in Part A, 
which accounts for potential expansion to 12 patients at each dose level (see Section 
11.2.2) and an inevaluability rate of 20%. COMPLETE 
 
Patients with medullary thyroid cancer may enroll to Part B of the study if there are no 
available slots on Part A. Part B will enroll concurrently at one dose level below that of 
solid tumor patients enrolled in Part A. If dose escalation has not yet occurred in Part A, 
patients in Part B will enroll at the initial dose level 1. Up to 6 patients may be enrolled 
onto each lagging dose level, for a maximum total of 18 evaluable patients in Part B. 
COMPLETE 
 
Once the MTD or RP2D is identified, intra-patient dose escalation will be allowed for 
patients with medullary thyroid cancer (MTC) remaining on study in cycles of therapy 
subsequent to cycle 1, provided that the patient did not experience dose-limiting toxicity 
(DLT) at the dose at which they began therapy. Patients who are one dose level below the 
MTD or RP2D can escalate to the MTD or RP2D. Patients who are more than one dose 
level below the MTD or RP2D can escalate one dose level per cycle until they reach the 
MTD or RP2D as long as they do not experience a DLT when escalating.  COMPLETE  
 
The recommended Phase 2 dose (RP2D) in patients with solid tumors was determined to 
be 40 mg/m2 (see details in Section 2.6).  In order to acquire additional PK data at this dose 
level, an additional 6  evaluable patients will be enrolled for a total of 12 evaluable patients 
at this dose level (6 < 12 years of age and 6 ≥ 12 years of age).  If at any time cycle 1 DLT 
occurs in ≥ 33% of evaluable patients in Part A at 40 mg/m2, the maximum tolerated dose 
will have been exceeded and the cohort will be closed to further enrollment.  Part B will 
remain open with Part A at 40 mg/m2 (the RP2D) to patients with MTC and may enroll a 
maximum of 6 evaluable patients (4 more in addition to the 2 already enrolled).  Part B 
will close to enrollment when the PK cohort in Part A at 40 mg/m2 has completed 
enrollment, or if 2 or more out of 6 evaluable patients in the Part B cohort experience cycle 
1 DLT.  Up to 12 additional patients will be enrolled for a maximum total of 41 patients in 
the study, which accounts for a 20% inevaluability rate.  It should take an additional 3-6 
months for completion of enrollment. 
 
 


                                
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11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Effects 
Any patient who experiences DLT at any time during protocol therapy is 
considered evaluable for Adverse Effects. Patients without DLT who receive at 
least 85% of the prescribed dose per protocol guidelines and had the appropriate 
toxicity monitoring studies performed are also considered evaluable for Adverse 
Effects. Patients who are not evaluable for Adverse Effects at a given dose level 
will be replaced. 
 
11.2.2 Maximum Tolerated Dose (Part A): COMPLETE 
The MTD will be the maximum dose at which fewer than one-third of patients 
experience DLT (See Section 5.5) during Cycle 1 of therapy. In the event that two 
DLTs observed out of 6 evaluable patients are different classes of Adverse Effects 
(e.g. hepatotoxicity and myelosuppression), expansion of the cohort to 12 
patients will be considered if all of the following conditions are met:  
 
•  One of the DLTs does not appear to be dose-related 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation can proceed. 
 
11.3 
Dose Escalation and Determination of MTD:- COMPLETE 
 
The rolling six phase 1 trial design will be used for the conduct of this study. 17 Two to six 
patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of 
patients enrolled at the current dose level, (2) the number of patients who have experienced 
DLT at the current dose level, and (3) the number of patients entered but with tolerability 
data pending at the current dose level.  Accrual is suspended when a cohort of six has 
enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one 
DLT has been observed, the new participant is entered at the same dose level. Lastly, if 
two or more DLTs have been observed, the dose level is de-escalated. This process is 
repeated for participants five and six. In place of suspending accrual after every three 
participants, accrual is only suspended when a cohort of six is filled. When participants 
are inevaluable for toxicity, they are replaced with the next available participant if 
escalation or de-escalation rules have not been fulfilled at the time the next available 
participant is enrolled onto the study. 
 
 


                                
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The following table provides the decision rules for enrolling a patient at (i) the current 
dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the 
study is suspended to accrual: 
# Pts 
Enrolled 
# Pts 
with 
DLT 
# Pts without 
DLT 
# Pts with 
Data 
Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
 
 
 
 
 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule). 
 
In addition to determination of the MTD or RP2D, a descriptive summary of all toxicities 
will be reported. 
 
11.4 
Inclusion of Children, Women and Minorities 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
 


                                
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11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of XL184 will be performed to 
define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK 
parameters will be summarized with simple summary statistics, including means, medians, 
ranges, and standard deviations (if numbers and distribution permit).   
 
While the primary aim of this study is to evaluate the toxicity of XL184 patients will have 
disease evaluations performed as indicated in Section 8.1.  Disease response will be 
assessed according to RECIST criteria for patients with solid tumors, and will be reported 
descriptively. Overall survival from study entry will also be assessed and summarized 
using the Kaplan-Meier method at the 6 month, 12 month, and 5 year timepoints. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
 
 
 
 


                                
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12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
 
12.2 
Response Criteria for Patients with Solid Tumors  
See the table in section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained 21-28 days following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
12.2.1 Definitions 
 
12.2.1.1 Evaluable for objective response: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will be considered evaluable for 
response. For all other patients, only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, 
and have had their disease re-evaluated will be considered evaluable for 
response.  
 
12.2.1.2 Evaluable Non-Target Disease Response: Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
12.2.2 Disease Parameters 
 
12.2.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥20 mm by chest 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). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable.  If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
 


                                
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12.2.2.2 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 no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.2.2.3 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. 
 
12.2.2.4 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 that 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. 
 
12.2.2.5 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.  
 
 
 


                                
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12.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
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. 
 
12.2.3.1 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.  
 
12.2.3.2 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.  
 
12.2.3.3 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). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 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.  
 
12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
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12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
12.2.4 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
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). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 


                                
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an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
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 
 
12.2.4.2 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.     
 
12.2.5 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.8 from a sequence of overall response assessments. 
 
12.3 
Biomarker Response Criteria for Patients with MTC 
 
Patients with MTC will use the response criteria outlined above in Section 12.2 to 
evaluate response and progression. Additional biomarker response data will be collected 
in patients with tumor markers (CEA and/or calcitonin) 2x ULN at baseline. 
 
Complete Response (CR): 
Normalization (≤ ULN) of CEA or calcitonin 
(CTN) level following treatment, confirmed with 
a repeat CEA/CTN level at least 4 weeks apart. 
 
Partial Response (PR): 
A ≥ 50% decrease in the CEA or CTN level 
relative to the baseline level, confirmed with a 
repeat CEA/CTN level at least 4 weeks apart. 


                                
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Progressive Disease (PD): 
A ≥ 50% increase in the CEA or CTN relative to 
the prior value on 2 consecutive measurements at 
least 4 weeks apart (e.g., if the last prior CTN 
value was 1,000 pg/ml, consecutive values of 
1,500 pg/ml and then 2,250 pg/ml at least 4 weeks 
later would represent progression). The patient 
must have been taking XL184 for 4 weeks prior 
to the first measurements and must have 
continued to take the drug through the time that 
the second measurement was drawn. 
 
