Phase 2 Trial of XL184 (Cabozantinib) an Oral Small-Molecule Inhibitor of Multiple Kinases, in Children and Young Adults With Refractory Sarcomas, Wilms Tumor, and Other Rare Tumors
Phase: PHASE2
Conditions: Adrenal Cortical Carcinoma, Alveolar Soft Part Sarcoma, Central Nervous System Neoplasm, Childhood Clear Cell Sarcoma of Soft Tissue, Clear Cell Sarcoma of Soft Tissue, Ewing Sarcoma, Hepatoblastoma, Hepatocellular Carcinoma, Osteosarcoma, Recurrent Adrenal Cortical Carcinoma, Recurrent Alveolar Soft Part Sarcoma, Recurrent Clear Cell Sarcoma of Soft Tissue, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Hepatocellular Carcinoma, Recurrent Kidney Wilms Tumor, Recurrent Malignant Solid Neoplasm, Recurrent Osteosarcoma, Recurrent Primary Malignant Central Nervous System Neoplasm, Recurrent Renal Cell Carcinoma, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent Thyroid Gland Medullary Carcinoma, Refractory Adrenal Cortical Carcinoma, Refractory Alveolar Soft Part Sarcoma, Refractory Clear Cell Sarcoma of Soft Tissue, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Hepatocellular Carcinoma, Refractory Malignant Solid Neoplasm, Refractory Osteosarcoma, Refractory Primary Central Nervous System Neoplasm, Refractory Primary Malignant Central Nervous System Neoplasm, Refractory Renal Cell Carcinoma, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory Thyroid Gland Medullary Carcinoma, Refractory Wilms Tumor, Renal Cell Carcinoma, Rhabdomyosarcoma, Soft Tissue Sarcoma, Solid Neoplasm, Thyroid Gland Medullary Carcinoma, Wilms Tumor
Sponsor: National Cancer Institute (NCI)

Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@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 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
 
 
 
 
Page i 
 
April 16, 2019 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Please find attached Amendment #3 to ADVL1622, A Phase 2 Trial of XL184 
(Cabozantinib) an Oral Small-Molecule Inhibitor of Multiple Kinases, in Children and 
Young Adults with Refractory Sarcomas, Wilms Tumor, and Other Rare Tumors. 
 
The protocol and ICD have been amended in response to an RRA received from Dr. John 
J. Wright due to the release of new XL184 toxicity information. 
 
Please contact us if you have any further questions. 
 
 
Sincerely, 
 
Alina Stout, Protocol Coordinator for 
Srivandana Akshintala MBBS, MPH, ADVL1622 Study Chair, and 
Brenda Weigel, MD, PI, PEP-CTN 
 
 
 

 
 
ADVL1622 
 
Version Date: 04/16/19 
 
 
Page ii 
SUMMARY OF CHANGES 
 
The following specific revisions have been made to the protocol and ICD. Additions are 
in boldfaced font and deletions in strikethrough font.  
 
I. 
PROTOCOL CHANGES:  
 
# 
Section 
Comments 
1. 
Title Page 
The version date has been updated. 
 
The amendment number has been updated.  
 
2. 
6.1 
The XL184 CAEPR has been updated per the guidelines in the RRA.  
 
 
II. 
ICD CHANGES:  
 
# 
Section 
Comments 
3. 
General 
The version date has been updated.  
4. 
“What side 
effects…?” 
The XL184 risk language has been updated per the guidelines in the RRA.  
 
The XL184 toxicity list has been updated per the guidelines in the RRA.  
 
 

 
Page 1 
 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ADVL1622 
 
 
Phase 2 Trial of XL184 (Cabozantinib) an Oral Small-Molecule Inhibitor of Multiple  
Kinases, in Children and Young Adults with Refractory Sarcomas, Wilms Tumor, and Other Rare 
Tumors 
 
 
 
An Intergroup NCTN Phase 2 Study 
 
NCI Supplied Agent: XL184 (cabozantinib, NSC# 761968)  
 
IND Sponsor for XL184: DCTD, NCI 
 
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 
 
Srivandana Akshintala MBBS, MPH  
The Stephen D. Hassenfeld Children's Center for Cancer and 
Blood Disorders  
160 East 32nd Street, 2nd Floor 
New York, NY 10016 
Phone: (212) 263-0188 
Fax: 
(212) 263-8410 
E-mail: srivandana.akshintala@nyumc.org  
 
 
 
For Statistics and Data Center Contact Person see:  http://members.childrensoncologygroup.org 
 
Activated: 
05/08/17      
Version Date: 
04/16/19 
Closed: 
      
Amendment #: 
3 

  
 
ADVL1622 
 
Version Date: 04/16/19 
 
 
Page 2 
 
 
Participating Organizations 
 
COG / Children's Oncology Group 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
 
NRG / NRG Oncology  
 
SWOG / SWOG 
 
 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
Data Submission Schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and 
password. Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 

  
 
ADVL1622 
 
Version Date: 04/16/19 
 
 
Page 3 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 
 
 
 
 
 
 

  
 
ADVL1622 
Version Date: 04/16/19 
 
 
Page 4 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
7 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Aim 
11 
1.2 
Secondary Aims 
11 
1.3 
Exploratory Aims 
11 
2.0 
BACKGROUND 
12 
2.1 
Rationale for Development 
12 
2.2 
Preclinical Studies 
12 
2.3 
Adult Studies 
15 
2.4 
Pediatric Studies 
17 
2.5 
Pneumothorax 
18 
2.6 
Overview of Proposed Pediatric Phase 2 Trial 
19 
2.7 
Rationale for Inclusion of Osteosarcoma Cohort (Amendment #1) 
20 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
20 
3.1 
Study Enrollment 
20 
3.2 
Eligibility: Inclusion Criteria 
24 
3.3 
Eligibility: Exclusion Criteria 
28 
3.4 
Regulatory 
30 
4.0 
TREATMENT PROGRAM 
31 
4.1 
Overview of Treatment Plan 
31 
4.2 
Cycle 1 
34 
4.3 
Cycles 2 & 3 
37 
4.4 
All Subsequent Cycles 
40 
5.0 
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY 
43 
5.1 
Definition of Dose-Limiting Toxicity (DLT) 
43 
5.2 
Dose Modifications for Hematological Toxicity 
44 
5.3 
Dose Modifications for Non-Hematological Toxicity 
44 
5.4 
Dose Modifications for Proteinuria 
45 
5.5 
Dose Modifications for Hypertension 
45 
5.6 
Dose Modifications for Thromboembolic Events 
48 
5.7 
Dose Modifications for Liver Toxicity 
48 
5.8 
Dose Modifications for Pancreatic Toxicity 
48 
5.9 
Dose Modifications for Diarrhea 
48 
5.10 
Monitoring for Specific Toxicities 
49 
5.11 
XL184 Dose Reduction Table 
51 
6.0 
DRUG INFORMATION 
52 
6.1 
XL184 
52 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
59 
7.1 
End of Therapy& Follow-up 
59 
7.2 
Correlative Biology Studies 
60 
7.3 
Central Review 
64 

  
 
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Page 5 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
64 
8.1 
Criteria for Removal From Protocol Therapy 
64 
8.2 
Off Study Criteria 
65 
9.0 
STATISTICAL CONSIDERATIONS 
66 
9.1 
Sample Size and Study Duration 
66 
9.2 
Study Design 
67 
9.3 
Methods of Analysis 
69 
9.4 
Evaluability for Response 
71 
9.5 
Evaluability for Toxicity 
71 
9.6 
Evaluability for Pharmacokinetic Analysis 
71 
9.7 
Gender and Minority Accrual Estimates 
72 
9.8 
Analysis of the Pharmacokinetic Parameters 
72 
9.9 
Analysis of Biological and Correlative Endpoints 
73 
10.0 
EVALUATION CRITERIA 
73 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
73 
10.2 
Response Criteria 
73 
10.3 
Response Criteria for Patients with Solid Tumors (non-CNS) 
73 
10.4 
Response Criteria for Neuroblastoma Patients with 123I-MIBG Positive Lesions 
74 
10.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
76 
10.6 
Best Response (Solid Tumors) 
76 
10.7 
Response Criteria for Patients with CNS Tumors 
77 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
78 
11.1 
Purpose 
78 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
79 
11.3 
Specific Examples for Expedited Reporting 
79 
11.4 
Reporting Requirements for Specialized AEs 
81 
11.5 
Exceptions to Expedited Reporting 
82 
11.6 
Reporting Requirements - Investigator Responsibility 
82 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
82 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies 
84 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
85 
11.10 Routine Reporting of Adverse Events 
85 
12.0 
STUDY REPORTING AND MONITORING 
85 
12.1 
CDUS 
85 
12.2 
Data and Safety Monitoring Committee 
85 
12.3 
CRADA/CTA 
85 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
88 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
90 
APPENDIX III:  XL184 PATIENT DIARY 
92 
APPENDIX IV: XL184 DOSING NOMOGRAM 
95 
APPENDIX V:  BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE 
96 
APPENDIX VI: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
98 
APPENDIX VII:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-ENZYME 
INDUCING ANTICONVULSANTS 
100 

  
 
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APPENDIX VIII: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
101 
APPENDIX IX: YOUTH INFORMATION SHEETS 
102 
APPENDIX X: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
104 
APPENDIX XI: TOXICITY-SPECIFIC GRADING 
106 
REFERENCES 
107 
 

  
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Page 7 
 
STUDY COMMITTEE 
STUDY CHAIR 
AeRang Kim, M.D. 
Srivandana Akshintala MBBS, MPH  
Hematology/Oncology 
Hematology/Oncology 
Children’s National Medical Center 
The Stephen D. Hassenfeld Children's Center  
111 Michigan Avenue, N.W. 
160 East 32nd Street, 2nd Floor 
Washington, DC 20010 
New York, NY 10016 
Phone: (202) 476-4744 
Phone: (212) 263-0188 
Fax: 
(202) 476-5685 
Fax: 
(212) 263-8410 
E-mail: aekim@childrensnational.org 
E-mail: srivandana.akshintala@nyumc.org 
 
 
Emily Dunn Stern, R.N., BSN, CPON, CCRP 
STUDY VICE CHAIR 
Nursing 
Brigitte C. Widemann, M.D.  
Children’s National Medical Center 
Hematology Oncology 
111 Michigan Avenue, N.W. 
National Institutes of Health Clinical Center 
Washington, DC 20010 
10 Center Dr. 10-CRC, Rm 1-5750 MSC 1101 
Phone: (202) 476-2802 
Bethesda, MD 20892 
Fax: 
(202) 476-2021 
Phone: (301) 496-7387  
E-mail: estern@childrensnational.org 
Fax: 
(301) 480-8871 
 
E-mail: widemanb@mail.nih.gov 
Gina Martin, BSN 
 
Clinical Research Associate 
STUDY STATISTICIAN 
Washington University School of Medicine 
Donald A. Barkauskas, Ph.D.  
1 Children’s Place, 9 South 
Biostatistics 
St. Louis, MO 63110 
222 E. Huntington Drive, Suite 100 
Phone: (314) 454-6018  
Monrovia, CA 91016 
Fax: 
(314) 454-2780 
Phone: (626) 241-1540  
E-mail: martin_g@kids.wustl.edu 
Fax: 
(626) 445-4334 
 
E-mail: dbarkauskas@childrensoncologygroup.org 
Joel Reid, Ph.D. 
 
Pharmacology 
STUDY COMMITTEE MEMBERS 
Mayo Clinic 
Brenda J. Weigel, M.D. 
17-42C Guggenheim Building 
Hematology/Oncology 
200 First Street SW 
University of Minnesota /Masonic Cancer Center 
Rochester, MN 55905 
420 Delaware Street, SE MMC 366 
Phone: (507) 284-0822 
Minneapolis, MN 55455 
Fax: 
(507) 284-3906 
Phone: (612) 626-5501 
E-mail: reid.joel@mayo.edu 
Fax: 
(612) 624-3913 
 
E-mail: weige007@umn.edu 
Stephan D. Voss, M.D. 
 
Diagnostic Imaging 
Elizabeth Fox, M.D.  
Dana-Farber/Harvard Cancer Center 
Hematology/Oncology 
300 Longwood Avenue 
Children’s Hospital of Philadelphia 
Boston, MA 2115 
3501 Civic Center Blvd., CTRB-4016 
Phone: (617) 355-8377 
Philadelphia, PA 19104 
Fax: 
(617) 730-0573 
Phone: (267) 425-3010  
Email: stephan.voss@childrens.harvard.edu 
Fax: 
(267) 425-0113 
 
E-mail: foxe@email.chop.edu 
 
 
 

  
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Page 8 
STUDY PHARMACIST 
ALLIANCE NCTN STUDY CHAMPION 
Olga Militano, PharmD 
Gary K. Schwartz, MD 
Children’s Oncology Group 
Columbia University/Herbert Irving Cancer Center 
222 E. Huntington Drive, Suite 100 
Division of Medical Oncology 
Monrovia, CA 91016 
177 Fort Washington Ave, 6GN-435 Milstein Hospital 
Phone: (626) 241-1517 
New York, NY 10032 US 
Fax: 
(626) 445-4334 
Phone: (212) 305-8615 
E-mail: omilitano@childrensoncologygroup.org 
Email: gks2123@columbia.edu 
 
 
COG OPERATIONS STAFF 
PROTOCOL COORDINATOR 
RESEARCH COORDINATOR 
Alina Stout, BS 
Lorraine Sarmiento, MHA 
Children’s Oncology Group – Operations Center 
Children’s Oncology Group – Operations Center 
222 E. Huntington Drive, Suite 100 
222 E. Huntington Drive, Suite 100 
Monrovia, CA 91016 
Monrovia, CA 91016 
Phone: (626) 241-1566 
Phone: (626) 241-1755 
Fax: 
(626) 445-4334 
Fax: 
(626) 445-4334 
E-mail: astout@childrensoncologygroup.org 
E-mail: lsarmiento@childrensoncologygroup.org 
 
 
MASTER STATISTICIAN 
 
Xiaowei Liu, M.S. 
 
Children’s Oncology Group – Operations Center 
 
222 E. Huntington Drive, Suite 100 
 
Monrovia, CA  91016 
 
Phone: (626) 241-1535 
 
Fax: 
(626) 445-4334 
 
E-mail: xwliu@childrensoncologygroup.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AGENT 
 
XL184 (cabozantinib, NSC# 761968) 
 
 
 
IND Sponsor: NCI 
 
 
 
 
SEE SECTION 7.2 FOR SPECIMEN SHIPPING ADDRESSES 
 

  
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Page 9 
 
The Children's Oncology Group has received 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 your 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 is an oral small molecule inhibitor of multiple tyrosine kinases including MET, VEGFR2 and RET, 
which are potential therapeutic targets in many pediatric and adult solid tumors. Preclinical in vivo studies 
have shown that XL184 inhibits these kinases resulting in decreased tumor and endothelial cell 
proliferation, increased apoptosis, tumor growth inhibition, and tumor regression. XL184 is approved for 
adults with progressive, metastatic medullary thyroid carcinoma (MTC) and advanced renal cell carcinoma 
(RCC), and has shown preliminary clinical activity in glioblastoma, differentiated thyroid carcinoma, 
hepatocellular carcinoma (HCC), urothelial, endometrial, breast, and non-small cell lung cancer (NSCLC). 
In the ongoing COG/pilot consortium pediatric phase 1 trial of XL184, ADVL1211, partial responses and 
prolonged disease stabilization have been observed in several solid tumors at doses that were tolerable. 
This open label two-stage phase 2 trial includes the following solid tumor strata: Ewing sarcoma, 
rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), osteosarcoma, Wilms tumor 
(non-statistical cohort) and other rare solid tumors (non-statistical cohort). XL184 will be administered 
orally once daily on a continuous dosing schedule of 28 day cycles at a dose of 40 mg/m2/day (cumulative 
weekly dose of 280 mg/m2 using a dosing nomogram). The primary endpoint for the selected disease strata 
except osteosarcoma will be the objective response rate. We will also evaluate progression free survival 
(PFS), time to progression, overall survival, and if feasible, compare PFS to historical controls. For the 
osteosarcoma stratum, a two-stage design that incorporates dual end points of objective response based on 
RECIST criteria and treatment success as defined by stable disease for ≥ 4 months will be utilized. 
Pharmacokinetics and pharmacodynamics of XL184 in pediatric and adolescent patients will also be 
further studied. 
 
 
 

  
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Page 10 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
Off Protocol 
Therapy 
XL184* 
Cycles 5-6 
XL184* 
Evaluation 
Evaluation 
Study Entry 
Evaluation 
Progressive Disease or 
Unacceptable Toxicity 
Cycles 3-4 
XL184* 
Evaluation following 
every 3rd cycle 
Cycles 1-2 
XL184 
(Cabozantinib)* 
Off Protocol 
Therapy 
*XL184 (Cabozantinib) will be given on a continuous dosing schedule. A cycle is 28 days. 
Progressive Disease or 
Unacceptable Toxicity 

  
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Page 11 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aim 
 
1.1.1 
To determine the objective response rate (complete response + partial response) of 
XL184 in children and young adults in the following disease strata: 
• 
Ewing sarcoma   
• 
Rhabdomyosarcoma (RMS) 
• 
Non rhabdomyosarcoma soft tissue 
sarcomas (STS) including 
microphthalmia transcription factor associated STS (alveolar soft part 
sarcoma (ASPS) and clear cell sarcoma (CCS)) 
• 
Wilms tumor (non-statistical cohort) 
• 
Rare tumors (non-statistical cohort) 
o Medullary thyroid carcinoma (MTC) 
o Renal cell carcinoma (RCC) 
o Hepatocellular carcinoma (HCC) 
o Hepatoblastoma  
o Adrenocortical carcinoma 
o Pediatric solid tumors (including CNS tumors) with known 
molecular alterations in the targets of XL184 (i.e., MET 
amplification, overexpression, activating mutation, MET 
translocation, MET exon skipping mutations, activating RET 
mutations, RET rearrangement, overexpression or activation of 
AXL) 
 
1.1.2 
To estimate whether XL184 therapy either improves the disease control rate at 4 
months in patients with recurrent measurable osteosarcoma as compared to a 
historical COG experience or produces an objective response rate. 
 
1.2 
Secondary Aims 
 
1.2.1 
To further define XL184 related toxicities in pediatric, adolescent and young adult 
patients. 
 
1.2.2 
To further define XL184 pharmacokinetics in the pediatric and adolescent patients. 
 
1.2.3  To estimate 1-year time to progression, progression free survival (PFS) and overall 
survival for each stratum, and if feasible to compare to historical controls. 
 