Stable Disease (SD): 
<50% increase or decrease in CTN or CEA level 
relative to the baseline level. 
 
12.4 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.4.1 Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
12.4.2 Complete Response 
Disappearance of all evaluable disease. 
 
12.4.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
12.4.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
12.4.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.4.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.8 from a sequence of overall response assessments. 
 
 


                                
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12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.5.1 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.5.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.5.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess 
efficacy for study endpoint. See Section 8.3.1 for details on transferring images 
to the Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 


                                
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The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.5.4 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 5 in Section 12.8. 
 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.6.1 Bone Marrow Involvement  
Bone marrow obtained within 28 days prior to study enrollment with tumor cells 
seen on routine morphology (not by immunohistochemical staining only) of 
bilateral aspirate or biopsy on one bone marrow sample. 
 
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates. 
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 


                                
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Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
12.6.2 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.8. 
 
12.7 
Response Criteria for Patients with CNS Tumors 
 
12.7.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.7.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.7.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.7.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial response (PR): ≥50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD. 


                                
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• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
12.7.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.7.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.7.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.8 from a sequence of overall response assessments. 
 
 


                                
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12.8 
Best Response 
 
12.8.1 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. 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>28 days 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 
>28 days 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. 
 
Table 2: 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 
 
 
 


                                
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Table 3.  Sequences of overall response assessments with corresponding best 
response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly identified lesion by 
CT/MRI that occurs during therapy would be considered progressive disease. 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
12.8.2 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). 
 


                                
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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. 
 
 
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.  
 
 
 


                                
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13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the data collection packet 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source. The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 4.0.  The 
descriptions and grading scales found in the revised CTCAE version 4.0 will be 
used for AE reporting. All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported according to the instructions in the table 
below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
 


                                
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Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 


                                
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birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not due to cancer 
recurrence/progression must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, including Grade 4 lymphopenia, does not require expedited reporting unless it 
is associated with hospitalization. 
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via CTEP-
AERS: 
 
Category 
Adverse Events 
INFECTIONS AND INFESTATIONS  
Infection  
METABOLISM AND NUTRITION DISORDERS  
Dehydration  
METABOLISM AND NUTRITION DISORDERS  
Hypocalcemia    
METABOLISM AND NUTRITION DISORDERS  
Hypomagnesemia    
METABOLISM AND NUTRITION DISORDERS 
Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS  
Pain in extremity  
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
Arthralgia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
Musculoskeletal and connective tissue 
disorders - Other (muscle spasms) 
NERVOUS SYSTEM DISORDERS  
Dizziness  
NERVOUS SYSTEM DISORDERS  
Headache  
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS  
Cough 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
Dyspnea 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
Respiratory, thoracic and mediastinal 
disorders - Other (oropharyngeal pain) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS  
Pruritus  
 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.7 of the 
protocol. 
 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
13.2 
When to Report an Event in an Expedited Manner  


                                
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• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
(telephone CTEP at: (301) 897-7497 within 24 hours of becoming aware of the event if 
the CTEP-AERS 24-Hour Notification web-based application is unavailable) and by 
telephone call to the Study Chair. Once internet connectivity is restored, a 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.h
tm. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the CTEP Adverse Event 
Reporting System (CTEP-AERS) that can be found at http://ctep.cancer.gov. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm. If prompted to enter a sponsor email address, please type in: 
PEPCTNAERS@childrensoncologygroup.org. 
 
Fax supporting documentation to the NCI (fax # 301-230-0159) and send by email 
to the ADVL1211 COG Study Assigned Research Coordinator.  ALWAYS 
include the ticket number on all faxed and emailed documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data 
submission forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
13.4.4 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than Grade 1, whichever level is higher (note that the resolution 
date may therefore be different from the date at which the grade of the AE 
decreased from its highest grade).  If the AE does not return to baseline the 


                                
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resolution date should be recorded as "ongoing."   
 
13.4.5 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the data 
form packet (See Section 14.1). 
 
13.5.2 COG will forward reports and supporting documentation to the Study Chair, to 
the FDA (when COG holds the IND) and to the pharmaceutical company (for 
industry sponsored trials). 
 
13.5.3 Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.6 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients on NCI-sponsored trials following their chemotherapy for cancer must be 
reported to the Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation 
Program (CTEP) via CTEP-AERS and included as part of the second malignant neoplasm 
reporting requirements for this protocol (see data submission packet).  Submit the 
completed CTEP-AERS report within 14 days of an AML/MDS diagnosis occurring after 
treatment for cancer on NCI-sponsored trials. 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML]),  
2) Myelodysplastic syndrome (MDS), or  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified. 
 


                                
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13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and faxed along with any 
additional medical information to (301) 230-0159 (Appendix VI). Copies of all documents 
faxed to the NCI must also be emailed to the ADVL1211 COG Study Assigned Research 
Coordinator. The potential risk of exposure of the fetus to the investigational agent should 
be documented in the “Description of Event” section of the CTEP-AERS report. 
 
13.7.1 Pregnancy 
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
“Pregnancy, puerperium and perinatal conditions - Other (Pregnancy) 
under the Pregnancy, puerperium and perinatal conditions SOC and 
reported as Grade 3. 
 
• 
Pregnancy should be followed up until the outcome of the pregnancy is 
known at intervals deemed appropriate by her physicians. The “Pregnancy 
Information Form” should be used for all follow-ups. If the baby is born 
with a birth defect or other anomaly, then a second CTEP-AERS report is 
required. 
 
13.7.2 Fetal Death 
• 
Fetal death is defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of respiration, 
heartbeat, or definite movement of a voluntary muscle after expulsion 
from the uterus, without possibility of resuscitation.” 
 
• 
 Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.  
 
• 
 A fetal death should NOT be reported as “Fetal death,” a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC, as 
currently CTEP-AERS recognizes this event as a patient death. 
 
13.7.3 Death Neonatal 
• 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration- Other (neonatal loss)” under the General 
disorders and administration SOC. 
 
• 
Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event. If reported as 


                                
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such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
 
 


                                
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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are faxed, with the corresponding shuttle sheet to the Statistics & Data 
Center at (626) 447-2204. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in the COG Remote Data Entry System with the aid of schedules and 
worksheets (essentially paper copies of the RAVE screens) provided in the data 
form packet. 
 
See separate Data Form Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports 
are due January 31, April 30, July 31 and October 31.  This is not a responsibility of institutions 
participating in this trial. 
 
14.3 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
   
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 


                                
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agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting 
or publication in the proceedings. Press releases and other media presentations 


                                
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must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the PEP-CTN scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months 
to review current study results, as well as data available to the DSMC from other 
related studies. Approximately 6 weeks before each meeting of the Phase 1 and 2 
DSMC, study chairs will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG PEP-CTN Chair and the Group Chair for each study 
reviewed to change the study or to continue the study unchanged. Data and Safety 
Committee reports for institutional review boards can be prepared using the public 
data monitoring report as posted on the COG Web site. 
 
14.4.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the COG 
PEP-CTN Chair, Vice Chair and Statistician on a weekly conference call. 