1.3 
Exploratory Aims 
 
1.3.1 
To assess the effect of XL184 on patients’ immune cell subsets. 
 
1.3.2 
To obtain tumor tissue (snap frozen, FFPE blocks, or unstained slides) from 
diagnosis, recurrence, or both, for possible future studies. 
 

  
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Page 12 
2.0 BACKGROUND 
 
2.1 
Rationale for Development 
There is a great need for the development of novel and effective therapies for pediatric 
patients with refractory solid tumors and for tumors for which no standard therapy exists. 
XL184 is a small molecule inhibitor of multiple tyrosine kinases including MET (IC50 
8nm), VEGFR2 (IC50 2nm), RET (IC50 85nm), KIT (IC50 5nm), FLT3 (IC5011 nm) and 
TIE-2. Other recognized targets of XL184 include AXL, FMS, ROS1, TRKA, TRKB, 
TYRO3, MER, VEGFR1, and VEGFR3. XL184 has a broad spectrum of activity in vitro 
and in vivo in xenograft models that include medullary thyroid cancer, lung cancer, breast 
cancer, and glioblastoma.1,2 XL184 is approved for adults with progressive, metastatic 
MTC and advanced RCC who have received prior anti-angiogenic therapy. It has also 
shown preliminary clinical activity in glioblastoma, differentiated thyroid carcinoma, 
HCC, urothelial, endometrial, breast, and non-small cell lung cancer (NSCLC).1,3-7 There 
is a strong scientific rationale for the evaluation of XL184 in pediatric solid tumors: MET 
and its ligand HGF have been shown to be deregulated in many human cancers and 
correlate with poor prognosis.8 MET and VEGFR2 are important mediators of tumor 
growth and angiogenesis, and aberrant MET/HGF signaling pathway is particularly 
associated with tumor invasiveness and metastasis.1,9 In the ongoing COG/pilot consortium 
pediatric phase 1 trial of XL184, ADVL1211, partial responses and prolonged disease 
stabilization were observed in several solid tumor types at doses that were tolerable. This 
trial will assess the activity of XL184 in select pediatric solid tumors. 
 
2.2 
Preclinical Studies  
 
2.2.1 
Antitumor Activity 
XL184 has shown to inhibit several kinases in biochemical assays with potent 
inhibition of VEGFR2, MET (including MET with activating kinase domain 
mutations Y1248H, D1246N, or K1262R), KIT, RET, AXL, TIE2, and FLT3 
(IC50 ranging from 0.035 – 14.6 nmol/L). In cellular assays, inhibition of 
phosphorylation of MET, VEGFR2, KIT, FLT3, and AXl was noted at IC50s 
ranging from 1.9-77 nmol/L. XL184 has shown dose-dependent inhibition of 
tumor growth in a variety of xenograft models including human breast, lung, MTC, 
transgenic RIP-Tag2 model of pancreatic cancer and rat glioma.1,2  
 
MET, VEGFR, and RET are potential therapeutic targets in pediatric sarcomas, 
Wilms tumor, and other rare solid tumors. In soft tissue and bony sarcomas, tumor 
VEGF expression has been shown to positively correlate with increased tumor 
stage, tumor grade, increased risk of local and distant tumor metastasis, and lower 
overall survival.10 Over-expression of MET has been described in osteosarcoma 
and Ewing sarcoma, and MET expression has been shown to correlate with 
aggressive phenotype and poor prognosis.11-13 MET is a transcriptional target of 
PAX3 and PAX7 and MET is highly expressed in alveolar RMS cell lines.14 In 
alveolar RMS and embryonal RMS cell lines, HGF induces locomotion, 
chemotaxis, adhesion to umbilical vein and endothelial cells, trans-matrigel 
migration, matrix metalloproteinase secretion, and increased survival upon 
exposure to chemo- or radiation therapy.15 MET and HGF are highly expressed in 
malignant peripheral nerve sheath tumors (MPNST) and phosphorylated MET 
levels were shown to be of prognostic significance.16 Co-expression of HGF and 

  
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MET correlated with higher grade and poorer prognosis in synovial sarcoma tumor 
samples.17 Inhibition of MET has been shown to inhibit proliferation, survival, 
invasion, migration, anchorage independent growth, and increase apoptosis in 
osteosarcoma, RMS, and MPNST cell lines and inhibit tumor growth in xenograft 
models.11-17 Microphthalmia transcription factor associated sarcomas such as 
alveolar soft part sarcomas (ASPS) and clear cell sarcomas (CCS) are 
characterized by specific translocations leading to deregulation of microphthalmia 
transcription factor (MITF) family of proteins, which up-regulates MET 
expression.18 MET is a direct transcriptional target of TFE3-ASPL fusion protein 
that arises from the t(X;17)(p11;q25) translocation observed in all cases of ASPS 
and is highly expressed and activated in ASPS. Inhibition of MET has been shown 
to decrease cell growth in cell lines containing endogenous TFE3 fusion proteins.19 
The majority of cases of CCS have a t(12:22)(q13:q12) translocation resulting in 
the production of a chimeric transcription factor, EWS-ATF1, which activates 
MITF and leads to MET expression. MET expression was shown to be critical for 
invasion and survival in CCS cell lines and inhibition of HGF/MET pathway 
inhibited cell proliferation and viability in vitro, and suppressed tumor growth in 
xenograft models. Case reports of responses to the anti-angiogenic agents sunitinib 
and sorafenib have been described in patients with CCS, suggesting that MET and 
VEGFR are potential therapeutic targets in these tumors. 18,20 
 
Over-expression of MET has been documented in primary liver cancers such as 
hepatoblastoma and HCC.21 The β catenin pathway has been implicated in the 
development of hepatoblastoma, and MET has been shown to contribute to 
aberrant β catenin expression by wnt-independent activation in a majority of cases 
of hepatoblastoma.22 In HCC, high MET expression correlates with increased 
incidence of intra-hepatic metastasis and poor survival.23 MET inhibition has been 
shown to inhibit proliferation and induce apoptosis in MET-positive HCC cell lines 
and inhibit tumor growth in xenograft models.24 The VEGF pathway is a known 
target in RCC, and MET is a potential target particularly for pediatric RCC, as 
TFE+ RCC is now thought to account for close to 70% of pediatric RCC cases. 
TFE+ RCC is characterized by translocations involving the TFE3 gene (member 
of the microphthalmia transcription factor family) commonly found with fusion 
partners ASPL (at 17q25) or the PRCC gene (at 1q21), which leads to up-
regulation of MET as MET is a direct transcriptional target of TFE3 fusion 
proteins.19,25,26 In the Pediatric Pre-clinical Testing Program (PPTP), XL184 
demonstrated activity in Wilms tumor in-vivo xenograft models, with 2/3 cell lines 
(KT-11 and KT 13) showing complete tumor growth control at Day 21. [Personal 
communication Dr. Malcolm Smith] 
 
Expression levels of cabozantinib targets were evaluated in several indications 
using the R2 database, a genomics analysis and visualization platform 
(http://hgserver1.amc.nl/cgi-bin/r2/main.cgi, accessed September 2016 (personal 
communication Malcolm Smith)). A portion of the Ewing’s sarcoma tumor 
samples show elevated AXL, MER, MET and KIT expression and a portion of 
rhabdomyosarcoma (RMS) samples show elevated AXL, MER and KIT, 
compared to normal tissue. For renal cell carcinoma (RCC) elevated expression of 
AXL, MET and RET was observed in a subset of samples. Moreover, cabozantinib 
has been approved for adults with RCC. A large portion of the hepatoblastoma 
samples had elevated MER expression compared to normal tissue. A subset of 

  
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glioblastoma (GBM) samples, a pediatric solid tumor with CNS involvement, had 
elevated expression of AXL and MER. While two datasets for thyroid cancer were 
available, one set had a single medullary thyroid carcinoma (MTC) sample and the 
other had no MTC samples. But cabozantinib has been approved for MTC in 
adults. No normal tissue was available for hepatocellular carcinoma (HCC) or clear 
cell sarcoma (melanoma) but elevated MET levels in these indications have been 
reported previously.21,27,28 The adrenocortical carcinoma (ACC) data did not 
include normal tissue, but the MET pathway has been shown to be important in 
this malignancy and cabozantinib has shown activity in a preclinical models of 
ACC.29 In Wilms tumors, MER had higher expression in a small number of 
samples, but the Wilms tumor dataset is small (39 samples; 5 controls), so may not 
adequately represent cabozantinib-relevant targets. Cabozantinib has activity in 
Wilms tumor xenograft models (personal communication, Malcolm Smith). 
 
Based on the above extensive literature review as well as review of available on 
line databases of know potential targets of XL184, the following disease strata are 
proposed for evaluation in the phase 2 study: Ewing sarcoma, rhabdomyosarcoma 
(RMS), non-rhabdomyosarcoma soft tissue 
sarcomas 
(STS) including 
microphthalmia transcription factor associated STS (alveolar soft part sarcoma 
(ASPS) and clear cell sarcoma (CCS), osteosarcoma, Wilms tumor and rare tumors 
(medullary thyroid carcinoma (MTC), renal cell carcinoma (RCC), hepatocellular 
carcinoma (HCC), hepatoblastoma , adrenocortical carcinoma). In addition, to 
ensure that any pediatric solid tumor (including CNS tumors) with known 
molecular alterations in the targets of XL184 (i.e., MET amplification, 
overexpression, activating mutation, MET translocation, MET exon skipping 
mutations, activating RET mutations, RET rearrangement, overexpression or 
activation of AXL), a separate strata is included to allow enrollment of any tumor 
not in one of the outline strata that has documentation of the alteration from a CLIA 
certified laboratory. 
 
2.2.2 
Animal Toxicology 
The toxicity profile of XL184 was studied in mice, rats, beagle dogs, and 
cynomolgus monkeys and included single dose and repeat dose studies, 
reproductive, developmental toxicity, and genotoxicity studies. These studies 
identified GI tract, bone marrow, lymphoid tissues, reproductive tract tissues, 
endocrine tissues, kidney and skin as target tissues for XL184-related toxicity. 
Additionally, histopathologic changes were also noted in bone, central nervous 
system (CNS) tissues and liver/gall bladder. No significant adverse effects on 
neurobehavioral or respiratory function were observed in rats, or in cardiovascular 
or electrocardiographic parameters (including QTc) in dogs at plasma exposures 
(AUC values) ≥ 10-fold higher than clinically relevant plasma exposures. XL184 
associated adverse effects were generally dose-related, reversible upon 
discontinuation of the drug, and correlated with clinical findings. XL184 was 
shown to reduce fertility in both male and female rats. It was also embryotoxic in 
rats and caused fetal malformations in rats and rabbits.1  
 
2.2.3 
Preclinical Pharmacology 
In vitro metabolism and drug-drug interaction studies showed that XL184 highly 
protein bound (99.9% at 0.2 and 1 µM, and 99.7% at 10 µM). It is metabolized 
primarily by amide cleavage and demethylation or oxidation, and subsequent 

  
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sulfation. XL184 is a substrate of CYP3A4 but not an inducer of CYP1A2, 
CYP2B6, or CYP3A4.1  
 
Preclinical pharmacokinetics of a liquid aqueous formulation of XL184 studied in 
mice, rats, dogs, and monkeys showed moderate to high oral bioavailability with 
80-86% in rats, 87% in dogs, 73% in monkeys and 42-51% in mice. Oral 
bioavailability was lower with capsule formulation in dogs (18%) and monkeys 
(13%). In rats and dogs, the peak concentration (Cmax) and drug exposure (AUC) 
of XL184 increased less than dose-proportionally with increasing single oral 
doses, and generally dose-proportionally with repeat daily oral dosing. Moderate 
accumulation was noted with repeat daily dosing in rats (≤ 4-fold), however this 
was not observed in dogs (≤ 2-fold increase).1  
 
2.3 
Adult Studies 
 
2.3.1 
Adult Phase 1 Studies 
In the initial phase 1 trial of XL184 in adults with advanced solid tumors, two 
different schedules of administration and formulations of XL184 were evaluated 
in 85 patients. Dose levels studied included escalating doses of 0.08 to 11.52 mg/kg 
given on an intermittent schedule once daily for 5 days followed by 9 days rest 
with a suspension formulation, continuous fixed daily dosing of 175 or 265 mg 
with a suspension formulation, or continuous fixed daily dosing of 175 or 250 mg 
with capsule formulation (doses in salt weights). This study concluded 175 mg 
dose given continuously in capsule formulation as the maximum tolerated dose 
(MTD). Dose limiting toxicities (DLTs) included Grade 3 palmar-plantar 
erythrodysesthesia (PPE), Grade 3 aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) elevations, Grade 3 lipase elevation, and Grade 2-3 
mucositis. Most frequent treatment-related adverse effects observed (>20% of 
patients) were diarrhea, fatigue, decreased appetite, nausea, PPE, rash, increased 
AST, vomiting, and mucosal inflammation. 10/35 MTC patients had a confirmed 
objective response.4 Although the MTD in the initial phase 1 trial was 175 mg 
daily, a significant percentage of patients receiving this dose required dose-
reductions for toxicity, and lower doses were found to be better tolerated in 
subsequent trials. Doses as low as 40 mg PO daily were determined to be active 
and tolerable based on Week 6 bone scan response rate in men with castration 
resistant prostate cancer (CRPC) and bone metastasis and a dose of 60 mg PO daily 
was used in many recent single agent trials.30  
 
2.3.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
XL184 pharmacokinetics were evaluated in the phase 1 trial described above. The 
study showed dose proportional increase in Cmax and AUC. After repeat daily 
dosing, terminal half-life values was 91.3 ± 33.3 hours, and apparent steady-state 
plasma levels were reached by Day 15. Steady-state exposure (AUC) was 4-5 fold 
higher compared with day 1 exposure, suggesting accumulation with repeat daily 
dosing.4  
 
From a population pharmacokinetics (PopPK) analysis in patients with MTC who 
received repeated oral daily dosing of XL184 (cabozantinib) capsules at 140 mg, 
the predicted effective half-life of XL184 is approximately 55 hours, the oral 
volume of distribution (V/F) is approximately 349 L, and the estimated clearance 

  
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(CL/F) at steady-state is 4.4 L/h. The terminal half-life was approximately 
120 hours, median time to maximum plasma concentrations (Tmax) for XL184 was 
noted to range from 2 to 5 hours post-dose after oral administration of XL184 
(cabozantinib) capsule. Accumulation was noted with repeat dosing, with mean 
exposure 4- to 5-fold higher with daily dosing compared with a single dose 
administration and steady state was achieved by Day 15. In another PopPK 
analysis that was conducted in subjects with RCC who received repeated oral daily 
XL184 (cabozantinib) tablet dosing at 60 mg (with dose reductions to 40 mg and 
20 mg permitted per protocol) and healthy subjects who received a single oral 
XL184 tablet dose of 20, 40, or 60 mg, the predicted terminal plasma half-life of 
XL184 was approximately 99 h; the terminal phase volume of distribution (Vz) 
was approximately 319 L; and the CL/F at steady-state was estimated to be 
approximately 2.2 L/h for a white male subject. Food may interfere with XL184 
absorption and a high-fat meal was shown to increase Cmax and AUC values by 
41% and 57% respectively. XL184 is highly protein bound in human plasma 
(≥ 99.7%), is a substrate of CYP3A4 in vitro, and elimination in feces and urine 
has been noted.1,31  
 
In a phase 2 trial of XL184 in urothelial carcinoma (NCT01688999), an association 
of clinical outcome with systemic immunity was demonstrated. Patients with low 
regulatory T-cells (Treg) at baseline had an improved partial response rate and 
improved PFS, and changes in Treg PD-1 and myeloid-derived suppressor cells 
(MDSC) CD40 expression were also associated with response suggesting that they 
may serve as prognostic markers in patients with advanced urothelial carcinoma.32 
Significant associations were seen with overall survival and PFS in analysis of 
monocyte subsets, MDSC subsets, Treg subsets, effector T-cells, and Th1 and Th2 
cell populations, all analyzed by multiparameter flow cytometry, and in gene 
expression in peripheral blood, analyzed by RT-qPCR or NanoString technology 
[Personal communication with Jane Trepel]. 
 
2.3.3 
Efficacy (Phase 2 and 3 studies) 
XL184 capsules 140 mg orally once daily was approved for adults with 
progressive, metastatic MTC based on a phase 3 2:1 randomized, placebo-
controlled trial of 330 patients with metastatic medullary thyroid cancer in which 
patients in the XL184 arm had an improved median PFS of 11.2 months compared 
to 4 months for those in the placebo arm (HR 0.28, 95% CI 0.19, 0.40, p<0.001).3,6 
XL184 tablets 60 mg PO daily (free base equivalent) has also been approved for 
patients with advanced RCC who have received prior anti-angiogenic therapy, 
based on improvement in PFS in patients receiving XL184 (60 mg PO daily) 
compared to everolimus (10 mg PO daily) in a phase 3 randomized study. The 
median PFS was 7.4 months in the XL184 arm compared to 3.8 months in 
everolimus arm (HR 0.58 (95% CI: 0.45, 0.74); p<0.0001), and the median overall 
survival in the intent-to-treat population was 21.4 and 16.5 months in the XL184 
and everolimus arms respectively [HR 0.66 (95% CI: 0.53, 0.83); p=0.0003]. 
Confirmed response rate was 17% (95% CI: 13, 22) in the XL184 arm and 3% 
(95% CI: 2, 6) in the everolimus arm.7,33 XL184 has also shown preliminary 
clinical activity in early phase trials in glioblastoma, differentiated thyroid 
carcinoma, HCC, breast, and NSCLC.1,5,34,35 Ongoing adult trials include a 
randomized phase 3 trial for HCC and phase 2 trials in many cancer types including 
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and advanced solid tumors with bone metastasis. Other ongoing trials include 
combination of XL184 with panitumumab (colorectal cancer), nivolumab +/- 
ipilimumab (urothelial cancer), and traztumumab (breast cancer with brain 
metastasis). 
 
2.4 
Pediatric Studies 
 
2.4.1 
Pediatric Phase 1 Studies 
An ongoing COG/Pilot Consortium phase 1 trial (ADVL1211) of XL184 in 
pediatric patients with solid tumors is nearing completion. This trial enrolled 
patients at 3 dose levels: 30 mg/m2, 40 mg/m2, and 55 mg/m2 once daily on a 
continuous dosing schedule. In this trial, 41 patients were enrolled of whom 36 
patients were fully evaluable. Patients with a variety of solid tumors enrolled: MTC 
(n=5), osteosarcoma (n=2), Ewing sarcoma (n=4), rhabdomyosarcoma (n=2), 
other soft tissue sarcoma (n=4), Wilms tumor (n=2), hepatoblastoma (n=2), HCC 
(n=2), RCC (n=3), CNS tumors (n=9), and other (n=6). Cycle 1 DLTs were fatigue, 
headache, proteinuria, hypertension, reversible posterior leukoencephalopathy 
syndrome (RPLS), palmar-plantar erythrodysesthesia, oral mucositis, ALT 
increase, lipase increase, and bilirubin increase. The most frequent adverse events 
were increased ALT, hypertension, proteinuria, diarrhea, thrombocytopenia, 
fatigue, hypothyroidism, nausea, anorexia, palmar-plantar erythrodysesthesia, 
neutropenia, and vomiting. Based on DLTs in cycle 1 and in later cycles requiring 
dose reductions, the 40 mg/m2/day on a continuous schedule (1 cycle = 28 days) 
was determined to be the recommended phase 2 dose. This dose corresponds to an 
adult fixed dose of 72 mg/day, which is similar to the current adult recommended 
dose of 60 mg/dose/day. Based on central review, partial responses were seen in 
2/5 patients with MTC, one patient with Wilms tumor, and one patient with clear 
cell sarcoma. In addition, 7 patients experienced stable disease and received ≥ 8 
treatment cycles (1 patient each with paraganglioma, Ewing sarcoma, synovial 
sarcoma, ependymoma, and alveolar soft part sarcoma, and 2 patients with MTC). 
A CTEP sponsored phase 2 study conducted by INCA investigators in patients 
greater than 12 years of age with recurrent/relapsed osteosarcoma and Ewing 
sarcoma is also currently ongoing. 
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
Pharmacokinetics of XL184 were evaluated in the COG/Pilot Consortium phase 1 
trial (ADVL1211). A preliminary (October 2014) pharmacokinetic analysis was 
performed using available plasma concentration data from 37 subjects enrolled in 
ongoing study XL184-011 (ADVL1211). Steady state pharmacokinetics were 
analyzed in 32 patients where full set of samples were available on Cycle 1 day 
22. Drug exposure (AUC) was similar for the 3 dose levels (30 mg/m2, 40 mg/m2, 
and 55 mg/m2) evaluated with no dose proportional increase in exposure. The peak 
concentration (Cmax) was also similar across the 3 doses levels. The BSA-
normalized oral clearance appeared to be similar across the dose levels with a 
mean ± SD value of 1649 ± 754 L/h/m2 for all patients. BSA-normalized Cl/F 
values were similar in females and males (1539 ± 547 L/h/m2 versus 1835 ± 940 
L/h/m2), and were higher in children ages 12 or younger compared to older children 
(1889 ± 828 L/h/m2 versus 1533 ± 694 L/h/m2); however, this did not reach 
statistical significance (p value 0.31, Wilcoxon rank sum test). Since the 
elimination half-life could not be calculated for most patients, an accumulation 

  
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ratio was calculated from the plasma concentrations measured 4 hours after drug 
administration on day 1 and day 21. The half-life was then calculated from this 
value. The accumulation ratio was 4.3 ± 3.9 and the half-life was 66.2 ± 64.7 
hours. Estimates of the cabozantinib pharmacokinetic parameters are summarized 
below:  
 
Dose Level 
30 mg/m2/d 
40 mg/m2/d 
55 mg/m2/d 
N 
6 
16 
10 
Cmax, ng/ml 
2025 ± 658 (32%) 
1693 ± 692 (41%) 
2389 ± 802 (34%) 
Tmax, h 
5.24 ± 8.93 (170%) 
7.38 ± 8.46 (115%) 
4.7 ± 6.57 (140%) 
AUC0-24h, h*ng/ml 
32216 ± 8022 (25%) 
30010 ±10985 (37%) 38101 ± 12785 (34%) 
Cl/f, ml/h 
1621 ± 430 (26%) 
2210 ± 857 (39%) 
2307 ± 1045 (45%) 
Cl/f/m2, ml/h 
1140 ± 357 (31%) 
1809 ± 872 (48%) 
1790 ± 638 (36%) 
Accumulation Ratio 
C4hr,day21/ C4hr,day1 
5.25 ± 2.17 (41%) 
4.72 ± 5.06 (107%) 
2.82 ± 1.23 (44%) 
Accumulation 
Adjusted t1/2, h 
78.7 ± 36.3 (46%) 
79.1 ± 86.3 (109%) 
37.8 ± 20.8 (55%) 
 
In light of this PK variability observed in study ADVL1211, additional PK 
sampling is proposed for the planned Ph2 study in order to determine more reliable 
and precise PK data for cabozantinib in the pediatric population.  
 
Assays of circulating plasma markers prior to (baseline) and after administration 
of XL184 (cycle 1 day 21 and day 28) including AXL, interleukin 6, osteopontin, 
tissue inhibitor of metalloproteinase 1, carbonic anhydrase 9, HGF, sMET, PlGF, 
sVEGFR2, and erythropoietin have been completed, and the data is currently being 
analyzed. 
 
2.5 
Pneumothorax 
 
As of 7 November 2016, the following observations have been made with regards to 
pneumothorax cases in subjects exposed to cabozantinib: 
• 
Ten of the 60 patients accrued in the NCI-CTEP sarcoma trial 9620 have experienced 
Grade 1 – Grade 3 pneumothorax (16.7%). Four of the 10 patients experienced Grade 1 
or Grade 2 pneumothorax events and the remaining 6 experienced Grade 3 events. 
Overall, the median age of the 10 patients experiencing pneumothorax was 19.5 years 
(range 13-45 years), with 8 males and 2 females. Five of the 10 patients received 
cabozantinib for Ewing sarcoma and 5 for osteosarcoma.  
 
Upon review, all 10 patients had metastatic pulmonary lesions at study entry: 7 bilateral 
and 3 unilateral. Other confounding risk-factors for pneumothorax were identified in 
4 of the 10 patients: Marfanoid morphotype; post-surgical pleuro-pulmonary fistula 
following a thoracic surgery at approximately 2 months after cabozantinib 
discontinuation; prior Staph aureus pneumopathy and preexisting pleural metastases. 
All 10 patients had resolution of pneumothorax: resolution occurred in 8 patients with 
treatment that involved O2 therapy or procedures such as drain placement, silver 
nitrate/talc pleurodesis, subtotal pleurectomy and spontaneously without treatment in 
2 patients. Cabozantinib therapy was continued or restarted in 5 of the 10 patients after 
pneumothorax was resolved. 
 

  
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• 
In the cabozantinib development program, 21/2584 (0.8%) patients exposed to 
cabozantinib in unblinded, controlled and open-label, Exelixis-sponsored trials, 
irrespective of causality association, grade or seriousness, have been documented to 
have sustained one or more pneumothoraces. Seven of the 21 patients apparently 
experienced their events in association with either traumatic rib fractures or invasive 
medical procedures. In the remaining 14 patients, potential confounders were identified 
in the majority of cases and included: lung and/or mediastinal metastases (n=13), 
probable pneumonia (n=5), pleural metastases (n=4), prior history of pneumothorax 
(n=3), chronic obstructive lung disease/bullous lung disease (n=3), probable bronchial 
obstruction (n=2); and baseline cavitary lesions (n=1). 
 
• 
In the postmarketing setting, 4 cases of pneumothorax were reported with Cometriq™ 
and 0 cases with Cabometyx™. None of the cases were medically confirmed and 
information regarding diagnosis and clinical course was limited. Possible confounders 
included pneumonia in two and lung metastases in one case. 
 
2.5.1 
Published Pneumothorax Rates in Sarcoma Patients  
Information about the prevalence and the risk factors of pneumothorax in sarcoma 
patients has been limited. In the published literature, spontaneous pneumothorax 
has been described at an approximately 5% rate in untreated osteosarcoma and 
Ewing sarcoma patients with pulmonary metastases, with a high frequency of 
recurring episodes up to 30% in some series.36 Multiple reports suggest that 
therapy with anti-angiogenic agents may increase the frequency of this event, 
especially in young patients. A frequency as high as 25% has been observed in 
patients treated with a combination of sorafenib, bevacizumab and 
cyclophosphamide.37,38 Nakano and colleagues reported a pneumothorax incidence 
of 10.3% in 58 children with soft tissue sarcomas treated with pazopanib. Further, 
the maximum diameter of lung metastases ≥ 30 mm and a history of pneumothorax 
before pazopanib treatment were significantly predictive of pneumothorax in their 
study.39 Histologies associated with pneumothorax included rhabdoid tumor, 
synovial sarcoma, osteosarcoma, Ewing sarcoma, Wilms’ tumor, and renal cell 
carcinoma. Cavitation of pulmonary nodules in response to antiangiogenic therapy 
has been observed to be associated with pneumothorax.37 
 
2.6 
Overview of Proposed Pediatric Phase 2 Trial 
 
This will be an open label two-stage phase 2 trial in the following solid tumor strata: Ewing 
sarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), 
osteosarcoma, Wilms tumor (non-statistical cohort) and other rare solid tumors (non-
statistical cohort). The XL184 dose for this trial will be 40 mg/m2/day (cumulative weekly 
dose of 280 mg/m2 using a dosing nomogram), the recommended phase 2 dose determined 
from ADVL1211. XL184 will be administered orally once daily (20 and 60 mg tablets) on 
a continuous dosing schedule for cycles of 28 days with no rest period between cycles. 
Dosing will be performed based on body surface area (BSA), and rounded to the nearest 
20 mg using a dosing nomogram as used in ADVL1211. Treatment will continue until 
tumor progression or unacceptable toxicity. 
 
The primary endpoint for all non-osteosarcoma disease strata will be the objective response 
rate. In each of the statistical cohorts, 13 patients will be enrolled on the first stage. If at 
least 1 response is noted, the study will proceed to the second stage where up to an 

  
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additional 7 patients may be enrolled. If 3 or more responses are noted, the drug will be 
considered to have sufficient activity to suggest further evaluation in that strata. We will 
also evaluate PFS, time to progression, and overall survival, and if feasible, compare PFS 
to historical controls to assess if XL184 may demonstrate activity via tumor stabilization 
rather than tumor shrinkage. For the osteosarcoma stratum, a two-stage design that 
incorporates dual end points of objective response based on RECIST criteria (CR+PR) and 
treatment success as defined by stable disease for ≥ 4 months will be utilized (see section 
9.4 for details). This end point has been used in recent COG phase 2 trials for osteosarcoma 
as it is felt that tumor shrinkage may not be always be observed in bone-based lesions and 
some agents may demonstrate activity by prolonged disease stabilization. Toxicity will be 
graded using version 5.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE v5.0). Pharmacokinetics of XL184 will be further studied in pediatric and 
adolescent patients, as pharmacokinetic studies on the pediatric phase 1 trial ADVL1211 
were performed on a small sample size, and showed significant variability. To gain 
additional information on pharmacokinetics of XL184 in the pediatric population 
especially in a subpopulation of different age groups, additional pharmacokinetic studies 
will be performed on this study. The effect of XL184 on patients’ immune cells will be 
evaluated by collecting blood samples prior to and after treatment with XL184, as an 
association of clinical outcome with systemic immunity has been demonstrated in a phase 
2 trial of XL184 in urothelial carcinoma (NCT01688999). Tumor tissue (snap frozen, 
FFPE blocks, or unstained slides), if available, from diagnosis, relapse, or both, will also 
be collected for potential future studies. 
 
2.7 
Rationale for Inclusion of Osteosarcoma Cohort (Amendment #1) 
 
There is a strong biologic rationale for targeting VEGF and MET in osteosarcoma. 
Elevated tumor and circulating levels of VEGF have been shown to positively correlate 
with increased pulmonary metastasis in osteosarcoma and may be associated with worse 
prognosis10. MET overexpression has been observed in >80% of osteosarcoma tissue 
samples, and MET expression was shown to correlate with aggressive phenotype and poor 
prognosis. Overexpression of MET by lentiviral genetransfer converted human osteoblast 
cells into osteosarcomas, and tumorigenesis and transformation were abolished when MET 
expression and signaling was impaired by shRNA or dominant negative MET receptor. PF-
2341066, an orally available MET inhibitor inhibited proliferation, survival, invasion and 
clonogenecity in osteosarcoma cell lines and tumor growth and associated osteolysis and 
extracortical bone matrix formation in nude mice osteosarcoma xenograft models.12,13 
 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number.  
 
COG sites: This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been obtained. 
The COG patient ID number is used to identify the patient in all future interactions 
with COG. If you have problems with the registration, please refer to the online help. 

  
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For additional help or information, please contact the CTSU Help Desk at 1-888-
823-5923 or ctsucontact@westat.com.  
  
Non-COG sites: Fax the patient registration information (demography) to the Cancer 
Trials Support Unit (CTSU) registrar at 1-888-691-8039. Sites may notify the 
registration office of an incoming fax by calling 1888-462-3009; the office hours are 
9:00 – 5:30 pm Eastern Time, Monday – Friday. The CTSU registrar will then register 
the patient within the COG system on behalf of the institution and obtain a COG 
patient ID number. The CTSU registrar will provide the COG patient ID number to 
the site, which can then enroll the patient in the OPEN system.  
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
NOTE: In order for a COG institution to maintain COG membership requirements, 
every patient with a known or suspected neoplasm needs to be offered participation 
in APEC14B1, Project:EveryChild A Registry, Eligibility Screening, Biology and 
Outcome Study. 
 
3.1.2 
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. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I.  

  
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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. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. However, these sites must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate 
their intention to open the study locally. The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office for compliance in the RSS. The 
Signatory Institution must inform the CTSU which CIRB-approved institutions 
aligned with the Signatory Institution are participating in a given study so that the 
study approval can be applied to those institutions. Other site registration 
requirements 
(e.g., 
laboratory 
certifications, 
protocol-specific training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system. Patients must 
be enrolled within 5 calendar days of making a reservation. 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for the patient. 
Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient number. 
Click on the ‘Slot Reservation’ tab to create an OPEN patient number, under 
‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 

  
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Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under 
the ‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF  
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://ctepcore.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on 
either the lead protocol organization (LPO) or participating organization roster. 
Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org.  
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than 5 calendar days after the date of study 
enrollment. Patients who are started on protocol therapy prior to study 
enrollment will be considered ineligible and will not be able to receive further 
protocol therapy.  
 
See Section 3.2 for timing requirements for eligibility studies. Note: Repeat 
laboratory and imaging studies may be required if enrollment and start of 
therapy do not occur on the same day. 
 
3.1.6 
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 

  
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and accession numbers. Personal identifiers, including the patient’s name and 
initials must be removed from the institutional pathology report prior to 
submission.  
 
3.1.7 
Participation in Biology Studies (COG sites) 
In order to minimize the potential for non-compliance once enrolled, 
patients/guardians must be made aware that some of the biology research studies 
are mandatory and understand that a number of non-standard blood samples will 
be required.  
 
 
3.2 
Eligibility: Inclusion Criteria  
 
Important note: The inclusion criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record. These source documents must be available for verification at the time of audit.  
 
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 > 7 days old, 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, bone marrow biopsy and/or 
aspirate, if applicable, must be obtained within 2 weeks prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
3.2.1 
Age: Patients must be ≥ 2 and ≤ 30 years of age at the time of study entry for all 
strata except upper age limit of ≤ 18 years of age for MTC, RCC and HCC. 
 
3.2.2 
Body Surface Area (BSA): Patients must have a body surface area ≥ 0.35 m2.  
 
3.2.3 
Diagnosis: Patients must have recurrent or refractory disease, or newly diagnosed 
disease with no known curative therapy or therapy proven to prolong survival with 
an acceptable quality of life. Patients must have had histologic verification of one 
of the malignancies listed below at original diagnosis or at relapse. 
 
• 
Ewing sarcoma  
• 
Rhabdomyosarcoma (RMS) 
• 
Non-rhabdomyosarcoma soft 
tissue 
sarcomas 
(STS) 
including 
microphthalmia transcription factor associated STS (alveolar soft part 
sarcoma (ASPS) and clear cell sarcoma (CCS)) 
• 
Osteosarcoma 
• 
Wilms tumor  
• 
Rare tumors  
o Medullary thyroid carcinoma (MTC) 

  
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o Renal cell carcinoma (RCC) 
o Hepatocellular carcinoma (HCC) 
o Hepatoblastoma  
o Adrenocortical carcinoma 
o Pediatric solid tumors (including CNS tumors) with known 
molecular alterations in the targets of XL184 (i.e., MET 
amplification, overexpression, activating mutation, MET 
translocation, MET exon skipping mutations, activating RET 
mutations, RET rearrangement, overexpression or activation of 
AXL). Documentation of the alteration from a CLIA certified 
laboratory will be required. 
 
Note: Documentation of any known tumor molecular alterations and RET 
mutation status for patients with MTC (germline) must be uploaded 
via the RAVE system. 
 
3.2.4 
Disease Status  
3.2.4.1 Patients must have radiographically measurable disease.  
 
Measurable disease is defined as the presence of at least one lesion on 
MRI or CT scan that can be accurately measured with the longest 
diameter a minimum of 10 mm in at least one dimension (CT scan slice 
thickness no greater than 5 mm).   
 
Note:  The following do NOT qualify as measurable disease:  
• 
malignant fluid collections (e.g., ascites, pleural effusions) 
• 
bone marrow infiltration 
• 
lesions only detected by nuclear medicine studies (e.g., bone, 
gallium or PET scans)  
• 
elevated tumor markers in plasma or CSF  
• 
previously radiated lesions that have not demonstrated clear 
progression post radiation  
• 
leptomeningeal lesions that do not meet the measurement 
parameters noted above. 
 
3.2.5 
Performance Level  
Patients must have a Lansky or Karnofsky performance status score of ≥ 50, 
corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for patients > 16 years 
of age and Lansky for patients ≤ 16 years of age. 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. 
(See https://members.childrensoncologygroup.org/prot/reference_materials.asp) 
 
3.2.6 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
 

  
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3.2.6.1 Myelosuppressive chemotherapy: 
3.2.6.1.1 Solid Tumors:  
Patients with solid tumors must not have received 
myelosuppressive chemotherapy within 3 weeks of 
enrollment onto this study (6 weeks if prior nitrosourea). 
 
3.2.6.2 Hematopoietic growth factors: At least 7 days must have elapsed since 
the completion of therapy with a growth factor. At least 14 days must 
have elapsed after receiving pegfilgrastim. 
 
3.2.6.3 Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the last 
dose of agent. See DVL homepage for commercial and investigational 
agent classifications. For agents not listed, the duration of this interval 
must be discussed with the study chair and the study-assigned Research 
Coordinator prior to enrollment. 
 
3.2.6.4 Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
3.2.6.5 Radiotherapy: ≥ 2 weeks must have elapsed since local palliative XRT 
(small port); ≥ 6 weeks must have elapsed since treatment with 
therapeutic doses of MIBG; ≥ 3 months must have elapsed if prior 
craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or 
if TBI was received; ≥ 6 weeks must have elapsed if other substantial 
bone marrow irradiation was given.   
 