                                
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REFERENCES 
 
1. Gschwind A, Fischer OM, Ullrich A: The discovery of receptor tyrosine kinases: targets for cancer 
therapy. Nat Rev Cancer 4:361-70, 2004 
2. DuBois S, Demetri G: Markers of angiogenesis and clinical features in patients with sarcoma. Cancer 
109:813-9, 2007 
3. Ramirez R, Hsu D, Patel A, et al: Over-expression of hepatocyte growth factor/scatter factor (HGF/SF) 
and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for 
children and young adults with papillary thyroid carcinoma. Clin Endocrinol (Oxf) 53:635-44, 2000 
4. Kong DS, Song SY, Kim DH, et al: Prognostic significance of c-Met expression in glioblastomas. 
Cancer 115:140-8, 2009 
5. Traugott AL, Moley JF: The RET Protooncogene. Cancer Treat Res 153:303-19, 2009 
6. Investigator's Brochure XL184. July 2010. Exelixis. San Francisco, CA 94083, 2010 
7. Paez-Ribes M, Allen E, Hudock J, et al: Antiangiogenic therapy elicits malignant progression of tumors 
to increased local invasion and distant metastasis. Cancer Cell 15:220-31, 2009 
8. Sennino B NR, Tabruyn SP, Weon-Kyoo Y, Aftab DT, McDonald DM: Reduction of tumor 
invasiveness and metastasis and prolongation of survival of RIP-Tag2 mice after inhibition of VEFGR 
plus c-MET by XL-184. Abstract A13: AACR-NCI-EORTC International Conference, November 
2009, 2009 
9. Yakes FM, Chen J, Tan J, et al: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, 
simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther, 2011 
10. Lee RJ, Michaelson MD, Saylor PJ, et al: Investigator-sponsored trial of efficacy and tolerability of 
cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer 
(CRPC) and bone metastases. ASCO Meeting Abstracts 30:4566 
11. Kurzrock R CE, Sherman SI, Pfister DG, Cohen RB, Ball D, Hong DS, Ng CS, Salgia R, Ratain MJ 
Long-term results on a cohort of medullary thyroid carncer (MTC) patients (pts) in a phase I study of 
XL184 (BMS 907351), and oral inhibitor of MET, VEGFR2, and RET. Clin Oncol 28:7s, 2010 (suppl; 
abstr 5502), 2010 
12. Kurzrock R, Sherman SI, Ball DW, et al: Activity of XL184 (Cabozantinib), an oral tyrosine kinase 
inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29:2660-6, 2011 
13. Salgia R SS, Hong DS, Ng CS, Frye J, Janisch L, Ratain MJ, Kurzrock R: A phase I study of XL184, 
a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including 
patients with medullary thyroid carcinoma (MTC). J Clin Oncol 26:2008 (May 20 suppl; abst 3522), 
2008 
14. Wen PY PM, Schiff D, et al. : Phase II study of XL184 (BMS 907351), an inhibitor of MET, VEGFR2, 
and RET, in patients (pts) with progressive glioblastoma (GBM). J Clin Oncol 28:7s, 2010 (suppl; abstr 
2006), 2010 
15. Gordon MS VN, Schoffsky P, et al.: Cabozantinib (XL184) has activity in both soft tissue and bone: 
results of a phase 2 randomized discontinuation trial (RDT) in patients with advanced solid tumors. 
ASCO 2011 abstract, 2011 
16. Exelixis: Exelixis' Cabozantinib Meets Primary Endpoint in Phase 3 Clinical Trial for Medullary 
Thyroid Cancer, Exelixis Press Release, 2011 
17. Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: the rolling 
six design. J Clin Oncol 26:190-5, 2008 
18. Xin G, Wang M, Jiao LL, et al: Protein-to-creatinine ratio in spot urine samples as a predictor of 
quantitation of proteinuria. Clin Chim Acta 350(1-2):35-9, 2004  
 
 
 


                                
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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 


                                
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APPENDIX IIA: XL184 DOSING NOMOGRAM 
 
Patients must have a body surface area ≥ 1.04 m2 when enrolling on dose level -1, a BSA ≥ 0.96 m2 to enroll 
on dose level 1, a BSA ≥ 0.72 m2 to enroll on dose level  2, and a BSA ≥ 0.65 m2 to enroll on dose level 3.  
If dose reduction is required due to toxicity, patients will decrease their administered dose per the tables 
below each respective dose level. 
 
Patients enrolled after Amendment #1 should follow the dosing nomogram in Appendix IIB. Patients 
enrolled on study prior to Amendment #1 must not change their dosing schedule and should continue to 
use the same dosing nomogram below. 
 
Dose Level -1 
Dose Level 23 mg/m2 (DOSE LEVEL -1) 
BSA (m2) 
Dose (mg) 
Total Weekly Dose (mg) 
1.04 – 1.55 
40 mg po q M, W, Th, Sat, Sun 
200 mg 
1.56- ≥ 2.00 
40 mg once daily 
280 mg 
 
 
Dosing if Dose Reduction for Toxicity at 23 mg/m2  Dose Level 
BSA (m2) 
Dose (mg) 
Total Weekly Dose 
1.04 – 1.55 
20 mg once daily 
140 mg 
1.56 - ≥ 2.00 
40 mg po q M, W, Th, Sat, Sun 
200 mg 
 
 
Dose Level 1 
XL184 Dose Assignment:  30 mg/m2 (DOSE LEVEL 1) 
BSA (m2) 
Administered dose (mg) 
Total Weekly Dose (mg) 
0.96 – 1.14 
40 mg po q M, T, W, Fri, Sat, Sun 
240 mg 
1.15 – 1.42 
40 mg po once daily 
280 mg 
1.43 – 1.67 
60 mg po q M, T, W, Fri, Sat, Sun 
360 mg 
1.68 – ≥ 2.0 
60 mg po once daily 
420 mg 
 
 
Dosing if Dose Reduction for Toxicity at 30 mg/m2 Dose Level 
BSA (m2) 
Administered dose (mg) 
Total Weekly Dose (mg) 
0.96 – 1.14 
60 mg po q M, W, Fri 
180 mg 
1.15 – 1.42 
40 mg po q M, W, Th, Sat, Sun 
200 mg 
1.43 – 1.67 
40 mg po once daily 
280 mg 
1.68 – ≥ 2.0 
60 mg po q M, W, Th, Sat, Sun  
300 mg 
 


                                
 
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APPENDIX IIB: XL184 DOSING NOMOGRAM (AMENDMENT #5A) 
Patients enrolled on any amendment should follow the dosing nomogram below. Patients enrolled on study prior to Amendment #1 must not 
change their dosing schedule and should continue to use the same dosing nomogram (see Appendix IIA). If a patient’s dose is reduced due to 
toxicity, any future XL184 total weekly dose should not exceed a previously un-tolerated dose. 
 
Dose Level 
-1 
 
23 mg/m2 
 
Dose Level 
1 
 
30 mg/m2 
Dose Level 
2 
 
40 mg/m2 
Dose Level 
3 
 
55 mg/m2 
BSA (m2) 
BSA (m2) 
BSA (m2) 
BSA (m2) 
Weekly Dose/ Schedule 
for Initial Dosing 
Weekly Dose/Schedule 
for 1st Dose Reduction 
due to Toxicity 
Weekly Dose/Schedule for 2nd 
Dose Reduction due to Toxicity 
0.44 – 0.55 
0.35 – 0.42 
 
 
80 mg = 20 mg M, W, F, 
Sun 
60 mg = 20 mg M, W, F 
Off therapy 
0.56 – 0.68 
0.43 – 0.52 
0.35 – 0.39 
 
100 mg = 20 mg M, W, 
Th, Sat, Sun 
60 mg = 20 mg M, W, F 
Off therapy 
0.69 – 0.79 
0.53 – 0.60 
0.40 – 0.45 
 
120 mg =20 mg M, T, 
W, F, Sat, Sun 
80 mg = 20 mg M, W, F, Sun 60 mg = 20 mg M, W, F 
0.80 – 0.96 
0.61 – 0.73 
0.46 – 0.55 
0.35 – 0.40 
140 mg =20 mg Daily 
100 mg = 20 mg M, W, Th, 
Sat, Sun 
60 mg = 20 mg M, W, F 
0.97 – 1.11 
0.74 – 0.85 
0.56 – 0.64 
0.41 – 0.46 
160 mg = 40 mg M, W, 
F, Sun 
120 mg = 20 mg M, T, W, F, 
Sat, Sun 
80 mg = 20 mg M, W, F, Sun 
1.12 – 1.36 
0.86 – 1.04 
0.65 – 0.78 
0.47 – 0.57 
200 mg = 40 mg M, W, 
Th, Sat, Sun 
140 mg = 20 mg Daily 
100 mg = 20 mg M, W, Th, Sat, 
Sun 
1.37 – 1.58 
1.05 – 1.21 
0.79 – 0.90 
0.58 – 0.66 
240 mg = 40 mg M, T, 
W, F, Sat, Sun 
160 mg = 40 mg M, W, F, 
Sun 
120 mg = 20 mg M, T, W, F, 
Sat, Sun 
1.59 – 1.86 
1.22 – 1.46 
0.91 – 1.09 
0.67 – 0.80 
280 mg = 40 mg Daily 
200 mg = 40 mg M, W, Th, 
Sat, Sun 
140 mg = 20 mg Daily 
1.87 – 2.04 
1.47 – 1.57 
1.10 – 1.17 
0.81 – 0.85 
300 mg = 60 mg M, W, 
Th, Sat, Sun 
200 mg = 40 mg M, W, Th, 
Sat, Sun 
140 mg = 20 mg Daily 
≥ 2.05 
1.58 – 1.85 
1.18 – 1.36 
0.86 – 0.99 
360 mg = 60 mg M, T, 
W, F, Sat, Sun 
240 mg = 40 mg M, T, W, F, 
Sat, Sun 
160 mg = 40 mg M, W, F, Sun 
 
1.86 – 2.14 
1.37 – 1.65 
1.00 – 1.16 
420 mg = 60 mg Daily 
300 mg = 60 mg M, W, Th, 
Sat, Sun 
200 mg = 40 mg M, W, Th, Sat, 
Sun 
 
≥ 2.15 
1.66 – 1.85 
1.17 – 1.35 
480 mg = 80 mg M, T, 
W, F, Sat, Sun 
360 mg = 60 mg M, T, W, F, 
Sat, Sun 
240 mg = 40 mg M, T, W, F, 
Sat, Sun 


                                
 
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Dose Level 
-1 
 
23 mg/m2 
 
Dose Level 
1 
 
30 mg/m2 
Dose Level 
2 
 
40 mg/m2 
Dose Level 
3 
 
55 mg/m2 
BSA (m2) 
BSA (m2) 
BSA (m2) 
BSA (m2) 
Weekly Dose/ Schedule 
for Initial Dosing 
Weekly Dose/Schedule 
for 1st Dose Reduction 
due to Toxicity 
Weekly Dose/Schedule for 2nd 
Dose Reduction due to Toxicity 
 
 
1.86 – 2.07 
1.36 –  1.5 
560 mg = 80 mg Daily 
420 mg = 60 mg Daily 
300 mg = 60 mg M, W, Th, Sat, 
Sun 
 
 
≥ 2.08 
1.51 – 1.68 
600 mg = 100 mg M, T, 
W, F, Sat, Sun 
420 mg = 60 mg Daily 
300 mg = 60 mg M, W, Th, Sat, 
Sun 
 
 
 
1.69 – 2.00 
700 mg =100 mg Daily 
480 mg = 80 mg M, T, W, F, 
Sat, Sun 
360 mg = 60 mg M, T, W, F, 
Sat, Sun 
 
 
 
≥ 2.01 
840 mg = 120 mg Daily 
600 mg = 100 mg M, T, W, 
F, Sat, Sun 
420 mg = 60 mg Daily 
 
 


                                
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APPENDIX III: XL184 PATIENT DIARY  
 
COG Patient ID:___________   ACC # : _____     Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the date, time and number of XL184 tablets taken. Make note of other drugs and 
supplements taken. Your doctor will tell you what foods you should avoid. If a dose of XL184 is missed 
and less than 6 hours have passed since the scheduled dosing time, the dose should be taken immediately. 
If more than 6 hours have passed since the scheduled dosing time, you should not take the missed dose but 
should wait and take the next regularly scheduled dose. If you vomit after the dose of XL184 is 
administered, that dose should NOT be repeated. Wait until the next regularly scheduled dose to take the 
drug again. Return the completed diary to your institution weekly during Cycle 1, and then after each 
treatment cycle. Your institution will upload this document into RAVE weekly during Cycle 1, and then 
after each treatment cycle. 
 
Sites will fill out the day of the week and number of prescribed tablets per day according to the dosing 
nomogram in Appendix II. 
 
EXAMPLE 
 
Number of Tablets taken 
Comments 
WEEK 1 
Date 
Time 
20 mg 
60 mg 
He felt nauseated an 
hour after taking the 
drug but did not vomit. 
Day 1: 
Monday 
1/15/
12 
8:30 
AM 
# prescribed:__3__ 
# taken: __3___ 
# prescribed:__0__ 
# taken: __0__ 
 
 
 
Cycle #: _____              Start Date: |__/__|__/__|__/__|              End Date: |__/__|__/__|__/__|  
 
BSA: _____   Dose: ________mg/m2     Weekly Cumulative Dose per Nomogram: ___________ mg 
 
WEEK 1 
Date 
Time 
20 mg 
60 mg 
Comments 
Day 1: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 2: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 3: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 4: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 5: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 6: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 7: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 


                                
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WEEK 2 
Date 
Time 
20 mg 
60 mg 
Comments 
Day 8: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 9: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 10: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 11: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 12: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 13: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 14: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
 
 
 
  
WEEK 3 
Date 
Time 
20 mg 
60 mg 
Comments 
Day 15: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 16: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 17: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 18: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 19: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 20: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 


                                
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Day 21: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
 
WEEK 4 
Date 
Time 
20 mg 
60 mg 
Comments 
Day 22: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 23: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 24: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 25: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 26: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 27: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
Day 28: 
__________ 
 
 
AM / PM 
# prescribed:_____ 
 
# taken: _____ 
# prescribed:_____ 
 
# taken: _____ 
 
 
 
 
Comments:


 
                                
 
 
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APPENDIX IV: CORRELATIVE STUDIES GUIDE 
 
Correlative Study 
Appx. 
Tube 
Type 
Blood 
Volume 
per 
Sample 
Total 
Volume 
Cycle 1 
Total Volume  
 