Subjects should not have any clinically relevant ongoing complications 
from prior radiation therapy (i.e., radiation esophagitis or other 
inflammation of the viscera).  
 
3.2.6.6 Stem Cell Transplant or Rescue without TBI: No evidence of active graft 
vs. host disease and ≥ 2 months must have elapsed since transplant. 
 
3.2.6.7 Study specific limitations on prior therapy: Not previously received 
XL184 or another MET/HGF inhibitor (tivantinib or crizotinib). There 
are no limits on number of prior therapeutic regimens. Patients who have 
been treated with prior VEGF pathway, or RET inhibitors (except 
XL184) may be eligible. 
 
3.2.7 
Organ Function Requirements 
 
3.2.7.1 
Adequate Bone Marrow Function Defined As: 
3.2.7.1.1 For patients with solid tumors without bone marrow 
involvement: 
▪ Peripheral absolute neutrophil count (ANC)  1000/L 
▪ Platelet count  100,000/L (transfusion independent, 
defined as not receiving platelet transfusions within a 

  
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7 day period prior to enrollment) 
▪ Hemoglobin  8.0 g/dL (may receive RBC transfusions). 
 
3.2.7.1.2 For patients with solid tumors and known bone marrow 
metastatic disease: 
• 
Peripheral absolute neutrophil count (ANC) ≥ 750/L 
• 
Platelet count ≥ 50,000/L 
• 
Hemoglobin ≥ 8.0 g/dL 
 
Transfusions are permitted to meet both the platelet and hemoglobin 
criteria. Patients must not be known to be refractory to red blood cell 
or platelet transfusions. 
 
3.2.7.2 Adequate Renal Function Defined As: 
• 
Creatinine clearance or radioisotope GFR  70 mL/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 
 
3.2.7.3 Adequate Liver Function Defined As: 
• 
Total bilirubin  1.5 x upper limit of normal (ULN) for age 
• 
SGPT (ALT) ≤  135 U/L (3x ULN) (for the purpose of this 
study, the ULN for SGPT is 45 U/L) 
• 
Serum albumin ≥ 2.8 g/dL. 
 
3.2.7.4 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).  
 

  
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3.2.7.5 Central Nervous System Function Defined As: 
• 
Patients with a known seizure disorder who are receiving non-
enzyme inducing anticonvulsants and have well-controlled 
seizures may be enrolled. See Appendix VII for a list of 
recommended non-enzyme inducing anticonvulsants. 
• 
CNS toxicity ≤ Grade 2 with the exception of decreased tendon 
reflex (DTR). Any grade of DTR is eligible. 
 
3.2.7.6 Adequate Blood Pressure Control defined as: 
A blood pressure (BP) ≤ the 95th percentile for age, height, and gender 
for pediatric patients < 18 years old (Appendix V) and ≤ 140/90  mmHg 
for patients ≥ 18 years old. BP should be measured as described in 
Section 5.5, and patients should not be receiving medication for 
treatment of hypertension (except patients with Wilms tumor and RCC 
who may be eligible if on stable doses of no more than one anti-
hypertensive medication with a baseline BP ≤ ULN for pediatric patients 
and ≤ 140/90 for adult patients). Please note that 3 serial blood pressures 
should be obtained and averaged to determine baseline BP. 
 
3.2.7.7 Adequate Coagulation Defined as: 
• 
INR ≤ 1.5  
 
3.2.7.8 Adequate Pancreatic Function Defined as: 
• 
Serum amylase ≤ 1.5 x ULN 
• 
Serum lipase ≤ 1.5 x ULN 
 
3.3 
Eligibility: Exclusion Criteria 
Important note: The exclusion criteria listed below are interpreted literally and cannot 
be waived. All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient's medical/research record. 
These source documents must be available for verification at the time of audit.  
 
3.3.1 
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. 
 
3.3.2 
Concomitant Medications  
3.3.2.1 Growth factor(s): Growth factors that support platelet or white cell 
number or function must not have been administered within the 7 days 
prior to enrollment (14 days if pegfilgrastim). 
 
3.3.2.2 Corticosteroids: Patients requiring corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for the 7 days prior to 

  
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enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid. 
 
3.3.2.3 Previous treatment with XL184 (cabozantinib) or another MET/HGF 
inhibitor (tivantinib, crizotinib).  
 
3.3.2.4 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
3.3.2.5 Anti-cancer Agents: Patients who are currently receiving other anti-
cancer agents are not eligible. 
 
3.3.2.6 Anti-GVHD or agents to prevent organ rejection post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent either graft-versus-host disease post bone marrow transplant or 
organ rejection post-transplant are not eligible for this trial. 
3.3.2.7 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 II. 
3.3.2.8 Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, 
direct thrombin, and Factor Xa inhibitors) or platelet inhibitors (e.g., 
clopidogrel) are prohibited.  
Note: Low-dose aspirin for cardioprotection (per local applicable 
guidelines) and low dose, low molecular weight heparins (LMWH) are 
permitted. Anticoagulation with therapeutic doses of LMWH is allowed 
in subjects without radiographic evidence of brain metastasis, who are on 
a stable dose of LMWH for at least 6 weeks before first dose of study 
treatment, and who have had no complications from a thromboembolic 
event or the anticoagulation regimen.  
3.3.2.9 Enzyme-inducing Anticonvulsants: Patients must not have received 
enzyme–inducing anticonvulsants within 14 days prior to enrollment 
(See Appendix VII for a list of unacceptable enzyme inducing 
anticonvulsants). 
 
3.3.2.10 QTc Agents: Patients who are receiving drugs that prolong QTc are not 
eligible (See Appendix VIII for a list of drugs that prolong QTc).  
 
3.3.3 
Patients who are unable to swallow intact tablets are not eligible. 
 
3.3.4 
Patients who have an uncontrolled infection are not eligible. 
 

  
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3.3.5 
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. 
 
3.3.6 
Patients with active bleeding are not eligible. Specifically, no clinically significant 
GI bleeding, GI perforation, intra-abdominal abscess or fistula for 6 months prior 
to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3 months 
prior to enrollment. 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). In patients with CNS tumors, an MRI with ECHO 
gradient sequences would be required to exclude presence of petechial 
hemorrhages. 
 
3.3.7 
Patients who have had or are planning to have the following invasive procedures 
are not eligible: 
- 
Major surgical procedure, laparoscopic procedure, or open biopsy 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 catheter, peripherally inserted central catheter 
(PICC)) and at least 7 days prior to enrollment for a subcutaneous port. 
- 
Core biopsy within 7 days prior to enrollment. 
- 
Fine needle aspirate within 7 days prior to enrollment. 
- 
Surgical or other wounds must be adequately healed prior to enrollment 
NOTE: For purposes of this study, bone marrow aspirate and biopsy are not 
considered surgical procedures and therefore are permitted within 14 days prior to 
start of protocol therapy. 
 
3.3.8 
Patients who have had significant traumatic injury within 28 days prior to 
enrollment are not eligible. 
 
3.3.9 
Patients with any medical or surgical conditions that would interfere with 
gastrointestinal absorption of the study drug are not eligible.  
 
3.4 
Regulatory 
 
3.4.1 
All patients and/or their parents or legal guardians must sign a written informed 
consent. 
 
3.4.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
  
 

  
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4.0 
TREATMENT PROGRAM 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
Open label two-stage single arm study, with XL184 administered at 40 mg/m2/day 
(cumulative weekly dose of 280 mg/m2) on a continuous dosing schedule (one cycle = 
28 days). Based on patients’ BSA, there may be days that the dose will not be administered. 
The weekly dosing schedule can be found in Appendix IV. Dosing will be performed based 
on body surface area (BSA), and rounded to the nearest 20 mg using a dosing nomogram 
(see Appendix IV). Treatment will continue until tumor progression or unacceptable 
toxicity. 
 
4.1.1 
Dose Reduction 
Dose reductions will be allowed for toxicities as outlined in Section 5.0 for patients 
who recover to eligibility criteria as outlined in Section 3.2 within 21 days of drug 
interruption.   
 
4.1.2 
Dose Escalation 
There will be no drug dose escalation. 
 
4.1.3 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and 
has again met laboratory parameters as defined in the eligibility section, 
Section 3.2.7 and has not experienced study-drug related adverse events 
warranting permanent discontinuation. 
 
4.1.4 
Concomitant Therapy 
 
4.1.4.1 No other cancer chemotherapy, radiotherapy, or immunomodulating 
agents will be used. 
 
 
4.1.4.2 Medications that are strong inhibitors or inducers of CYP3A4 should 
be avoided (see Appendix II). 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. 
 
4.1.4.3 In vitro data indicate that XL184 is an inhibitor of P-glycoprotein (P-gp) 
transport activity. Co-administration of XL184 with a P-gp substrate may 
result in an increase in P-gp substrate plasma concentration.  Therefore, use 

  
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caution when administering XL-184 with drugs known to be P-gp 
substrates (e.g., fexofenadine, aliskiren, ambrisentan, digoxin, colchicine, 
maraviroc, posaconazole, tolvaptan, etc.). XL184 is also a substrate of drug 
transporter MRP2, which may result in an increased plasma concentration 
of XL184 when administered with an inhibitor of MRP2. Use caution and 
monitor adverse events when administering XL184 with MRP2 inhibitors 
such as cyclosporine, delavirdine, efavirenz, and emtricitabine 
 
4.1.4.4 
The use of enzyme inducing anticonvulsants is not permitted. See 
Appendix VII for a list 
of unacceptable enzyme inducing and 
recommended non-enzyme inducing anticonvulsants. 
 
4.1.4.5 XL184 has been associated with prolonged QTc, so medications that 
prolong or may prolong QTc should be avoided when possible (see 
Appendix VIII). If other medications that prolong QTc or may prolong 
QTc have to be used concomitantly, then QTc should be carefully 
monitored. 
 
4.1.4.6 XL184 is highly protein bound (99.9%). Use caution when 
coadministering XL184 with medications that are highly protein-bound 
(e.g., diazepam, furosemide, dicloxacillin, and propranolol).  
 
4.1.4.7 
Patient drug information handout and wallet card should be provided to 
patients on study, see Appendix X. 
 
4.1.5 
Study Specific Supportive Care: 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and 
general supportive care are to be used as necessary. See Section 4.1.4 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 VI). 
 
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. 
 
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. 
 
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]). 
 

  
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Page 33 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
under 
Standard Sections for Protocols. 
 

  
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Page 34 
Cycle 1 
 
4.2 
Cycle 1 
4.2.1 
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Each cycle lasts 28 
days.  
____________________________ 
Patient COG ID number 
_______________________ 
DOB  
 
Criteria to start each cycle are listed in Section 3.2.7. Extensive treatment details are in Section 4.2.3.  
This TDM is on 1 page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
XL184 
(cabozantinib)  
 
PO 
40 mg/m2/day 
1-28 
See Appendix IV for dosing nomogram. 
The cumulative weekly dose is 280 mg/m2. 
XL184 should be taken at approximately the 
same time each day on an empty stomach; 
patients should fast 2 hours before and 1 hour 
after taking the drug. 
 
 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
XL184 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual 
dose administered below 
 
 
 
1 
_____________________mg 
a-n 
 
 
2 
_____________________mg 
 
 
 
3 
_____________________mg 
 
 
 
4 
_____________________mg 
 
 
 
5 
_____________________mg 
 
 
 
6 
_____________________mg 
 
 
 
7 
_____________________mg 
 
 
 
8 
_____________________mg 
a 
 
 
9 
_____________________mg 
 
 
 
10 
_____________________mg 
 
 
 
11 
_____________________mg 
 
 
 
12 
_____________________mg 
 
 
 
13 
_____________________mg 
 
 
 
14 
_____________________mg 
 
 
 
15 
_____________________mg 
a, c, d, k 
 
 
16 
_____________________mg 
 
 
 
17 
_____________________mg 
 
 
 
18 
_____________________mg 
 
 
 
19 
_____________________mg 
 
 
 
20 
_____________________mg 
 
 
 
21 
_____________________mg 
 
 
 
22 
_____________________mg 
a, m 
 
 
23 
_____________________mg 
 
 
 
24 
_____________________mg 
 
 
 
25 
_____________________mg 
 
 
 
26 
_____________________mg 
 
 
 
27 
_____________________mg 
 
 
 
28 
_____________________mg 
g, i, k 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care 
Guidelines. 

  
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Page 35 
Cycle 1 
 
 
 
4.2.2 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
a. Hx/PE with VS including BP. Prior to Cycle 1 and weekly during Cycle 1. Please 
see Section 5.5 for additional guidance regarding BP. 
b. Wt /Ht/Performance status.  
c. 
CBC/diff/platelets. Prior to Cycle 1 and every 2 weeks during Cycle 1. 
d. Electrolytes, BUN, creatinine, Ca ++, PO4, Mg++, AST, ALT, bilirubin, albumin, 
urinalysis, amylase, lipase. Prior to Cycle 1 and every 2 weeks during Cycle 1. See 
Section 5.4 for dose modifications due to proteinuria. 
e. 
TSH. Patients found to have an abnormal TSH level should have a free T4 level 
measured. Patients who enter the study on thyroid replacement should have their 
medication adjusted to maintain TSH in the normal range. 
f. 
PT/INR/APTT.  
g. 
ECG including QTc interval. Prior to Cycle 1 and at the end of Cycle 1. 
h. Tumor disease evaluation. Prior to Cycle 1. 
i. 
CEA, calcitonin (for patients with MTC only). Prior to Cycle 1 and at the end of Cycle 
1. Calcitonin measurements should be obtained in the fasting state. 
j. 
X-ray tibial growth plate. Prior to start of therapy in all patients ≤ 18 years of age at 
enrollment. See Section 5.10.1 for details. 
k. Patient diary. Every other week during Cycle 1. For patient diary see Appendix III. 
l. 
Pharmacodynamics. See Section 7.2.2 for details. 
m. Pharmacokinetics. Cycle 1. See Section 7.2.1 for details. 
n. Pregnancy test. Female patients of childbearing potential require a negative pregnancy 
test prior to the start of each cycle; sexually active patients must use an acceptable 
method of birth control. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 

  
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Page 36 
Cycle 1 
 
4.2.3 
Treatment Details: Cycle 1  
One cycle of XL184 treatment is described below. A cycle may be repeated every 
28 days if the patient has at least stable disease and has again met laboratory 
parameters as defined in the eligibility Section 3.2.7.   
 
XL184: PO 
Days: 1-28 
Dose: 40 mg/m2/day 
 
Dosing will be performed based on body surface area (BSA), and rounded to the 
nearest 20 mg using the dosing nomogram (see Appendix IV). The cumulative 
weekly dose is 280 mg/m2. Treatment will continue until tumor progression or 
unacceptable toxicity. 
 
XL184 will be administered orally at approximately the same time each day.   
 
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 IV). 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 every 2 weeks during 
Cycle 1. 
 
If a patient vomits after the dose of XL184 is administered, the dose should not be 
repeated. The tablet should be taken with a large glass of water on an empty stomach, 
and patient should not eat 2 hours before or 1 hour after each dose of XL184. The 
tablet should not be crushed or broken. Furthermore, a missed dose should not be 
taken within 12 hours of the next dose.  
 
Patients should not eat grapefruit or drink grapefruit juice while being treated with 
XL184.  
 
A note should be made in the patient diary if any of the above events take place. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of cycle, the next cycle starts on Day 29 or when starting 
criteria are met (see Section 3.2.7), whichever occurs later. 
 
 
 

  
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Page 37 
Cycles 2 & 3 
4.3 
Cycles 2 & 3 
4.3.1 
Therapy Delivery Map – Cycles 2 & 3 
This Therapy Delivery Map (TDM) relates to Cycles 2 and 3. Each cycle lasts 28 days. 
Treatment may continue in the absence of disease progression or unacceptable toxicity. Use 
a copy of this page once for Cycle 2 and once for Cycle 3 (please note cycle number below).  
____________________________ 
Patient COG ID number 
_______________________
DOB  
 
Criteria to start each cycle are listed in Section 3.2.7. Extensive treatment details are in Section 4.3.3.  
This TDM is on 1 page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
XL184 
(cabozantinib)  
 
PO 
40 mg/m2/day 
1-28 
See Appendix IV for dosing nomogram. 
The cumulative weekly dose is 280 mg/m2. 
XL184 should be taken at approximately the 
same time each day on an empty stomach; 
patients should fast 2 hours before and 1 hour 
after taking the drug. 
 
Enter Cycle #: _____  
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
XL184 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual 
dose administered below 
 
 
 
1 
_____________________mg 
a-e, g, i, j 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
a, c, d 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
_____________________mg 
f#, h, k#, l# 
#Cycle 2 only. See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive 
Care Guidelines. 
 

  
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Page 38 
Cycles 2 & 3 
 
 
4.3.2 
Required Observations in Cycles 2 &3 
 
a. Hx/PE with VS including BP. Every 2 weeks. Please see Section 5.5 for additional 
guidance regarding BP. 
b. Wt /Ht/Performance status. Day 1 of each Cycle. 
c. 
CBC/diff/platelets. Every 2 weeks. 
d. Electrolytes, BUN, creatinine, Ca ++, PO4, Mg++, AST, ALT, albumin, bilirubin, 
urinalysis, amylase, lipase. Every 2 weeks. See Section 5.4 for dose modifications due 
to proteinuria. 
e. 
TSH. Day 1 of each cycle. Patients found to have an abnormal TSH level should have 
a free T4 level measured. See Section 5.10.2 for details and management of thyroid 
toxicity. 
f. 
ECG including QTc interval. End of Cycle 2. 
g. 
X-ray tibial growth plate. Prior to Cycle 2 in patients with open growth plates, follow-
up plain radiographs of the same growth plate(s) should be obtained. See Section 
5.10.1 for details and management of growth plate toxicity. 
h. Patient diary. End of each cycle. For patient diary see Appendix III. 
i. 
Pharmacodynamics. Prior to Cycles 2 and 3. See Section 7.2.2 for details. 
j. 
Pregnancy test. Female patients of childbearing potential require a negative pregnancy 
test prior to the start of each cycle; sexually active patients must use an acceptable 
method of birth control. 
k. Tumor disease evaluation. End of Cycle 2. 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. 
l. 
CEA, calcitonin (for patients with MTC only). End of Cycle 2. Calcitonin 
measurements should be obtained in the fasting state. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Page 39 
Cycles 2 & 3 
 
4.3.3 
Treatment Details: Cycles 2 & 3  
One cycle of XL184 treatment is described below. A cycle may be repeated every 
28 days if the patient has at least stable disease and has again met laboratory 
parameters as defined in the eligibility Section 3.2.7.   
 