Cycle 1 
 
Cycle 
3+** 
Day 1 
Day 21(± 2 days) 
Day 22 
Day 28(± 2 days) 
Day 1 
Pre- 
Dose 
4 hr 
Pre- Dose 
2 hr 
4 hr 
8 hr 
24±2hr 
Pre- Dose 
Pre- Dose 
Pharmacokinetic 
COMPLETE 
V 
Refer to 
Sample 
Kit 
3 mL 
21 mL 
24 mL** 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pharmacodynamics 
X, 
XII 
Refer to 
Sample 
Kit 
5 mL 
20 mL 
20 mL 
X* 
 
X 
 
 
 
 
X 
 
Tissue Studies 
XI, 
XII 
 
Total Volume for All 
Studies 
 
41 mL 
44 mL** 
 
*Two pre-treatment samples will be collected: at baseline and prior to dose on Day 1 of Cycle 1 
 
** For patients enrolled after Amendment #5A trough (pre) dose PK should be obtained with each disease evaluation within 72 hours before Day 
1 dose of subsequent cycle.  An additional 3 mL of blood will be collected with each disease evaluation.  COMPLETE 
 
 


                                
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APPENDIX V: PHARMACOKINETIC STUDY FORM   COMPLETE  
 
COG Pt ID # ______________   ACC # ______   Institution _____________________________     Dose Level: _______mg/m2  
Please do not write patient names on this form or on samples. 
 
Total Weekly Dose per Nomogram: ______mg   Cycle 1, Day 1 Date: |__/__|__/__|__/__|   Body Surface Area: ______m2 
 
 
Blood samples (3 mL each) will be obtained on Cycle 1, Day 1 (pre-dose and 4 hours post dose), Cycle 1 Day 21 (± 2 
days) (pre-dose, 2, 4, 8 and 24 hours post dose), Cycle 3 Day 1 (pre-dose). A sample on Cycle 4 Day 1 (pre-dose) and 
on Day 1 (pre-dose) with each disease evaluation should be obtained for patients enrolled after Amendment #5A. If 
possible, a sample should be collected at the time of DLT. Record the exact date and time each sample is drawn and the 
XL184 dose is administered.  
 
Blood 
Sample  
No. 
Barcode # 
(from 
Sample 
Label) 
Time Point 
Scheduled Collection 
Time 
Scheduled 
Dose  
Last Dose Given; 
Record Actual 
Date and Time 
(24-hr clock) 
Actual Date 
Sample 
Collected or 
Dose Given 
Actual Time 
Sample 
Collected or 
Dose Given 
(24-hr clock) 
1 
 
Cycle 1, Day 1 
Prior to first dose^ 
 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, 
Day 1 Dose 
 
___/___/___ 
|__|__| : |__|__| 
2 
 
Cycle 1, Day 1 
4 hours after first dose 
 
 
___/___/___ 
|__|__| : |__|__| 
3 
 
Cycle 1, Day 21 
(± 2) 
Prior to dose on Day 21 
(± 2)^  
 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, 
Day 21 Dose 
 
___/___/___ 
|__|__| : |__|__| 
4 
 
Cycle 1, Day 21 
2 hrs after Day 21 dose 
 
 
___/___/___ 
|__|__| : |__|__| 
5 
 
Cycle 1, Day 21 
4 hrs after Day 21 dose 
 
 
___/___/___ 
|__|__| : |__|__| 
6 
 
Cycle 1, Day 21 
8 hrs after Day 21 dose 
 
 
___/___/___ 
|__|__| : |__|__| 
7 
 
Cycle 1, Day 22 
24 (±2) hrs after Day 21 
dose* 
 
 
___/___/___ 
|__|__| : |__|__| 
8@ 
 
Cycle 3, Day 1 
Prior to Cycle 3, Day 1 
dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
                  
For patients enrolled after Amendment #5A: 
9@ 
 
Cycle 4, Day 1 
Prior to Cycle 4, Day 1 
dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
                       
   With Each Disease Evaluation (For patients enrolled after Amendment #5A): 
 10@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 11@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 12@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 13@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 14@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 15@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 


                                
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Blood 
Sample  
No. 
Barcode # 
(from 
Sample 
Label) 
Time Point 
Scheduled Collection 
Time 
Scheduled 
Dose  
Last Dose Given; 
Record Actual 
Date and Time 
(24-hr clock) 
Actual Date 
Sample 
Collected or 
Dose Given 
Actual Time 
Sample 
Collected or 
Dose Given 
(24-hr clock) 
 16@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 17@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 18@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 19@ 
 
Cycle #___,  
Day 1 
Prior to Cycle ___, 
Day 1 dose 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
                                                                                      
                                                                                        For patients enrolled on any Amendment: 
 
 
At time of 1st DLT  
unscheduled 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 
 
 
At time of  2nd DLT  
unscheduled 
 
 
___/___/___ 
 
|__|__| : |__|__| 
___/___/___ 
|__|__| : |__|__| 
 
 
^ Blood samples should be drawn within 15 minutes prior to dose. 
* Drug should be held on Cycle 1, Day 22 until PK sample is drawn. 
@ The pre-dose sample can be collected within 72 hours prior to the start of the subsequent cycle. 
 
Sample Processing/ Shipping Procedures: Samples should be processed according to Section 8.4.4 and then batched 
and shipped as described in the PK Lab Manual. Please indicate on the sample label whether the shipped sample is the 
primary sample or the back-up sample. 
 
One copy of this Pharmacokinetic Study Form should be should be uploaded into RAVE. A second copy should be sent with the 
samples to the lab at the address listed in the PK Lab Manual provided by Exelixis. Refer to PK Lab Manual for detailed 
guidelines for packaging and shipping PK samples. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date: _________________________ 


                                
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APPENDIX VI: PREGNANCY INFORMATION FORM 
 
Attach to CTEP-AERS 5-Day Report 
 
NOTE: For initial reporting, fax both the Pregnancy CTEP-AERS Report and this additional Pregnancy Information 
Form. For follow-up reporting, fax only this Pregnancy Information Form (See Section 13.7). Copies of all documents 
that are faxed to the NCI during initial and follow-up reporting must also be sent via email to the ADVL1211 COG Study 
Assigned Research Coordinator.   


                                
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APPENDIX VII:  URINE PROTEIN TO CREATININE (UPC) RATIO 
 
 
Clinical Meaning of UPC 
There is a good correlation between the ratio of urine protein to creatinine concentrations (UPC) in a random 
urine sample and the amount of protein excreted in a 24-hour urine collection period.18 Thus, the UPC 
allows for an estimation of the 24-hour urine protein excretion from a random sample.  The creatinine 
excretion is fairly constant throughout the day regardless of changes in urine flow rate: 
• 
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day 
• 
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day 
• 
Normal protein excretion is <100 mg to 150 mg per 24 hours. 
• 
The UPC ratio is roughly equal to the 24 hour urine protein excretion in g/day 
 
 
Calculating UPC Ratio 
UPC ratio = (Urine protein [mg/dL]) / (urine creatinine [mg/dL]) = numerically equivalent to grams (g) 
protein excreted in urine over 24 hours.  
 
Example:  If a subject has a urine protein of 90 mg/dL and urine creatinine of 30 mg/dL,   
then UPC ratio =  
90 (mg/dL)  = 3 
30 (mg/dL) 
Result UPC is 3 correlating to roughly 3g of protein excretion in a 24-hour period. 
 
 
Units for UPC ratio 
UPC is a calculated ratio. The guidelines in the protocol are based on having urine protein and urine 
creatinine measured in the same units (e.g., mg/dL). The SI units for urine protein and urine creatinine are 
not the same, so these must be converted to mg/dL before calculating the ratio.  For reference, the 
conversion factors for commonly used units for protein and creatinine are provided below. 
 
Starting units 
Conversion to mg/dL 
Protein (g/L) 
Multiply by 100 
Creatinine (mol/L) 
Divide by 88.4 
Creatinine (mmol/L) 
Multiply by 11.3 


 
                                
 
 
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APPENDIX VIII: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT PERCENTILE 
 
 
Blood pressure (BP) levels for BOYS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) Percentile 
5th 
10th 
25th 50th 
75th 90th 95th 5th 
10th 25th 50th 75th 
90th 95th 
1 
95th 
98 
99 
101 
103 
104 
106 
106 
54 
54 
55 
56 
57 
58 
58 
2 
95th 
101 
102 
104 
106 
108 
109 
110 
59 
59 
60 
61 
62 
63 
63 
3 
95th 
104 
105 
107 
109 
110 
112 
113 
63 
63 
64 
65 
66 
67 
67 
4 
95th 
106 
107 
109 
111 
112 
114 
115 
66 
67 
68 
69 
70 
71 
71 
5 
95th 
108 
109 
110 
112 
114 
115 
116 
69 
70 
71 
72 
73 
74 
74 
6 
95th 
109 
110 
112 
114 
115 
117 
117 
72 
72 
73 
74 
75 
76 
76 
7 
95th 
110 
111 
113 
115 
117 
118 
119 
74 
74 
75 
76 
77 
78 
78 
8 
95th 
111 
112 
114 
116 
118 
119 
120 
75 
76 
77 
78 
79 
79 
80 
9 
95th 
113 
114 
116 
118 
119 
121 
121 
76 
77 
78 
79 
80 
81 
81 
10 
95th 
115 
116 
117 
119 
121 
122 
123 
77 
78 
79 
80 
81 
81 
82 
11 
95th 
117 
118 
119 
121 
123 
124 
125 
78 
78 
79 
80 
81 
82 
82 
12 
95th 
119 
120 
122 
123 
125 
127 
127 
78 
79 
80 
81 
82 
82 
83 
13 
95th 
121 
122 
124 
126 
128 
129 
130 
79 
79 
80 
81 
82 
83 
83 
14 
95th 
124 
125 
127 
128 
130 
132 
132 
80 
80 
81 
82 
83 
84 
84 
15 
95th 
126 
127 
129 
131 
133 
134 
135 
81 
81 
82 
83 
84 
85 
85 
16 
95th 
129 
130 
132 
134 
135 
137 
137 
82 
83 
83 
84 
85 
86 
87 
≥17 
95th 
131 
132 
134 
136 
138 
139 
140 
84 
85 
86 
87 
87 
88 
89 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
4. 
See Section 5.5.1 for definition of dose limiting hypertension, Section 6.4 for management and grading of hypertension, and Section 7.7 for medical 
treatment of XL184 related hypertension.  
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS 
Vol. 114 No. 2 August 2004, pp. 555-576. 
 


 
                                
 
 
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Blood pressure (BP) levels for GIRLS  
 
 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) Percentile 
5th 
10th 
25th 50th 
75th 90th 95th 5th 
10th 25th 50th 75th 
90th 95th 
1 
95th 
100 101 
102 
104 
105 
106 
107 
56 
57 
57 
58 
59 
59 
60 
2 
95th 
102 103 
104 
105 
107 
108 
109 
61 
62 
62 
63 
64 
65 
65 
3 
95th 
104 104 
105 
107 
108 
109 
110 
65 
66 
66 
67 
68 
68 
69 
4 
95th 
105 106 
107 
108 
110 
111 
112 
68 
68 
69 
70 
71 
71 
72 
5 
95th 
107 107 
108 
110 
111 
112 
113 
70 
71 
71 
72 
73 
73 
74 
6 
95th 
108 109 
110 
111 
113 
114 
115 
72 
72 
73 
74 
74 
75 
76 
7 
95th 
110 111 
112 
113 
115 
116 
116 
73 
74 
74 
75 
76 
76 
77 
8 
95th 
112 112 
114 
115 
116 
118 
118 
75 
75 
75 
76 
77 
78 
78 
9 
95th 
114 114 
115 
117 
118 
119 
120 
76 
76 
76 
77 
78 
79 
79 
10 
95th 
116 116 
117 
119 
120 
121 
122 
77 
77 
77 
78 
79 
80 
80 
11 
95th 
118 118 
119 
121 
122 
123 
124 
78 
78 
78 
79 
80 
81 
81 
12 
95th 
119 120 
121 
123 
124 
125 
126 
79 
79 
79 
80 
81 
82 
82 
13 
95th 
121 122 
123 
124 
126 
127 
128 
80 
80 
80 
81 
82 
83 
83 
14 
95th 
123 123 
125 
126 
127 
129 
129 
81 
81 
81 
82 
83 
84 
84 
15 
95th 
124 125 
126 
127 
129 
130 
131 
82 
82 
82 
83 
84 
85 
85 
16 
95th 
125 126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
≥17 
95th 
125 126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
4. 
See Section 5.5.1 for definition of dose limiting hypertension, Section 6.4 for management and grading of hypertension, and Section 7.7 for medical 
treatment of XL184 related hypertension.  
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” PEDIATRICS 
Vol. 114 No. 2 August 2004, pp. 555-576.


                                
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Page 87 
APPENDIX IX:  CYP3A4 INDUCERS AND INHIBITORS 
 
The use of the following medications should be discontinued prior to initiation of protocol therapy and 
should be avoided during protocol therapy if reasonable alternatives exist. This is not an inclusive list; 
please refer to other resources such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx for additional 
information. 
 
Strong 
Inhibitors 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Other 
Inhibitors 
Inducers 
Clarithromycin 
Indinavir 
Itraconazole 
Ketoconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telithromycin 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Grapefruit 
Grapefruit juice 
Verapamil 
Cimetidine 
Amiodarone 
Bocepravir 
Chloramphenicol 
Ciprofloxacin 
Delaviridine 
Fluvoxamine 
Imatinib 
Mifepristone 
Norfloxacin 
Norfluoxetine 
(fluoxetine) 
Star fruit 
Telaprevir 
Voriconazole 
Barbiturates 
Carbamazepine 
Efavirenz 
Glucocorticoids* 
Modanfinil 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
 
       * Refer to Section 7.5 regarding use of corticosteroids. 
 
 


                                
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Page 88 
APPENDIX X: PHARMACODYNAMIC/BIOMARKER STUDY FORM 
 
COG Pt ID # _______________ 
ACC # _______________ 
 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|  
 
  Body Surface Area: ______m2 
 
 
Dose Level: _______mg/m2 
Total Weekly Dose per Nomogram: ______mg 
 
 
NOTE: To be accessioned for Exelixis. 
 