XL184: PO 
Days: 1-28 
Dose: 40 mg/m2/day 
 
Dosing will be performed based on body surface area (BSA), and rounded to the 
nearest 20 mg using the dosing nomogram (see Appendix IV). The cumulative 
weekly dose is 280 mg/m2. Treatment will continue until tumor progression or 
unacceptable toxicity. 
 
XL184 will be administered orally at approximately the same time each day as 
prescribed.  
 
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 IV). 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. The tablet should be taken with a large glass of water on an empty stomach, 
and patient should not eat 2 hours before or 1 hour after each dose of XL184. The 
tablet should not be crushed or broken but be swallowed whole. Furthermore, a 
missed dose should not be taken within 12 hours of the next dose.  
 
Patients should not eat grapefruit or drink grapefruit juice while being treated with 
XL184.  
 
A note should be made in the patient diary if any of the above events take place. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of cycle, the next cycle starts on Day 29 or when starting 
criteria are met (see Section 3.2.7), whichever occurs later. 
 
 
 

  
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Page 40 
All Subsequent Cycles 
4.4 
All Subsequent Cycles 
4.4.1 
Therapy Delivery Map – All Subsequent Cycles 
This Therapy Delivery Map (TDM) relates to all subsequent cycles. Each cycle lasts 28 
days. Treatment may continue in the absence of disease progression or unacceptable 
toxicity. Use a copy of this page once for each cycle (please note cycle number below).  
____________________________ 
Patient COG ID number 
_______________________ 
DOB  
 
Criteria to start each cycle are listed in Section 3.2.7. Extensive treatment details are in Section 4.4.3. 
This TDM is on 1 page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
XL184 
(cabozantinib)  
 
PO 
40 mg/m2/day 
1-28 
See Appendix IV for dosing nomogram. 
The cumulative weekly dose is 280 mg/m2. 
XL184 should be taken at approximately the 
same time each day on an empty stomach; 
patients should fast 2 hours before and 1 hour 
after taking the drug. 
 
Enter Cycle #: _____  
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
XL184 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual 
dose administered below 
 
 
 
1 
_____________________mg 
a-e, (f-h)*, i#, k 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
_____________________mg 
j 
*Prior to Cycle 5 and 7, and every 3rd cycle thereafter. 
#Prior to Cycle 5 and every 6 cycles thereafter. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 

  
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Page 41 
All Subsequent Cycles 
 
 
4.4.2 
Required Observations in All Subsequent Cycles 
 
a. Hx/PE with VS including BP. Day 1 of each cycle. Please see Section 5.5 for 
additional guidance regarding BP. 
b. Wt /Ht/Performance status. Day 1 of each cycle. 
c. 
CBC/diff/platelets. Day 1 of each cycle. 
d. Electrolytes, BUN, creatinine, Ca ++, PO4, Mg++, bilirubin, AST, ALT, albumin, 
urinalysis, amylase, lipase. Day 1 of each cycle. See Section 5.4 for dose 
modifications due to proteinuria. 
e. 
TSH. Day 1 of each cycle. Patients found to have an abnormal TSH level should have 
a free T4 level measured. See Section 5.10.2 for details and management of thyroid 
toxicity.  
f. 
ECG including QTc interval. Prior to Cycle 5 and 7 and then every 3rd cycle. 
g. 
Tumor disease evaluation. Prior to Cycle 5 and 7 and then every 3rd cycle. 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. 
h. CEA, calcitonin (for patients with MTC only). Prior to Cycle 5 and 7 and then every 
3rd cycle. Calcitonin measurements should be obtained in the fasting state. 
i. 
X-ray tibial growth plate. Prior to Cycle 5 and every 6 cycles thereafter in patients 
with open growth plates, follow-up plain radiographs of the same growth plate(s) 
should be obtained. See Section 5.10.1 for details and management of growth plate 
toxicity. 
j. 
Patient diary. End of each cycle. For patient diary see Appendix III. 
k. Pregnancy test. Female patients of childbearing potential require a negative pregnancy 
test prior to the start of each cycle; sexually active patients must use an acceptable 
method of birth control. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Page 42 
All Subsequent Cycles 
 
4.4.3 
Treatment Details: All Subsequent Cycles  
One cycle of XL184 treatment is described below. A cycle may be repeated every 
28 days if the patient has at least stable disease and has again met laboratory 
parameters as defined in the eligibility Section 3.2.7.   
 
XL184: PO 
Days: 1-28 
Dose: 40 mg/m2/day 
 
Dosing will be performed based on body surface area (BSA), and rounded to the 
nearest 20 mg using the dosing nomogram (see Appendix IV). The cumulative 
weekly dose is 280 mg/m2. Treatment will continue until tumor progression or 
unacceptable toxicity. 
 
XL184 will be administered orally at approximately the same time each day as 
prescribed.  
 
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 IV). 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. The tablet should be taken with a large glass of water on an empty stomach, 
and patient should not eat 2 hours before or 1 hour after each dose of XL184. The 
tablet should not be crushed or broken. Furthermore, a missed dose should not be 
taken within 12 hours of the next dose.  
 
Patients should not eat grapefruit or drink grapefruit juice while being treated with 
XL184.  
 
A note should be made in the patient diary if any of the above events take place. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of cycle, the next cycle starts on Day 29 or when starting 
criteria are met (see Section 3.2.7), whichever occurs later. 
 
 
 

  
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Page 43 
 
5.0 
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY 
All dose modifications should be based on the worst preceding toxicity. The severity of adverse events 
will be graded utilizing the NCI CTCAE, Version 5.0. 
 
5.1 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are at least (possibly, probably or 
definitely) attributable to XL184.  
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.1.1 
Non-Hematological Dose-Limiting Toxicity 
• 
Any Grade 4 non-hematological toxicity 
 
• 
Any Grade 3 non-hematological toxicity with the specific exception of: 
o Grade 3 nausea and vomiting of less < 3 days duration 
o Grade 3 diarrhea ≤ 3 days duration 
o Grade 3 liver enzyme elevation including ALT/AST/GGT/bilirubin that return 
to levels that meet initial eligibility criteria within 7 days of study drug 
interruption and that do not recur upon re-challenge with study drug. Note: For 
the purposes of this trial the ULN for ALT is defined as 45 U/L and the ULN 
for AST is defined as 50 U/L. See Section 5.7 for dose modifications for liver 
toxicity. Adverse event grades will be based on increases above the upper limit 
of normal, regardless of the subject’s baseline. See appendix XI for toxicity-
specific grading table. 
o Grade 3 fever or infection < 5 days duration. 
o Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
and/or 
hypomagnesemia responsive to supplementation 
o 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 5.8 for dose modifications for pancreatic 
toxicity. 
o Grade 3 proteinuria (urine protein/creatinine (P/C) ratio > 1.9) unless it is 
confirmed with a second measurement within 72 hours 
 
• 
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 
 
• 
Dose-limiting hypertension 
o Any Grade 4 hypertension 
o A blood pressure > 25 mmHg above the ULN confirmed by repeated 
measurement on the same day is dose limiting. For pediatric patients ULN is 
the 95th percentile for age, height, and gender (Appendix V) and for patients 
≥ 18 years of age ULN is 140/90 mmHg.  
o In patients who begin antihypertensive therapy a blood pressure > 10 mmHg 
but ≤ 25 mmHg above the ULN (Appendix V) for > 14 days is dose limiting.. 
 
• 
QTc prolongation > 500 ms that persists despite correction of serum electrolyte 
abnormalities will be considered dose limiting 
 

  
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Page 44 
• 
Grade 2 or higher allergic reactions that necessitate discontinuation of study drug 
will not be considered a dose-limiting toxicity. 
 
5.1.2 
Hematological dose limiting toxicity  
• 
In patients evaluable for hematological toxicity (see Section 3.2.7.1), 
o Grade 4 thrombocytopenia (platelet count < 25,000/µL) or Grade 
4 neutropenia, not due to malignant infiltration.  
 
• 
Myelosuppression that causes a delay of > 21 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. 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.  
 
Note: Grade 4 febrile neutropenia will not be considered a dose-limiting toxicity.  
 
5.2 
Dose Modifications for Hematological Toxicity 
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 dose that was previously not tolerated. 
 
5.2.1 
If a patient experiences Grade 4 neutropenia or Grade 4 thrombocytopenia, the 
treatment will be held. Counts should be checked twice weekly during this time. If the 
toxicity resolves to meet eligibility parameters within 21 days of drug discontinuation, 
the patient may resume treatment at the next lower dose level (see Section 5.11). Doses 
reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity 
with the reduced dose.  
 
5.2.2 
If toxicity does not resolve to meet eligibility parameters within 21 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
5.2.3 
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. For patients with BSA 0.35-0.39, only 1 dose reduction will be allowed as the 
lowest weekly administered dose is 60 mg/week. 
 
5.3 
Dose Modifications for Non-Hematological Toxicity 
5.3.1 
XL184 will be discontinued in cases of serious toxicities such as GI perforation, fistula 
formation, significant bleeding, significant thrombotic events (such as myocardial 
infarction, cerebral infarction, other serious arterial thromboembolic events), Grade 
4 hypertension, reversible posterior leukoencephalopathy syndrome, or osteonecrosis 
of the jaw. For other toxicities, if a patient experiences non-hematological dose-
limiting toxicity as defined in Section 5.1.1, the treatment will be held. When the 
toxicity resolves to meet eligibility parameters or baseline within 21 days of drug 
discontinuation, the patient may resume treatment at the next lower dose level (see 
Section 5.11). Doses reduced for toxicity will not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose. 
 

  
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Page 45 
5.3.2 
If toxicity does not resolve to meet eligibility or baseline parameters within 21 days of 
drug discontinuation, the patient must be removed from protocol therapy. The 
exception to this is Grade 3 weight loss as it is unlikely that the patient would return to 
baseline within 21 days. Patients who experience Grade 3 weight loss may resume 
study medication after 21 days with a dose-reduction (see Section 5.11) 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.  
 
5.3.3 
Two dose reductions will be allowed for toxicity. If a patient experiences a dose 
limiting toxicity after two dose reductions, the patient must be removed from protocol 
therapy. For patients with BSA 0.35-0.39, only 1 dose reduction will be allowed as the 
lowest weekly administered dose is 60 mg/week. 
 
5.4 
Dose Modifications for Proteinuria  
Proteinuria has been reported with XL184 in adult studies and pediatric trial ADVL1211. 
• 
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 ≥ 21 days then remove from protocol therapy. If the urine 
protein/creatinine (P/C) ratio decreases to ≤ 1.9 in < 21 days then resume XL184 at a lower 
dose as outlined in Section 5.11.  
• 
Monitor the UPC weekly for 2 consecutive weeks once protocol therapy resumes.  
 
5.5 
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 (ULN) is defined as a BP equal to the 95th percentile for age, height, and gender for 
pediatric patients (See Appendix V) For adult patients (ages ≥ 18 years), the ULN is 140/90 
mmHg.  
• 
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.  

  
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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. 
 
Elevations in BP are based on systolic or diastolic pressures. 
 
1 Elevated blood pressure (BP) measurements should be repeated on the same day to confirm the elevation. 
Patients with elevated BP at any time should have BP measurements performed at least twice weekly until 
BP within the ULN (Upper Limit of Normal). 
2 ULN for pediatric patients is a BP equal to the 95th percentile for age, height, and gender-appropriate normal 
values (see Appendix V). For adult patients (ages ≥ 18 years) the ULN is 140/90 mmHg. 
3 If BP > 25 mm Hg above ULN for age (verified) or Grade 4 HTN at any time, hold drug. Study drug should 
also be held for BP ≤ 25 mm Hg above the ULN age for > 14 days or 35 mm Hg above baseline for > 14 days. 
Antihypertensive agents can be used to control hypertension as clinically indicated after study drug is held. 
4 Anti-hypertensive therapy should be prescribed as clinically indicated, including the use of multiple anti-
hypertensive agents. 
 
Arm 1 of algorithm:  
• 
If blood pressure (BP) ≤ ULN, continue XL184 at the same dose.  
 
Arm 2 of algorithm:  
• 
If BP ≤ 10 mm Hg above the ULN, continue XL184 at the same dose and recheck the 
BP within 72 hours.  
• 
If the BP is ≤ ULN on recheck, continue XL184 at the same dose.  
• 
If the BP remains above the ULN on recheck, then start antihypertensive therapy and 
follow Arm 3 of the algorithm from the point that anti-hypertensive therapy is started.  
 

  
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Arm 3 of algorithm:  
• 
If BP is 11 to 25 mm Hg above the ULN on ≥ 2 of 3 measurements or > 35 mmHg 
above baseline on ≥ 2 of 3 measurements, start anti-hypertensive therapy, 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.  
o If the BP remains elevated ≤ 25 mm Hg above the ULN 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 (see Section 5.11).  
▪ 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 (see Section 5.11).  
▪ If the BP is > ULN for > 14 days, the patient is Off Protocol Therapy.  
 
Arm 4 of algorithm:  
• 
If BP is > 25 mm Hg above the ULN 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 (see Section 5.11).  
o If the BP is > ULN for >14 days, the patient is Off Protocol Therapy.  
 
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. 
 
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 < ULN. 
 
 

  
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5.6 
Dose Modifications for Thromboembolic Events  
Subjects who develop a pulmonary embolism (PE) or deep venous thrombosis (DVT) should 
have XL184 treatment held until therapeutic anticoagulation with heparins (eg, LMWH) is 
established. (Note: therapeutic anticoagulation with oral anticoagulants or oral platelet inhibitors 
such as clopidogrel is not allowed in this study). XL184 treatment may be resumed in subjects 
who are stable and have uncomplicated PE or DVT and are deriving clinical benefit from XL184 
treatment (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.) During anticoagulation treatment, 
subjects need to be monitored on an ongoing basis for bleeding risk and signs of bleeding which 
may require additional or more frequent laboratory tests according to institutional guidelines. If 
there are any signs of clinically relevant bleedings, XL184 treatment should be interrupted 
immediately and the investigator/ sponsor contacted to discuss further study participation. 
Subjects with life-threatening PE or DVT should have study treatment discontinued unless 
toxicity can be managed and subject is deriving clear clinical benefit as determined by the 
investigator and agreed by the investigator/ sponsor. 
 
Arterial thrombotic events (e.g., transient ischemic attack, myocardial infarction) have been 
observed in studies with XL184. Subjects should be evaluated for preexisting risk factors for 
arterial thrombotic events and cardiac or thromboembolic events that occurred before initiation 
of study treatment. XL184 treatment should be discontinued in subjects who develop an acute 
myocardial infarction, cerebral infarction or any other clinically relevant arterial 
thromboembolic complication. 
 
5.7 
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 regardless of the patient’s baseline, and the 
ULN for AST is defined as 50 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 are 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 5.1.1. The XL184 will be reduced according to Section 5.11 when eligibility criteria 
are met. 
 
5.8 
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 5.1.1. XL184 will then be 
dose-reduced according to Section 5.11 when eligibility criteria are met. 
 
5.9 
Dose Modifications for Diarrhea  
See Appendix VI 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 Section 5.11.  

  
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5.10 
Monitoring for Specific Toxicities 
5.10.1 Growth Plate Toxicity 
Patients ≤ 18 years of age at enrollment 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 every 6 cycles thereafter 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, 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. 
 
5.10.2 Thyroid Toxicity 
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 below. 
 
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 5.3  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. 
 
5.10.3 QT Prolongation 
If the average QTcF from the three ECGs is > 500 ms or increased by > 60 ms above 
baseline.  
The following actions must be taken:  
• 
Withhold study treatment  
• 
Hospitalize symptomatic subjects (e.g., with palpitations, dizziness, syncope, 
orthostatic hypotension, a significant ventricular arrhythmia on ECG) for a 
thorough cardiology evaluation and management.  
• 
Consider cardiology consultation for asymptomatic subjects for evaluation and 
management.  
• 
Check electrolytes, especially magnesium, potassium and calcium; correct 
abnormalities as clinically indicated.  
• 
Check concomitant medications for any medication that may have contributed 
to QT prolongation, and if possible, discontinue these medications (See 
Appendix VIII for a list of drugs that prolong QTc).  

  
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Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec, or 
otherwise determined by consultation with a cardiologist or appropriate expert.  
 
Subjects with QTc prolongation and symptoms must be monitored closely until the 
QTc elevation and symptoms have resolved. Study treatment may be restarted at a 
reduced dose level if all of the following conditions are met:  
• 
Symptoms are determined to be unrelated to the QT interval prolongation  
• 
The QTcF value > 500 ms or increase of > 60 ms above baseline is not 
confirmed according to protocol procedures  
• 
Study treatment has been interrupted through a minimum of 1 week following 
the return of the QTcF to ≤ 500 msec or return to ≤ 60 ms above baseline.  
• 
QT prolongation can be unequivocally associated with an event other than 
XL184 administration and is treatable/has been resolved  
• 
Sponsor has reviewed all available information and has agreed to the 
continuation of study treatment.  
 
Following re-initiation of study treatment, ECGs must be repeated weekly for 2 weeks, 
then every 2 weeks for 1 month, then according to the protocol-defined time points.  
 
All study treatment must be permanently discontinued if either of the following 
applies:  
• 
Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation  
• 
Recurrence of QTcF prolongation (confirmed by central ECG lab) after re-
initiation of study treatment at a reduced dose 
 
 

  
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5.11 
XL184 Dose Reduction Table 
XL184 
(Cabozantinib) 
40 mg/m2/day 
BSA (m2) 
Weekly Dose/Schedule for 1st 
Dose Reduction due to Toxicity 
Weekly Dose/Schedule for 2nd Dose Reduction 
due to Toxicity 
0.35 – 0.39 
60 mg = 20 mg M, W, F (or Day 1, 3, 5 of 
each week) 
Off therapy 
0.40 – 0.45 
80 mg = 20 mg M, W, F, Sun (or Day 1, 
3, 5, 7 of each week) 
60 mg = 20 mg M, W, F (or Day 1, 3, 5 of each 
week) 
0.46 – 0.55 
100 mg = 20 mg M, W, Th, Sat, Sun (or 
Day 1, 3, 4, 6, 7 of each week) 
60 mg = 20 mg M, W, F (or Day 1, 3, 5 of each 
week)
0.56 – 0.64 
120 mg = 20 mg M, T, W, F, Sat, Sun (or 
Day 1, 2, 3, 5, 6, 7 of each week) 
80 mg = 20 mg M, W, F, Sun (or Day 1, 3, 5, 7 of 
each week) 
0.65 – 0.78 
140 mg = 20 mg Daily 
100 mg = 20 mg M, W, Th, Sat, Sun (or Day 1, 
3, 4, 6, 7 of each week) 
0.79 – 0.90 
160 mg = 40 mg M, W, F, Sun (or Day 1, 
3, 5, 7 of each week) 
120 mg = 20 mg M, T, W, F, Sat, Sun (or Day 1, 2, 
3, 5, 6, 7 of each week) 
0.91 – 1.09 
200 mg = 40 mg M, W, Th, Sat, Sun (or 
Day 1, 3, 4, 6, 7 of each week) 
140 mg = 20 mg Daily 
1.10 – 1.17 
200 mg = 40 mg M, W, Th, Sat, Sun (or 
Day 1, 3, 4, 6, 7 of each week) 
140 mg = 20 mg Daily 
1.18 – 1.36 
240 mg = 40 mg M, T, W, F, Sat, Sun (or 
Day 1, 2, 3, 5, 6, 7 of each week) 
160 mg = 40 mg M, W, F, Sun (or Day 1, 3, 5, 7 of 
each week) 
1.37 – 1.65 
300 mg = 60 mg M, W, Th, Sat, Sun (or 
Day 1, 3, 4, 6, 7 of each week) 
200 mg = 40 mg M, W, Th, Sat, Sun (or Day 1, 
3, 4, 6, 7 of each week) 
1.66 – 1.85 
360 mg = 60 mg M, T, W, F, Sat, Sun (or 
Day 1, 2, 3, 5, 6, 7 of each week) 
240 mg = 40 mg M, T, W, F, Sat, Sun (or Day 1, 2, 
3, 5, 6, 7 of each week) 
1.86 – 2.07 
420 mg = 60 mg Daily 
300 mg = 60 mg M, W, Th, Sat, Sun (or Day 1, 3, 
4, 6, 7 of each week) 
≥ 2.08 
420 mg = 60 mg Daily 
300 mg = 60 mg M, W, Th, Sat, Sun (or Day 1, 3, 
4, 6, 7 of each week) 
 
 
 

  
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6.0 
DRUG INFORMATION 
6.1 
XL184  
(Cabometyx®, cabozantinib s-malate) NSC# 761968 
(04/04/19) 
 
Source and Pharmacology:  
XL184 (cabozantinib) is an oral small molecule potent inhibitor of proinvasive receptor 
tyrosine kinases (RTKs), including AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, 
TRKB, and VEGFR-1, -2, and -3. Most notably, it strongly inhibits VEGFR-2, MET, and RET. 
Met and VEGFR2 are important mediators of tumor growth and tumor angiogenesis, and in 
vivo pharmacodynamic activity of XL184 against c-Met and VEGFR2 has been demonstrated 
in both preclinical and clinical studies. Treatment with XL184 results in anti-angiogenic effects 
in xenograft tumors, with disruption of the vasculature beginning within 24 hours after 
administration, and is associated with pro-apoptotic effects. These effects translate into 
significant tumor growth inhibition or tumor regression after XL184 treatment in multiple 
tumor models including metastatic medullary thyroid cancer (MTC), breast cancer, lung 
carcinoma, and glioblastoma. XL184 is currently approved for the treatment of patients with 
progressive MTC and advanced renal cell carcinoma (RCC) who have received prior anti- 
angiogenic therapy. 
XL184 has shown clinical activity in adults with castration resistant prostate cancer, ovarian 
cancer, glioblastoma, differentiated thyroid carcinoma, renal cell carcinoma, hepatocellular 
carcinoma, breast, and non-small cell lung cancer. There is a strong scientific rationale for the 
evaluation of XL184 in pediatric solid tumors: over-expression of MET has been described in 
osteosarcoma and Ewing sarcoma and has been shown to correlate with aggressive phenotype 
and poor prognosis. MET is a transcriptional target of PAX3 and PAX7 and is highly expressed 
in alveolar rhabdomyosarcoma cell lines. Co-expression of HGF and MET correlated with 
higher grade and poorer prognosis in synovial sarcoma tumor samples. High VEGFR2 
expression is an unfavorable prognostic biomarker in hepatocellular carcinoma (HCC). 
Following oral administration of XL184 capsules, median time to peak plasma concentrations 
(Tmax) ranged from 2-5 hours post-dose. XL184 Cmax and AUC increased 41% and 57%, 
respectively, following a high fat meal relative to fasted condition in healthy volunteers; 
therefore, XL184 should be taken on an empty stomach (fasting is required 2 hours before and 1 
hour after each XL184 dose). The oral volume of distribution (V/F) of XL184 is approximately 
349 L. XL184 is highly protein bound (≥ 99.9%). Terminal-phase half-life (t1/2,z) values are 59.1 
to 136 hours and the clearance (CL/F) at steady- state is estimated to be 4.2 L/hr. Apparent 
steady-state plasma levels are reached by Day 15. This agent is primary excreted in feces (54%) 
and urine (27%). Pharmacokinetics of XL184 have not been studied in pediatric patients and 
patients with severe hepatic or renal impairment. 
Potential drug interactions: 
In vitro, XL184 is a substrate of CYP3A4 and a weak substrate of CYP2C9. Chronic use of strong 
CYP3A4 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, 
rifampentin, phenobarbital, and St. John’s wort) or inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) should be avoided while taking 
XL184. Avoid grapefruit/ grapefruit juice and Seville oranges while participating in this trial. 
 
In vitro data indicate that XL184 is an inhibitor of P-glycoprotein transport activity. Co-
administration of XL184 with a P-gp substrate may result in an increase in P-gp substrate plasma 
concentration.  Therefore, use caution when administering XL-184 with drugs known to be P-gp 

  
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substrates (e.g., fexofenadine, aliskiren, ambrisentan, digoxin, colchicine, maraviroc, 
posaconazole, tolvaptan, etc.). 
 
XL184 is also a substrate of drug transporter MRP2, which may result in an increase plasma 
concentration of XL184 when administered with an inhibitor of MRP2. Use caution and monitor 
adverse events when administering XL184 with MRP2 inhibitors such as cyclosporine, 
delavirdine, efavirenz, emtricitabine. 
 
QTc prolongation: 
Use caution when administering XL184 in patients with QT prolongation risk, a history of QT 
interval prolongation, or who are receiving antiarrhythmic drugs. Concomitant use of strong 
CYP3A4 inhibitors should be avoided as it may increase XL184 plasma concentrations. Refer to 
the protocol for QTcF criteria.  
 
Patient Care Implications   
Women of childbearing potential must use highly effective contraception while receiving XL184 
(cabozantinib) and for 4 months after the last dose.  Breastfeeding is not allowed while on study.  
Sexually active males must use highly effective contraception while on study and for 4 months 
after the last dose. 
 
Toxicity: 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
XL184 (Cabozantinib, NSC 761968) 
 
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/aeguidelines.pdf 
for 
further 
clarification.  Frequency is provided based on 3219 patients. Below is the CAEPR for XL184 (Cabozantinib). 
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 2.4, December 17, 20181 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 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) 

  
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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Dry mouth 
 Dry mouth (Gr 2) 
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 
 
Hypophosphatemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
Generalized muscle weakness 
 
Muscle cramp 
 
Osteonecrosis of jaw 
 
Pain in extremity 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Dysgeusia 
 Dysgeusia (Gr 2) 
Headache 
 
 
 
Intracranial hemorrhage  
 
 
Ischemia cerebrovascular 
 
Reversible 
posterior 
leukoencephalopathy 
syndrome 
 
Stroke 
 
Transient ischemic attacks 
 

  
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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
RENAL AND URINARY DISORDERS 
 
Hematuria 
 
 
Proteinuria 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
Dyspnea 
 
 
Pneumothorax6 
 
Respiratory fistula7 
 
Respiratory hemorrhage8 
 
 
Voice alteration 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
Dry skin 
 Dry skin (Gr 2) 
Hair color changes 
 Hair color changes (Gr 1) 
Palmar-plantar 
erythrodysesthesia syndrome 
 Palmar-plantar 
erythrodysesthesia syndrome (Gr 
3) 
Rash maculo-papular 
 Rash maculo-papular (Gr 3) 
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, Hemoptysis, 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) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that XL184 (Cabozantinib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile neutropenia; Hemolytic uremic 
syndrome 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; Cardiac disorders - 
Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; 
Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - Other 
(thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism; Hypopituitarism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; Anal pain; Anal 
ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; 
Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(glossitis); Gastrointestinal disorders - Other (pneumoperitoneum); Gastrointestinal pain; Gingival pain; 
Hemorrhoids; Ileus; Pancreatitis; Periodontal disease; Rectal pain; Rectal ulcer; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema face; 
Fever; Gait disturbance; General disorders and administration site conditions - Other (general physical health 
deterioration); General disorders and administration site conditions - Other (implant site inflammation); 
Hypothermia; Malaise; Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; Hepatobiliary disorders 
- Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other 
(hepatic thrombus); Hepatobiliary disorders - Other (hepatitis toxic); Hepatobiliary disorders - Other 
(hepatorenal syndrome); 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; Blood lactate dehydrogenase 
increased; CPK increased; Cardiac troponin I increased; Creatinine increased; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other (D-dimer); 
Investigations - Other (urine ketone body present); Lymphocyte count decreased; Neutrophil count decreased; 
Serum amylase increased; Thyroid stimulating hormone increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive); 
Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Chest wall pain; 
Flank pain; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other (muscle 
hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; Rhabdomyolysis 
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); Tumor 
hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory impairment; Nervous system disorders - Other 
(hemiparesis); Nervous system disorders - Other (vocal cord paralysis); Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; Psychiatric 
disorders - Other (mental status changes) 

  
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RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Glucosuria; Renal and 
urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system and breast 
disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; Vaginal inflammation; Vaginal 
perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Allergic 
rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal edema; Oropharyngeal pain; 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 (pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other 
(rales); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; Pain of skin; 
Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and 
erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin hypopigmentation; 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. 
 
Formulation and Stability: 
XL184 is available in 20 mg and 60 mg tablet. The tablets are yellow film coated containing XL184 equivalent to 
20 mg and 60 mg of XL184. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, 
and they are packaged as 30 tablets per HDPE bottle. 
 
XL184 should be dispensed in its original container; however, the tablets can be dispensed in a pill cup with an 
expiration date not to exceed 24 hours. It can also be repackaged in a pharmacy dispensing bottle with expiration 
date not to exceed 7 days.   
 
XL184 (Cabozantinib) Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910 / Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
 
Store intact bottles at controlled room temperature, 200 to 250C (680 to 770F); temperature excursions are permitted 
between 15° C and 30° C (59° F to 86° F) [see USP Controlled Room Temperature].  
If a storage temperature excursion is identified, promptly return XL184 (Cabozantinib) to 20° to 25°C 
(68° to 77° F) and quarantine the supplies.  Provide a detailed report of the excursion (including 

  
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documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
 
 
Stability testing of the intact bottles is ongoing. XL184 (cabozantinib) must be dispensed in original bottles. 
However, repackaging XL184 (cabozantinib) for a short period of time is acceptable and limited to: 
• 
Up to 24 hours when dispensed in an open container such as a pill cup. 
• 
Up to 7 days when dispensed in a closed container (e.g., a pharmacy dispensing bottle).  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
XL184 is administered orally on an empty stomach (do not eat 2 hours before or 1 hour after each dose of 
cabozantinib). Do not crush or chew. Take the dose with a full glass of water approximately at the same time each 
day.  Do not take missed dose within 12 hours of the next dose.  
Hazardous agent: use appropriate precautions for handling and disposal. 
 
Supplier:   
XL184 is supplied by Exelixis and distributed by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
Do not use commercial supply. 
 
Obtaining the Agent 
Agent Ordering 
NCI supplied agent may be requested by the eligible participating investigator (or their authorized designee) at 
each participating institution. 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), NIH Biosketch, Agent 
Shipment Form, 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 
participating investigator at that institution. 
 
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, a “current” password, and active person registration status.  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.   
 
Agent Accountability 
Agent Inventory Records: 
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. 
 
Agent Returns: 
Investigators/Designees must return unused DCTD supplied investigational agent to the NCI clinical repository 
as soon as possible when: the agent is no longer required because the study is completed or discontinued and 
the agent cannot be transferred to another DCTD sponsored protocol; the agent is outdated or the agent is 
damaged or unfit for use. Regulations require that all agents received from the DCTD, NCI be returned to the 
DCTD, NCI for accountability and disposition. Return only unused vials/bottles. Do NOT return opened or 
partially used vials/bottles unless specifically requested otherwise in the protocol. See the CTEP web site for 
Policy 
and 
Guidelines 
for 
Investigational 
agent 
Returns 
at: 

  
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http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The appropriate forms may be 
obtained at: http://ctep.cancer.gov/forms/docs/return_form.pdf.  
 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research staff through 
the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of 
a CTEP IAM account and the maintenance of an “active” account status, a “current” password and active person 
registration status. Questions about IB access may be directed to the PMB IB coordinator via email. 
 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://ctepcore.nci.nih.gov/OAOP/ 
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
7.1 
End of Therapy& Follow-up 
 
 
STUDIES TO BE OBTAINED 
End of Therapy 
History 
X 
Physical Exam with VS 
X 
Ht, Wt, BSA 
X 
Performance Status 
X 
Pregnancy test* 
X 
CBC, differential, platelets 
X 
Urinalysis 
X 
Electrolytes including Ca++, PO4, Mg++ 
X 
Creatinine, SGPT, bilirubin 
X 
Total protein/albumin 
X 
Tumor Disease Evaluation 
X 

  
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CEA and calcitonin (for patients with MTC only) 
X 
*For female patients of childbearing potential.  
 
Follow-up on this study is required at 30 days from the last date of protocol therapy, 6 months 
for the first year from the last date of protocol therapy and annually thereafter for up to five 
years from the date of study entry. 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs). 
 
 
7.2 
Correlative Biology Studies 
 
7.2.1 
Pharmacokinetics 
Pharmacokinetic (PK) studies will be required for the first 18 patients ≥ 2 to < 9 years 
of age at enrollment and optional for all patients ≥ 9 to < 19 years of age at enrollment 
at COG member sites.  
 
Patients enrolled in mandatory PK studies must consent to PK collection and agree to 
provide all required PK samples. 
 
7.2.1.1 Sample Collection and Handling Instructions 
Plasma samples will be collected for the purpose of determining concentrations 
of XL184 and/or metabolite concentrations for pharmacokinetic analysis.  
 
Sampling Schedule and Collection 
• 
Blood samples will be obtained at the following time points: 
o Cycle 1, Day 1: prior to dose; 2, 4, 8, and 20-28 hours after dose. 
o Cycle 1, Day 22 (± 2 days): trough level prior to dose and 2-4 hours post 
dose. As patients may not be receiving the drug on all days of the week, 
care should be taken to draw PK on a day when drug is actually 
administered. 
o Cycle 2, Day 1: prior to dose 
o Cycle 3, Day 1: prior to dose 
 
• 
For each time point, 3 mL of blood must be collected in a chilled K2-EDTA 
Vacutainer tubes (lavender top) 
 
• 
For Cycle 1 Day 1 samples: 
o Record the exact time and date each sample is drawn and the time the 
drug is given.  
 
• 
For Cycle 1 Day 22 samples: 
o Record the exact time and date each sample is drawn and the actual 
date and time the last dose of drug was administered prior to the 
collection of the trough sample. 
 
Sample Processing and Labeling 
• 
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 

  
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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. 
 
• 
Each tube must be labeled with the patient’s COG I.D. and study number. 
(ADVL1622), and the date and time the sample was drawn. Data should be 
recorded on the Pharmacokinetic Study Form, which must accompany the 
sample(s). 
 
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. 
 
7.2.2 
Pharmacodynamics 
For patients who provide consent, the effect of XL184 on immune cell subsets and 
immune gene signature will be analyzed by collecting blood samples at baseline (Cycle 1 
Day 1, prior to 1st dose), Cycles 2 and 3 Day 1 pre-treatment.  
 
7.2.2.1 Sample Collection and Handling Instructions 
 
Sampling Schedule and Collection 
• Blood samples will be obtained at the following time points: 
o Cycle 1, Day 1: prior to first dose 
o Cycle 2, Day 1: prior to dose 
o Cycle 3, Day 1: prior to dose 
 
• For each time point, the following samples will be required: 
o 8 mL CPT citrate tube 
o 2.5 mL PAXgene blood RNA tube 
 

  
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Sample Processing and Labeling 
• Please notify the lab by email (Jane Trepel- trepel@helix.nih.gov; Min-
Jung Lee- leemin@mail.nih.gov; Sunmin Lee-lees@pop.nci.nih.gov) 
that the blood draw has been scheduled.  
 
• 
Immediately after blood collection, blood tubes should be carefully 
inverted several times.  
 
• 
Samples should be collected Monday through Thursday only, to arrive 
Tuesday through Friday. Do not ship to arrive on a government holiday. 
Samples may be shipped at room temp. A refrigerant gel pack such as the 
ThermoSafe Polar Pack PP24 Refrigerant Gel Pack should be included. 
 
• 
Each tube must be labeled with the patient’s COG I.D. and study number 
(ADVL1622), and the date and time the sample was drawn. Data should 
be recorded on the Pharmacodynamic Study Form, which must 
accompany the sample(s). 
 
Sample Shipping Instructions 
Notify the lab when the sample is being shipped, including in the email the 
FedEx tracking number. Send samples by FedEx Priority Overnight 
Shipping. The NIH is not open on weekends or government holidays. Be 
careful not to ship any samples to arrive on a Saturday, Sunday or government 
holiday. If you are not certain whether the government will be open please 
send an email to the addresses below at any time and we will respond as 
quickly as possible.  
 
Ship Monday-Thursday only by FedEx Priority Overnight to:  
 
Trepel Lab, Developmental Therapeutics Branch, NCI, NIH  
Bldg 10, Rm  12C208  
10 Center Drive  
Bethesda, MD 20892  
Phone: 301-496-1547 
 
Please notify the lab by email (Jane Trepel trepel@helix.nih.gov; Min-
Jung Lee leemin@mail.nih.gov; Sunmin Lee lees@pop.nci.nih.gov) when the 
sample is being shipped and include the tracking number.  
 
Refer to the Trepel Lab Manual for additional details related to this correlative 
study. 
 
7.2.3 
Tissue Banking Study 
Submission of tumor tissue to be banked for future research studies is strongly 
encouraged. Tumor tissue obtained as a result of biopsy or resection at initial diagnosis, 
and/or of a suspected disease recurrence site prior to therapy, and/or of a suspected 
disease recurrence during the first 12 months from the time of enrollment is requested 
for banking. Snap frozen, formalin-fixed and paraffin-embedded (FFPE) blocks or 
unstained slides (at least 10 cut sequentially from the same block) will be accepted.  
 
COG sites: if a block or unstained slides have been submitted already on APEC14B1 
(Project:EveryChild), additional tissue is not required. 