Blood samples (5 mL each) will be obtained at baseline and prior to dose on Day 1, Day 21 (± 2 days) and 
Day 28 (± 2 days) of Cycle 1. Record the exact date and time each sample is drawn.  
Blood 
Sample 
No. 
Barcode # 
(from Sample 
Label) 
Time Point 
Scheduled Collection Time 
Actual Date 
Sample 
Collected 
Actual Time 
Sample 
Collected 
1 
 
Baseline/Pre-Study 
Prior to first dose on Day 1 
___/___/___ |__|__| : |__|__| 
2 
 
Cycle 1, Day 1 
Prior to first dose on Day 1* 
___/___/___ |__|__| : |__|__| 
3 
 
Cycle 1, Day 21 (± 2) Prior to dose on Day 21 (± 2)* 
___/___/___ |__|__| : |__|__| 
4 
 
Cycle 1, Day 28 (± 2) Prior to dose on Day 28 (± 2)* 
___/___/___ |__|__| : |__|__| 
 
* Blood samples should be drawn within 1 hour prior to dose. 
 
Sample Processing Procedures- Refer to PD Lab Manual for additional details 
1. Draw 5 mL of whole blood into a pre-labeled 6-mL Vacutainer tube (refer to PD Kit provided by 
Exelixis). 
2. Invert the collection tube gently at least 5 times. 
3. Within 30 minutes of collection, separate the plasma fraction by centrifugation (1200 × g for 10 
minutes). A refrigerated centrifuge is preferred, and if available, should be set to 4°C.  
4. Transfer the plasma to a 15 mL polypropylene tube and mix gently and thoroughly with a pipette. 
Be sure to avoid aspiration of cellular material near the buffy coat. Aliquot 0.5 mL into each of the 
4 pre-labeled 1.2-mL cryovials. Distribute any extra plasma evenly between the vials. 
5. Freeze plasma samples immediately (-70°C or colder). The samples must be stored on dry ice if a 
freezer is not immediately available. 
 
Sample Shipping Procedures- Refer to Appendix XII for sample shipping guidelines. 
 
 
One copy of this Biomarker Study Form should be should be uploaded into RAVE. A second copy should be sent with the samples 
to the lab at the address listed in Appendix XII. Refer to Pharmacodynamic Lab Manual provided by Exelixis for additional 
details. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form 
below: 
 
Signature: ______________________________________________                    Date: __________________________ 


                                
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APPENDIX XI:  TISSUE STUDY FORM  
 
COG Pt ID # _____________   ACC # _______________ Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Body Surface Area: ______m2  
Dose Level: ______mg/m2 
 
   
NOTE: To be accessioned for Exelixis. 
 
Tumor Sample Labeling: 
Samples should be labeled with the following information: 
 
Protocol number: ADVL1211 
Institution:        _________________ 
Patient ID #:     _________________ 
Accession #:     _________________ 
Sample Date:    _________________ 
Site of Acquired Tissue:  __________________ 
Number of Slides:  __________________ 
Barcode # :  __________________ 
(from Sample Label provided by Exelixis) 
 
Tissue obtained at (check one option below): 
Diagnosis      Relapse 
 
Tumor Tissue: 
Archival tumor tissue slides (10-15 unstained slides approximately 5 micron thickness on positively 
charged glass slides) from a formalin-fixed, paraffin-embedded tumor block will be shipped at room 
temperature .  
 
Fill two to three 5-place slide containers with the slides and label each container with a Pharmacodynamics 
Sample Label (provided by Exelixis). Please indicate above the date of the sample, site of tissue acquisition 
and whether it was obtained at diagnosis or relapse. One copy of this form should be uploaded into RAVE.  
 
Shipping Procedures- Refer to Appendix XII for sample shipping guidelines. 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and 
date this form below: 
 
Signature: ___________________________________________             Date:______________________ 
 
 
(site personnel who collected samples) 


                                
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APPENDIX XII:  PACKAGING AND SHIPPING INSTRUCTIONS FOR 
PHARMACODYNAMIC AND ARCHIVAL TISSUE SAMPLES 
 
Packaging Instructions:  
1. Shipments should be scheduled after all samples have been collected from at least one subject. 
Samples may be batched for shipment after the end of cycle. 
2. Once the pharmacodynamic and tissue samples are collected, the Pharmacodynamic Biomarker 
and Tumor Tissue CRFs and corresponding Study Forms (Appx X-XI) should be completed and 
uploaded into RAVE. An email notification must then be sent to the Study Research Coordinator. 
The Study Research Coordinator will notify each site when the shipment may proceed. 
3. Shipment of Plasma Samples 
a. Place the tubes into a sealable plastic bag (one subject per bag) surrounded by absorbent 
material.  
b. Place the plastic bags into a suitable Styrofoam shipping container (e.g., ThermoSafe) 
and fill with enough dry ice for 2 days in transit (e.g., 8 pounds). 
4. Shipment of Archival Tumor samples 
a. Make sure the microscope slide holders are properly labeled and taped closed. Surround 
the slide holders with packing material such as bubble wrap and pack into a shipping box 
such that the samples cannot move. 
5. The shipping address is:  
Covance Biorepository  Services 
Attn: Juan Rivera – Biorepository/LTS Building 210 
671 South Meridian Road 
Greenfield, Indiana, 46140 
(317) 467-7585 
 
Include a copy of Pharmacodynamic/Biomarker Study Form (Appendix X) and Tissue Study 
Form (Appendix XI) along with the sample shipment. 
 
  
Please DO NOT ship samples on a Thursday or Friday, or within 2 days of holiday. 


                                
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APPENDIX XIII:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED 
NON-ENZYME INDUCING ANTICONVULSANTS 
 
 
 
 
 
 
 
Recommended Non-enzyme inducing 
anticonvulsants 
 
Generic Name 
Trade Name 
Gabapentin 
Neurontin 
Lamotrigine 
Lamictal 
Levetiracetam  
Keppra 
Tigabine 
Gabitril 
Topiramate 
Topamax 
Valproic Acid 
Depakote, Depakene 
Zonisamide 
Zonegran 
 
Unacceptable Enzyme inducing anticonvulsants 
 
Generic Name 
Trade Name 
Carbamazepine 
Tegretol 
Felbamate 
Felbatol 
Phenobarbital 
Phenobarbital 
Phenytoin 
Dilantin 
Primidone 
Mysoline 
Oxcarbazepine 
Trileptal 
 


                                
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APPENDIX XIV:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
Each family will be instructed to have antidiarrheal medication available and begin treatment at the first 
episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than 
normally expected for the patient. Patients will also be instructed to contact their physician if any diarrhea 
occurs. Patients will be given loperamide based on body weight. The doses and schedules for loperamide 
included here are higher than the standard but consistent with COG protocols D9802, P9761, ARST0121, 
and ADVL0918. 
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any notable increase in the number of bowel movements over what is normal for him/her, begin taking 
loperamide (Imodium).  
 
Please follow these directions carefully, using dosing guidelines below: 
• 
Take _____________  at the first sign of diarrhea. 
• Continue taking __________ every 2 hours until the diarrhea slows or the normal pattern of 
bowel movements returns. Repeat the same doses and frequency if the diarrhea returns. 
• Do not exceed ___________ in a 24 hour period. 
• Please call your doctor if you have any questions about taking loperamide, if your child's diarrhea 
is not under control after two days, or if he/she is feeling extremely weak, lightheaded, or dizzy. 
• Make an extra effort to give your child lots of fluids (several glasses of pedialyte, fruit juices, 
soda, soup, etc.) while your child is participating in this study. 
• Side effects may include tiredness, drowsiness or dizziness. If your child experiences these side 
effects, or if your child is urinating less frequently than usual, please contact your child's 
physician. 
• 
Do not give your child any laxatives without consulting with his/her physician. 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                
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LOPERAMIDE DOSING RECOMMENDATIONS 
(NOTE: maximum dose of loperamide for adults is 16 mg/day) 
ALL patients: discontinue loperamide when the patient is no longer experiencing significant diarrhea. 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (one-half teaspoonful of the 1 mg/5 mL oral solution) after the first 
loose bowel movement, followed by 0.5 mg (one-half teaspoonful of the 1 mg/5 
mL oral solution) every 3 hours.  During the night, the patient may take 0.5 mg 
(one-half teaspoonful of the 1 mg/5 mL oral solution) every 4 hours.  Do not 
exceed 4 mg per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (1 teaspoonful of the 1 mg/5 mL oral solution or one-half capsule or 
tablet) after the first loose bowel movement, followed by 1 mg (one teaspoonful 
of the 1 mg/5 mL oral solution) every 3 hours. During the night, the patient may 
take 1 mg (one teaspoonful of the 1 mg/5 mL oral solution) every 4 hours.  Do not 
exceed 6 mg per day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 capsule or tablet) 
after the first loose bowel movement, followed by 1 mg (one teaspoonful of the 1 
mg/5 mL oral solution or one-half capsule or tablet) every 3 hours.  During the 
night, the patient may take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 
1 caplet) every 4 hours. Do not exceed 8 mg per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 1 capsule or tablet) 
after the first loose bowel movement, followed by 1 mg (one teaspoonful of the 1 
mg/5 mL oral solution or one-half capsule or tablet) every 2 hours.  During the 
night, the patient may take 2 mg (2 teaspoonfuls of the 1 mg/5 mL oral solution or 
1 capsule or tablet) every 4 hours. Do not exceed 12 mg per day. 
 
Over 43 kg 
Take 4 mg (4 teaspoonfuls of the 1 mg/5 mL oral solution or 2 capsules or tablets) 
after the first loose bowel movement, followed by 2 mg (2 teaspoonfuls of the 1 
mg/5 mL oral solution or 1 capsule or tablet) every 2 hours.  During the night, the 
patient may take 4 mg (4 teaspoonfuls of the 1 mg/5 mL oral solution or 2 capsules 
or tablets) every 4 hours. Do not exceed 16 mg per day. 
 
 


                                
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APPENDIX XV:  MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
 
For the most current list of medications, please refer to the following website: www.torsades.org. 
 
1.  Medications that prolong QTc  
Generic name 
Brand name 
 
Generic name 
Brand name 
Amiodarone 
Cordarone® 
 
Haloperidol 
Haldol® 
Arsenic trioxide 
Trisenox® 
 
Ibutilide 
Corvert® 
Astemizole 
Hismanal® 
 
Mesoridazine 
Serentil® 
Azithromycin 
Zithromax® 
 
Methadone 
Dolophine® 
Bepridil 
Vascor® 
 
Moxifloxacin 
Avelox® 
Chloroquine 
Aralen® 
 
Pentamidine 
Pentam® 
Chlorpromazine 
Thorazine® 
 
Pimozide 
Orap® 
Clarithromycin 
Biaxin® 
 
Probucol 
Lorelco® 
Disopyramide 
Norpace® 
 
Procainamide 
Procan® 
Dofetilide 
Tikosyn® 
 
Quinidine 
Quinaglute® 
Domperidone 
Motilium® 
 
Sotalol 
Betapace® 
Droperidol 
Inapsine® 
 
Sparfloxacin 
Zagam® 
Erythromycin 
Erythrocin® 
 
Terfenadine 
Seldane® 
Flecainide 
Tambocor® 
 
Thioridazine 
Mellaril® 
Halofantrine 
Halfan® 
 
Vandetanib 
Caprelsa® 
 
2. Medications that may prolong QTc 
Generic name 
Trade name 
 
Generic name 
Trade name 
Alfuzosin 
Uroxatral® 
 
Moexipril/HCTZ 
Uniretic® 
Amantadine 
Symmetrel® 
 
Nicardipine 
Cardene® 
Atazanavir 
Reyataz® 
 
Nilotinib 
Tasigna® 
Chloral hydrate 
Noctec® 
 
Octreotide 
Sandostatin® 
Clozapine 
Clozaril® 
 
Ofloxacin 
Floxin® 
Dolasetron 
Anzemet® 
 
Ondansetron 
Zofran® 
Dronedarone 
Multaq® 
 
Oxytocin 
Pitocin® 
Eribulin 
Halaven® 
 
Paliperidone 
Invega® 
Escitalopram 
Cipralex® 
 
Quetiapine 
Seroquel® 
Escitalopram 
Lexapro® 
 
Ranolazine 
Ranexa® 
Famotidine 
Pepcid® 
 
Risperidone 
Risperdal® 
Felbamate 
Felbatrol® 
 
Roxithromycin 
Rulide® 
Fingolimod 
Gilenya® 
 
Sertindole 
Serdolect® 
Foscarnet 
Foscavir® 
 
Sertindole 
Serlect® 
Fosphenytoin 
Cerebyx® 
 
Sunitinib 
Sutent® 
Gemifloxacin 
Factive® 
 
Tacrolimus 
Prograf® 
Granisetron 
Kytril® 
 
Tamoxifen 
Nolvadex® 
Iloperidone 
Fanapt® 
 
Telithromycin 
Ketek® 
Indapamide 
Lozol® 
 
Tizanidine 
Zanaflex® 
Isradipine 
Dynacirc® 
 
Vardenafil 
Levitra® 
Lapatinib 
Tykerb® 
 
Venlafaxine 
Effexor® 
Levofloxacin 
Levaquin® 
 
Voriconazole 
VFend® 
Lithium 
Lithobid® 
 
Ziprasidone 
Geodon® 
 
 
 


                                
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APPENDIX XVI: CTEP AND CTSU REGISTRATION PROCEDURES 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type 
of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the table 
below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI 
Biosketch 
(education, 
training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all 
clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the RCR Help 
Desk by email at < RCRHelpDesk@nih.gov >. 
 
 
 


                                
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CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and 
submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria 
including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required 
to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB 
approval information is received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager 
to indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then communicated 
to the CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the Signatory Institution are 
participating in the study. 
 
Requirements for ADVL1211 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-signed 
CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
For applicable studies with a radiation and/or imaging (RTI) component, the enrolling site must be 
aligned to a RTI provider.  To manage provider associations access the Provider Association tab on 
the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove 
associated providers.  Sites must be linked to at least one IROC credentialed provider to participate on 
trials with an RT component. Enrolling sites are responsible for ensuring that the appropriate 
agreements are in place with their RTI provider, and that appropriate IRB approvals are in place.   
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab →Regulatory 


                                
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Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 in order to receive further instruction and support.