  
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Sample Labeling and Shipping  
Label biology specimens with:  
• 
the patient’s COG ID number  
• 
specimen type (primary or metastatic)  
• 
collection date 
Include the surgical pathology ID (SPID) number and block number in the labeling 
when submitting a block or slides.  
 
Include a transmittal form, pathology report and operative report with each 
shipment. 
 
The Biopathology Center (BPC) will provide a specimen procurement kit for shipping 
frozen tumor tissue to the BPC. Kits are provided to sites in the US and Canada only.   
 
COG sites: Kits are ordered via the BPC Kit Management application. To access the 
application click on the ‘Biopathology Center Application’ link on either the Protocol 
or the CRA Home Page of the COG web site. On the Biopathology Center Applications 
page, select the BPC Kit Management link to enter the Kit Management application. 
 
Non-COG Sites: Sites can order kits online via the Kit Management link 
http://ricapps.nationwidechildrens.org/BPCKitManagement/.  
 
• 
Snap frozen tissue must be sent on dry ice. Using at least 4 lbs. total, layer dry 
ice in the bottom of the kit until it is approximately one third full. Place the 
frozen specimens on top of the dry ice. Cover the specimens with dry ice until 
the compartment is almost completely full. Secure the foam lid. Remember to 
include the COG Specimen Transmittal Form, pathology report and operative 
report with each shipment. Close the outer lid of the kit and tape with filament 
or other durable packing tape.  
 
• 
Attach a label to the top of the kit. COG sites will access the Kit Management 
application to print a FedEx shipping label. Non-COG sites should contact the 
BPC 
by 
phone 
(800-347- 
2486) 
or 
email 
(BPCBank@nationwidechildrens.org) to request a shipping label. A blank 
label is provided in the kit to use when printing the shipping label. A shipping 
label will only be provided when frozen tissue is submitted. Blocks and 
slides must be shipped using the institution’s courier account or regular mail. 
Complete the dry ice label (UN 1845) and secure both this label and the 
Exempt Human Specimen label to the side of the box. 
 
Send samples to:  
Biopathology Center Nationwide Children’s Hospital  
Protocol ADVL1622  
700 Children’s Drive, WA1340*  
Columbus, OH 43205  
Phone: (614) 722-2865  
Fax: (614) 722-2897  
Email: BPCBank@nationwidechildrens.org  
 
*Be sure to include the room number. Packages received without the room number 
may be returned to the sender. 

  
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Specimens should be shipped Monday through Thursday by Priority Overnight for 
delivery Tuesday through Friday. Do not ship any of the specimens for this protocol 
to the BPC for Saturday delivery.  
 
7.3 
Central Review 
 
The pertinent imaging studies (CT, MR, etc.) of those patients who respond to therapy or have 
long term stable disease on protocol therapy will be centrally reviewed. COG Operations 
Center will notify the Imaging Research Center of any patient requiring central review. The 
Imaging Research Center will then request that the treating institution forward the pertinent 
images for central review. The central image evaluation results will be entered into Rave for 
review and for data analysis.  
 
Long term stable disease for central review is defined as having at least 6 consecutive cycles 
of stable disease for the non-osteosarcoma strata and at least 4 consecutive cycles for the 
osteosarcoma stratum. 
 
The images are to be forwarded electronically to the Imaging Research Center at Children’s 
Hospital Los Angeles via the ImageInBox. 
 
Institutions that are not connected via the ImageInBox can send the images on hard copy film, 
CD ROM, DVD, USB flash drive or by FTP. Submitted imaging studies should be clearly 
marked with the COG patient ID, study number (ADVL1622) and date, and shipped to Syed 
Aamer at the address below: 
 
Syed Aamer, MBBS, CCRP 
Administrator, Imaging Research Center 
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone:  (323) 361-3898 
Fax: 
(323) 361-3054 
Email: saamer@chla.usc.edu  
 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA  
 
8.1 
Criteria for Removal From Protocol Therapy 
a) Progressive disease. 
b) Adverse Events requiring removal from protocol therapy, as stated in Section 5.0. 
c) Patients who receive concurrent anticancer or investigational therapy, as stated in 
Section 4.1.4. 
d) Refusal of further protocol therapy by patient/parent/guardian. 
e) Physician determines it is in patient’s best interest. 
f)  Repeat eligibility studies (if required) are outside the parameters required for eligibility. 
g) Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
h) Patients who develop a second malignant neoplasm. 

  
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i) Pregnancy. 
j) Study is terminated by sponsor. 
 
Patients who are removed from protocol therapy (except for 8.1.f) are to be followed until they 
meet the criteria for Off Study (see below). Follow-up data will be required unless consent was 
withdrawn.   
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Entry into another COG study with tumor therapeutic intent (e.g., at recurrence). 
d) Patient does not receive protocol treatment after study enrollment. 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 

  
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9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
Sample Size and Study Duration 
 
9.1.1 
Non-osteosarcoma strata 
 
Three disease strata have been identified for reporting upon completion of evaluation 
of each particular disease stratum (“primary disease groups”). These strata are: (1) 
Ewing sarcoma; (2) rhabdomyosarcoma; and (3) non-rhabdomyosarcoma soft tissue 
sarcoma. The evaluation rule is described in Section 9.2 below. 
 
In addition to the three main strata, enrollment into each of the following tumor groups 
(“secondary strata”): (4) Wilms tumor, and (5) rare tumors (medullary thyroid 
carcinoma, renal cell carcinoma, hepatocellular carcinoma, hepatoblastoma, 
adrenocortical carcinoma, and pediatric solid tumors with known molecular alterations 
in the targets of XL184); will be open to accrual. If thirteen response-evaluable patients 
of a particular histology are enrolled in any of the secondary strata, the two-stage 
design described in Section 9.2 below will be applied to that particular histology. (That 
is, up to seven additional response-evaluable patients with that tumor type may be 
studied.) 
 
If two of the three primary disease strata (Ewing sarcoma, rhabdomyosarcoma, and 
non-rhabdomyosarcoma STS) have met their accrual and one remains open, the Cancer 
Therapy Evaluation Program (CTEP) and the ADVL1622 Investigators will discuss 
the study timeline. 
 
Review of patient accrual onto recent phase 2 solid tumor studies indicates the 
following entry rates for the various tumors under study can be expected: 
 
Disease Group/Strata 
 
    Patients/Year 
Ewing sarcoma  
                         18 
Rhabdomyosarcoma 
 
            18 
Non-rhabdomyosarcoma STS             10 
 
With these entry rates, the probability of accruing 13 patients to complete the initial 
stage of evaluation in the three primary disease groups within 19 months is 80% and 
within 24 months is 90%. The corresponding probability for enrolling 20 patients in 
the three named disease categories within 28 months is 80% and within 37.5 months 
is 90%. The study will likely require 2 to 3 years for sufficient patient enrollments to 
evaluate response in the primary disease groups. If activity is detected in any category, 
further trials in subcategories of category may be conducted at the discretion of the 
Developmental Therapeutics Steering and study committees. If all three statistical 
cohorts are finished accruing (either all 20 patients or 13 patients with the early 
stopping criterion met), the Study Committee will evaluate the non-statistical strata 
and make a decision whether to continue accrual to those strata. A minimum of 39 
patients and a maximum of 110 patients are anticipated to get either 13 or 20 patients 
evaluable for response in each statistical stratum. 
 
 
 
9.1.2 
Osteosarcoma Cohort 
 

  
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Review of patient accrual onto recent phase 2 solid tumor studies indicates the 
following entry rates for the osteosarcoma stratum can be expected: 
 
Disease Group/Strata 
 
    Patients/Year 
Osteosarcoma 
 
            22 
 
With this entry rate, the probability of accruing 19 patients to complete the initial stage 
of evaluation in the osteosarcoma stratum within 12.3 months is 80% and within 18.2 
months is 90%. The corresponding probability for enrolling 29 patients in the 
osteosarcoma stratum within 20 months is 80% and within 26 months is 90%. The 
osteosarcoma will likely require 1.5 to 2.5 years for sufficient patient enrollments to 
evaluate response in osteosarcoma.  A minimum of 19 patients and a maximum of 36 
patients are anticipated to get either 19 or 29 patients evaluable for response in the 
osteosarcoma stratum. 
 
When the evaluation of the statistical strata (Ewing’s sarcoma, rhabdomyosarcoma, 
non-rhabdomyosarcoma STS, and osteosarcoma) is complete, enrollment to the study 
will be terminated. The non-statistical cohorts will remain open to enrollment until the 
statistical strata are closed to accrual unless the DVL committee leadership indicates 
further enrollment on the secondary strata is warranted. 
 
9.2 
Study Design 
 
9.2.1  Non-osteosarcoma Strata 
 
The primary endpoint for the non-osteosarcoma strata will be objective response by 
RECIST criteria v 1.1. The best response of disease to XL184 (defined in Section 10.4) 
will be examined separately in each of the 3 primary disease groups. If 13 patients of 
the same histology enroll on either of the secondary strata (i.e., 13 Wilms tumor 
patients or 13 of the same type of eligible rare tumor patients), then the rule below will 
be applied to that group of patients. The following Simon’s minimax two-stage design 
will be used in all the non-osteosarcoma strata. 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: 
Enter 13 
patients 
0 
Terminate the trial early: agent ineffective 
1 or more 
Inconclusive result, continue trial  
 
(proceed to Stage 2) 
Stage 2: 
Enter 7 
additional 
patients 
2 or fewer      
Terminate the trial: agent ineffective 
3 or more 
Terminate the trial: agent effective 
 
We will consider the agent not of sufficient interest for further evaluation in a disease 
category if the true response rate is 5% and of sufficient activity if the true response 
rate is 25%. If the agent has a true response rate of 5%, the rule described above will 
identify it of sufficient activity for further study with probability 0.074 (type I error), 

  
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and the trial will have an expected sample size of 16.4 with 51.3% probability of early 
termination. If the agent has a true response rate of 25%, the rule described above will 
identify it of sufficient activity for further study with probability 0.903 (power against 
the alternative hypothesis p = 0.25). An expanded table of possibilities is below: 
 
True 
response 
rate 
Probability of 
stopping early for 
lack of activity 
Probability of 
identifying agent 
as effective 
Expected 
number of 
patients accrued 
5% 
0.513 
0.074 
16.41 
10% 
0.254 
0.317 
18.22 
15% 
0.121 
0.586 
19.15 
20% 
0.055 
0.786 
19.62 
25% 
0.024 
0.903 
19.83 
30% 
0.010 
0.961 
19.93 
35% 
0.004 
0.986 
19.97 
 
9.2.2  Osteosarcoma stratum-specific Design 
 
For the osteosarcoma stratum, patients will be enrolled in two stages. In the first stage, 
19 disease control and RECIST response evaluable patients will be enrolled. Each 
patient will be evaluated for both outcome measures: (1) disease control success; and 
(2) RECIST response (CR or PR v. not CR or PR). The decision rule for the two stage 
study design is summarized as:   
 
 
Cumulative response results 
Decision 
Stage 1: 
Enter 19 
patients 
≤4 disease control successes AND 
≤1 RECIST responders 
Terminate the trial early: 
agent ineffective 
 
≥5 disease control successes OR 
≥2 RECIST responders 
Inconclusive result, continue 
trial (proceed to Stage 2) 
Stage 2: 
Enter 10 
additional 
patients 
≤8 disease control successes AND 
≤4 RECIST responders 
Terminate the trial: agent 
ineffective 
 
≥9 disease control successes OR 
≥5 RECIST responders 
Terminate the trial: agent 
effective 
 
Design Characteristics: Each patient enrolled will be evaluated for: (1) complete or 
partial response as defined by the RECIST criteria where the first evaluation of CR 
or PR is made at or before the end of the sixth cycle of study therapy (denoted as 
R below); or (2) stable disease after four months of therapy or at the end of the 
sixth cycle, whichever occurs first (denoted as S below). We will not be 
interested in promoting the agent for further investigation if the probability of 
response in any particular individual is less than or equal to 0.05 (P(R)≤0.05) and 
the probability of remaining analytic event free in any particular individual is less 
than or equal to 0.20 (P(S)≤0.20). We will be interested in promoting the agent for 
further investigation if the probability of response in any particular individual is 

  
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at least 0.22 (P(R)≥0.22) or the probability of remaining analytic event free 
in any particular individual is at least 0.42 (P(S)≥0.42). 
 
For the calculations below, it is assumed Pr (S | R) = 0.90. 
 
The statistical characteristics of this design are: 
 
Probability of four 
month disease 
control 
Probability of 
RECIST 
response 
Probability of 
Stopping After Stage 
1 (and concluding the 
drug is ineffective) 
Probability of 
Concluding the 
Drug is Ineffective 
at the Conclusion 
of the Trial 
Probability of 
Concluding the 
Drug is Effective 
at the Conclusion 
of the Trial 
0.20 
0.05 
0.56 
0.89 
0.11 
0.42 
0.22 
0.014 
0.05 
0.95 
0.42 
0.05 
0.044 
0.096 
0.904 
0.20 
0.22 
0.056 
0.21 
0.79 
 
  
9.3 
Methods of Analysis 
 
Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and 
grade. A patient will be counted only once for a given toxicity for the worst grade of that 
toxicity reported for that patient. Toxicity information recorded will include the type, severity, 
time of onset, time of resolution, and the probable association with the study regimen.   
 
Time-to-event analyses (time to progression, progression-free survival, and overall survival) 
will be computed when all patients in a stratum have at least one year of follow-up. 
 
9.3.1 
RECIST Response Criteria for all strata 
 
Response criteria are described in Section 10. A RECIST responder is defined as a 
patient who achieves a best response (as defined in Section 10.6) of PR or CR on the 
study. Response rates will be calculated as the percent of RECIST response-evaluable 
patients who are responders, and confidence intervals will be constructed accounting 
for the two-stage design. 
 
9.3.2  Disease control for osteosarcoma stratum 
 
Any patient who is evaluated free of all detectable disease (complete response) or is 
considered as having a partial response or is considered as having stable disease (‘at 
least stable disease’) after four months of therapy or at the end of the sixth cycle, 
whichever occurs first, will be considered a disease control success. 
 
Any evaluable patient who does not meet the criteria for disease control success 
(complete response, partial response or stable disease) will be considered to not have 
experienced disease control success. 
 
In particular, any patient who dies because of treatment-related toxicity during the first 
six cycles of therapy and/or within the first four months since starting treatment will  
be considered not to have experienced disease control success. Also, any patient who 
is eligible, receives one dose of XL184 and is lost to follow-up at (for example) the 
end of cycle 2 will not be considered a disease control success (complete response, 
partial response or stable disease)  
 

  
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Patients who are not evaluable for both disease control and response evaluation may 
be replaced for the purposes of the statistical rule. 
 
9.3.3 
Osteosarcoma Estimation of Disease Control and RECIST Response Rates 
 
 
P(R) and P(S) for the osteosarcoma cohort will be estimated using the maximum 
likelihood estimates, viz. 
 
 
R
S
Number of Patients Considered as PR or CR
ˆ
P(R) ˆ
Number of Response-Evaluable Patients in Cohort
Number of Patients with Disease Control at 4 Months
ˆ
P(S) ˆ
Number of Response-Evaluable Patients in 
p
p
=
=
=
=
Cohort
 
 
Confidence intervals will be constructed using the approximate normal distribution of 
each of the estimates and their asymptotic variances: 
 
R
R
R
S
S
S
ˆ
ˆ
(1
)
ˆ
V(
) ˆ Number of Response-Evaluable Patients in Cohort
ˆ
ˆ
ˆ
V(
) ˆ Number of Response-Evaluable Patients i
(
n Coh
t
1
or
)
p
p
p
p
p
p
−
−
=
=
 
           
9.3.4 
Adverse Event Monitoring Rule 
We will use a Bayesian rule to monitor for protocol-specific toxicities. We will assume 
a beta prior distribution with α = 0.52 and β = 2.08. At least once per month, we will 
calculate the posterior probability (given the data) that the probability of protocol-
specific toxicity exceeds the 20% threshold: 
 
 
 
Here n is the number of protocol-specific toxicity-evaluable cycles and x is the number 
of such cycles on which a protocol-specific toxicity event is observed. Examples of 
situations in which this rule will indicate protocol-specific toxicities have been noted 
and are presented below: 
 
Number of failures Number of patient-cycles 
2 
6 
3 
10 
4 
14 
5 
19 
6 
23 
7 
28 
8 
32 
9 
37 
10 
41 
11 
46 
12 
51 

  
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13 
55 
14 
60 
 
Protocol-specific toxicities of interest include fatigue, headache, proteinuria, hypertension, 
reversible 
posterior 
leukoencephalopathy 
syndrome 
(RPLS), 
palmar-plantar 
erythrodysesthesia, oral mucositis, ALT increase, lipase increase, bilirubin increase, diarrhea, 
thrombocytopenia, hypothyroidism, nausea, anorexia, neutropenia, weight loss and vomiting. 
 
If there is strong evidence (posterior probability of at least 70% with at least 2 observed 
toxicities) that there is a per course protocol-specific toxicity probability of more than 20%, 
such information will be presented to the DSMC. 
 
9.4 
Evaluability for Response 
Any patient who is enrolled and receives at least one dose of XL184 will be considered 
evaluable for response and disease control provided: (1) the patient demonstrates progressive 
disease or death while on protocol therapy; or (2) the patient is observed on protocol therapy 
for at least one cycle and the tumor is not removed surgically prior to the time complete 
response or partial response is confirmed, or (3) the patient demonstrates a complete or partial 
response as confirmed according to protocol criteria. Patients who demonstrate a complete or 
partial response confirmed by central review will be considered to have experienced a response 
for the application of the rule given in Section 10.2. The evaluation period for determination 
of the best response will be 6 treatment cycles. All other patients will be considered non-
responders. All patients considered to have a response (CR or PR) must have imaging studies 
reviewed centrally at the COG. Centers will be notified by the COG about requests for scans 
of patients with stable disease. See Section 7.3 regarding shipping instructions. Preliminary 
assessment of activity using institutionally provided tumor measurements will be entered into 
CDUS quarterly. The central review by COG will be provided as the final reviewed assessment 
of response when such becomes available. 
 
9.5 
Evaluability for Toxicity 
All patients who receive at least one dose of XL184 according to protocol guidelines will be 
considered in the evaluation of toxicity. 
 
 
9.6 
Evaluability for Pharmacokinetic Analysis 
 
 
Any patient who is enrolled, participates in the PK study, and receives the full dose of XL184 
on Cycle 1 Day 1 will be considered evaluable for PK analysis provided that the patient 
completes Cycle 1 Day 1 sample collection. 
 
Because PK can be evaluated in many different ways depending on how PK parameters are 
presented, the statistical analysis of the PK studies will proceed as follows: 
 
1) A descriptive analysis of the pharmacokinetic parameters of cabozantinib will be performed to 
define Day 1 systemic exposure. Parameters to be collected are: AUC (0-24h), Cmax, Tmax, and 
accumulation (the concentration before the dose on Day 22 divided by the concentration 24 
hours after the Day 1 dose). The PK parameters will be summarized with the following summary 
statistics: mean, median, range, and standard deviations (numbers and distribution permitting). 
 
  
2) The PK data in this study will be combined with the PK data from ADVL1211 for a population 
PK analysis to evaluate the effect of age on the clearance of XL184. The effect of age will be 
analyzed using the likelihood ratio test as implemented in the program NONMEM. 

  
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9.7 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
 
1 
 
 
1 
Asian 
2 
4 
 
 
6 
Native Hawaiian or 
Other Pacific Islander 
 
 
 
 
 
Black or African 
American 
4 
17 
 
 
21 
White 
47 
44 
8 
19 
118 
More Than One Race 
 
 
 
 
 
Total 
53 
66 
8 
19 
146 
 
This distribution was derived from the patients on ADVL0821, ADVL0921, and AOST1521 with 
diagnoses among the primary disease groups. 
 
9.8 
Analysis of the Pharmacokinetic Parameters 
PK will be required in the first 18 patients less than 9 years of age, then not done on the 
remaining patients in this age group. PK will be optional for all patients 9–18 years old. PK will 
not be done in patients older than 18. 
 
The clearance will be measured in the 2–8-year-olds (<9 year olds) and compared to historical 
data from ADVL1211. The test will be a one-sample equivalence test (using the two one-sided 
test (TOST) methodology of Schuirmann)40 of log(Clearance) compared to the historical data 
with mean 7.584 and standard deviation 0.383 on the log scale. The lower and upper equivalence 
boundaries will be 60% and 140%, respectively (–0.512 and 0.336 on the log scale). Equivalence 
will be declared if the two-sided 95% confidence interval on the log scale is entirely contained 
within the interval (–0.512, 0.336). The power of the test for various combinations of the true 
population mean and standard deviation in the 2–8-year-old population are displayed below.   
 
Power for sample size n = 18 
Ratio of 
means on 
raw scale 
Difference 
of means on 
log scale 
Actual variability on log scale 
(σ0 = 0.383) 
σ0 
1.25σ0 
1.5σ0 
0.90 
–0.105 
98.5% 
88.2% 
67.3% 
0.95 
–0.051 
97.8% 
86.7% 
66.0% 
1.00 
  0.000 
93.9% 
79.1% 
59.2% 
1.05 
  0.049 
84.8% 
66.3% 
48.7% 

  
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1.10 
  0.095 
69.4% 
50.5% 
36.6% 
 
If the true population mean and standard deviation are identical to the historical data (i.e., ratio 
of means on raw scale = 1 and actual variability on log scale = σ0 = 0.383), the test will have 
93.9% power to declare equivalence. If the true population mean is equal to the historical data, 
the test will still have 79.1% power to declare equivalence if the variability on the log scale is 
25% higher than expected and 59.2% power if the variability on the log scale is 50% higher than 
expected. 
 
If the trial is closed prior to enrolling 18 patients less than 9 years of age, the PK analysis will 
be done on just the enrolled patients. 
 
9.9 
Analysis of Biological and Correlative Endpoints 
The association between the host immune system and response to XL184 will be assessed in an 
exploratory manner. Immune biomarkers will be divided at their observed median at baseline, 
Cycle 2 Day 1 (pre dose), and Cycle 3 Day 1 (pre dose), as well as with respect to change from 
baseline. Then, each biomarker will be correlated with the clinical outcomes of objective 
response and progression free survival. 
 
Objective response will be assessed using the exact conditional test of proportions and 
progression-free survival will be assessed using the Log-rank test with hazard ratios estimated 
from a Cox proportional hazards regression model. 
 
 
10.0 EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. The descriptions and grading scales found in the revised CTCAE 
version 5.0 will be utilized for reporting. All appropriate treatment areas should have access to 
a copy of the CTCAE version 5.0, which can be downloaded from the CTEP web site ( 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
). Additionally, toxicities are to be reported on the appropriate case report forms. 
 
10.2 
Response Criteria  
As outlined, patients will be assigned to one of the following categories for assessment of response:  
solid tumor and measurable disease (Section 10.3 below). Note: Neuroblastoma patients who do 
not have MIBG positive lesions or bone marrow involvement should be assessed for response as 
solid tumor patients with measurable disease.  
 
10.3 
Response Criteria for Patients with Solid Tumors (non-CNS) 
Response and progression will be evaluated in this study using the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1).41 Key points are that 5 target 
lesions are identified and that changes in the largest diameter (unidimensional measurement) 
of the tumor lesions are used in the RECIST v 1.1 criteria. 
 
10.3.1 Measurable Disease  
The presence of at least one lesion that can be accurately measured in at least one 
dimension with the longest diameter at least 10 mm (CT scan slice thickness no greater 
than 5 mm). The investigator will identify up to 5 measurable lesions to be followed 

  
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for response. Previously irradiated lesions must demonstrate clear evidence of 
progression to be considered measurable. 
 
Serial measurements of lesions are to be done with appropriate imaging modalities, 
e.g., CT or MRI. Bone scans cannot be used to measure lesions. The same method of 
assessment is to be used to characterize each identified and reported lesion at baseline 
and during follow-up. 
 
10.3.2 Quantification of Disease Burden 
The sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the disease measurement. 
 
10.3.3 End-of-Cycle Response 
Note:  Please also see Table 1 in Section 10.6. 
 
a) Complete Response (CR)  
Disappearance of all target and non-target lesions. Normalization of urinary 
catecholamines (for patients with neuroblastoma), or other tumor markers if 
abnormal or elevated at study enrollment.  
 
b) Partial Response (PR) 
At least a 30% decrease in the disease measurement, taking as reference the disease 
measurement done to confirm measurable disease at study enrollment. No new 
lesions or progression of any non-target measurable lesion. 
 
c) Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD taking as reference the smallest disease measurement since the treatment 
started. 
 
d) Progressive Disease (PD)  
At least a 20% increase in the sum of the disease measurements for measurable 
lesions, taking as reference the smallest disease measurement recorded since the 
start of treatment, or the appearance of one or more new lesions. 
 
 
10.3.4 Overall Best Response Assessment   
Each patient will be classified according to their “best response” for the purposes of 
analysis of treatment effect. Best response is determined from the sequence of the 
objective statuses described in Section 10.6. 
 
 
10.4 
Response Criteria for Neuroblastoma Patients with 123I-MIBG Positive Lesions 
 
10.4.1 MIBG Positive Lesions 
Patients with measurable disease who have a positive MIBG scan at the start of therapy 
should also be evaluable for MIBG response. The use of 123I for MIBG imaging is 
recommended for all scans.  
 
10.4.2 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. 

  
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• 
Stable Disease: No change in MIBG scan in number of positive lesions (includes 
patients who have same number of positive lesions but decreased density). 
• 
Progressive Disease: Development of new MIBG positive lesions. 
 
10.4.3 The response of MIBG lesions will be assessed on central review using the Curie scale 
as outlined below. Central review responses will be used to assess efficacy for study 
endpoint. See Section 7.3 for details on transferring images to the Imaging Research 
Center. 
 
NOTE: This scoring is NOT required to 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: 
 
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 3 weeks 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  
 

  
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10.4.4 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of 
analysis of treatment effect. Best response is determined from the sequence of the 
objective statutes described in Table 2 in Section 10.6. 
 
10.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement  
 
10.5.1 Bone Marrow Involvement  
Bone Marrow response is 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 3 
weeks apart. Normalization of urinary catecholamines or other tumor markers if 
elevated at study enrollment.  
▪ 
Progressive Disease:  
o 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%). 
o 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 3 weeks apart. 
▪ 
Stable Disease: Persistence of tumor in bone marrow that does not meet the criteria 
for either complete response or progressive disease. 
 
10.5.2 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of 
analysis of treatment effect. Best response is determined from the sequence of the 
objective statutes described in Section 10.6. 
 
10.6 
Best Response (Solid Tumors) 
Two objective status determinations of disease status, by CT or MRI, obtained on two 
consecutive determinations, separated by at least a 3 week time period, are required to 
determine the patient’s overall best response. Two objective status determinations of CR before 
progression are required for best response of CR. Two determinations of PR or better before 
progression, but not qualifying for a CR, are required for a best response of PR. Two 
determinations of stable/no response or better before progression, but not qualifying as CR or 
PR, are required for a best response of stable/no response; if the first objective status is 
unknown, only one such determination is required. Patients with an objective status of 
progression on or before the second evaluations (the first evaluation is the first radiographic 
evaluation after treatment has been administered) will have a best response of progressive 
disease. Best response is unknown if the patient does not qualify for a best response of 
progressive disease and if all objective statuses after the first determination and before 
progression are unknown. 
 
 
 
Table 1: Sequences of objective statuses with corresponding best response. 
1st Status 
2nd Status 
3rd Status 
Best Response 
Progression 
 
 
Progressive disease 
Stable, PR, CR 
Progression 
 
Progressive disease 

  
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Unknown 
Progression 
 
Progressive disease 
Stable 
Stable 
Progression 
Stable 
Stable, Unknown 
PR, CR 
Progression 
Stable 
Stable, Unknown 
Unknown 
Progression 
Unknown 
PR 
PR 
Progression 
PR 
PR 
CR 
Progression 
PR 
PR, CR 
Unknown 
Progression 
Unknown 
CR 
CR 
Progression 
CR 
Unknown 
Stable 
Progression 
Stable 
 
Table 2: 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 
 
 
10.7 
Response Criteria for Patients with CNS Tumors 
 
10.7.1 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. 
 
10.7.2 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 and non-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. 
 

  
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• 
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. 
 
• 
Progressive Disease (PD): 25% or more increase in the product of perpendicular 
diameters of ANY target lesion, taking as reference the smallest product observed 
since the start of treatment, or the appearance of one or more new lesions. 
 
10.7.3 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. 
 
 
10.7.4 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally high 
levels. 
 
10.7.5 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 10.6 
from a sequence of overall response assessments. 
 
 
11.0 ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event (AE) 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 

  
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enroll in future studies using similar agents. Certain adverse events must be reported in an 
expedited manner to allow for timelier monitoring of patient safety and care. The following 
sections provide information about expedited reporting. 
 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI requires 
that AEs be submitted according to the timeframes in the AE reporting table assigned to the 
protocol, using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any untoward 
medical occurrence associated with the use of a drug in humans, whether or not considered 
drug related. A Serious Adverse Event (SAE) is any adverse drug event (experience) occurring 
at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part of 
routine medical practice. 
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 a serious adverse drug experience 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. 
 
11.3 
Specific Examples for Expedited Reporting  
11.3.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last administration 
of the investigational agent/intervention and has an attribution of a possible, probable, 
or definite relationship to the study therapy must be reported according to the CTEP-
AERS reporting table in this protocol.  
 
11.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
anomalies or birth defects, must be reported via CTEP-AERS if it occurs at any time 
following treatment with an agent under a NCI IND/IDE since these are considered serious 
AEs. 
 
11.3.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: “Newborn deaths occurring during the first 28 days after 
birth” 
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 

  
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onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
progression)” under the system organ class (SOC) of “General disorder and 
administration site conditions”. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
 
11.3.4 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 
metastasis of the initial neoplasm is not considered a secondary malignancy.  
The NCI 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:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) must also 
be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.3.5 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. 
 
11.3.6 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal loss”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregnancy
ReportForm.pdf, needs to be completed and faxed along with any additional medical 
information to (301) 230-0159. The potential risk of exposure of the fetus to the 
investigational agent(s) or chemotherapy agent(s) should be documented in the 
“Description of Event” section of the CTEP-AERS report. 
 
11.3.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs to 

  
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be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other (pregnancy)” 
under the Pregnancy, puerperium and perinatal conditions SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the baby is 
born with a birth defect or anomaly, then a second CTEP-AERS report is 
required. 
 
11.3.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
Any pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event since 
CTEP-AERS recognizes any Grade 5 event as a patient death 
 
11.3.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as Newborn deaths occurring during the 
first 28 days after birth” needs to be reported expeditiously, as Grade 4 
”Death neonatal” under the “General disorders and administration” 
SOC when the death is the result of a patient pregnancy or pregnancy 
in partners of men on study. Do NOT report a neonatal death resulting from 
a patient pregnancy or pregnancy in partners of men on study as a Grade 5 
event since CTEP-AERS recognizes any Grade 5 event as a patient death.  
 
11.4 
Reporting Requirements for Specialized AEs  
11.4.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an AE, 
when possible it is to be documented as “Course Zero” using CTCAE terminology and 
grade. An expedited AE report is not required if a patient is entered on a protocol with 
a pre-existing condition (e.g., elevated laboratory value, diarrhea). The baseline AE 
must be re-assessed throughout the study and reported if it fulfills expedited AE 
reporting guidelines. 
a. If the pre-existing condition worsens in severity, the investigator must reassess 
the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event to 
determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities existing 
at baseline. 
 
11.4.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between treatment 
cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade becomes 
more severe in a subsequent course. If the grade becomes more severe the AE must be 
reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade becomes 
more severe in the same or a subsequent course. 
 
11.4.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy and 
then reoccurs in a later cycle/course. 

  
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ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.5 
Exceptions to Expedited Reporting 
11.5.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and Potential 
Risks (CAEPR) that contains a list of events that are considered expected for CTEP-
AERS reporting purposes. (Formerly referred to as the Agent Specific Adverse Event 
List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the NCI 
via CTEP-AERS ONLY if they exceed the grade of the event listed in parentheses after 
the event. If the CAEPR is part of a combination IND using multiple investigational 
agents and has an SAE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
11.5.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is listed 
as expected. The exception or acceptable reporting procedures will be specified in the 
protocol. The protocol specific guidelines supersede the NCI Adverse Event Reporting 
Guidelines. These special situations are listed under the CTEP-AERS reporting table 
for this protocol. 
 
11.6 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports in 
a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report Form 
(CRF) within the study database.   
 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting and are located on the 
CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTCAE. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted electronically to NCI via CTEP-AERS at: https://eapps-ctep.nci.nih.gov/ctepaers 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to be 
made to the NCI for agents supplied under a CTEP IND by telephone call to (301) 897-7497.  
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must be entered into the electronic CTEP-AERS system by the original submitter of the report 
at the site.   
 
• 
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 event, 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 the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect, or is an 
IME, which based upon the medical judgment of the investigator may jeopardize the 
patient and require intervention to prevent a serious AE, must be reported via CTEP-
AERS if the event occurs following investigational agent administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of possible, 
probable, or definite to an agent/intervention under an NCI IND/IDE requires expedited 
reporting within 24 hours.  
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 1) 
whether the patient has received at least one dose of an investigational agent on this study; 2) 
the characteristics of the adverse event including the grade (severity), the relationship to the 
study therapy (attribution), and the prior experience (expectedness) of the adverse event; 3) the 
phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or prolongation of 
hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (e.g., H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to the 
NCI. NOTE: English is required for supporting documentation submitted to the numbers 
listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under a 
CTEP IND to: (301) 230-0159 (back-up: (301) 897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# (310) 640-
9193; email: COGAERS@childrensoncologygroup.org; Attention: COG AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 

  
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11.8 
Reporting Table for Late Phase 2 and Phase 3 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 
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) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours. This  does not include hospitalizations that are part of routine medical practice. 
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 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour 
Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar 
Days 
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. Additional Special 
Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“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 
notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of 
learning of the AE.  
 
1SAEs 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 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 

  
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11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
• 
Grades 1- 4 myelosuppression (anemia, neutropenia, thrombocytopenia, leukopenia, 
lymphopenia) do not require expedited reporting unless it is associated with 
hospitalization.  
 
11.10 Routine Reporting of Adverse Events 
Note: The guidelines below are for routine reporting of study specific adverse events on the 
COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) within 
the study database. For this study, routine reporting will include all CTEP-AERS reportable 
events and Grade 3 and higher Adverse Events. 
 
 
12.0 STUDY REPORTING AND MONITORING 
 
The Case Report Forms and the submission schedule are posted on the COG website with each protocol 
under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP by 
electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS reporting 
is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research by 
the Children’s Oncology Group, the COG Data and Safety Monitoring Committee (DSMC) 
reviews reports of interim analyses of study toxicity and outcomes prepared by the study 
statistician, in conjunction with the study chair’s report. The DSMC may recommend the study 
be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified in the 
protocol document. 
 
 
12.3 
CRADA/CTA 
 
NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving Agent(s) 
Covered by a Clinical Trials Agreement (CTA), a Cooperative Research and Development 
Agreement (CRADA) or a Clinical Supply Agreement, hereinafter referred to as 
Collaborative Agreement: 
 

  
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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 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 Agent(s), each the subject of different Collaborative 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 NCI, 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 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 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available 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. 

  
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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 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. 
 
 
 

  
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all investigators participating in any NCI-sponsored clinical trial to register and to renew their 
registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions, please 
contact the CTEP Investigator Registration Help Desk by email at <pmbregpend@ctep.nci.nih.gov>. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application 
is a web-based application intended for use by both Investigators (i.e., all physicians involved in the 
conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-
sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator 
Registration Procedures above for information on registering with CTEP as an Investigator, which must 
be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support 
Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact the 
CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the ADVL1622 protocol page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted and is based on person and site roster assignment housed in the CTSU RSS. 
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 

  
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▪ Click on the Protocols tab in the upper left of your screen 
▪ Click on the By Lead Organization folder to expand 
▪ Click on the COG link to expand, then select trial protocol ADVL1622 
▪ Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided. 
 
Requirements for ADVL1622 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI CIRB)  
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
Online: www.ctsu.org   (members’ section) → Regulatory Submission Portal 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
Fax: 
215-569-0206 
Phone: 1-866-651-2878 
Mail: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page of 
the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password 
▪ Click on the Regulatory tab at the top of your screen 
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 
 
 
 

  
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Page 90 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to regularly 
consult frequently updated medical references. 
 
 
CYP3A4 substrates  
Strong 
Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant5 
atorvastatin5 
benzodiazepines 
bortezomib 
brentuximab 
budesonide5 
buspirone5 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
conivaptan5 
glucocorticoids2 
crizotinib 
cyclosporine4 
cyclophosphamide  
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
ergotamine4 
eplerenone5 
erlotinib 
esomeprazole 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
fosaprepitant 
gefitinib 
haloperidol 
HIV antiretrovirals 
HMG Co-A inhibitors5 
ifosfamide 
imatinib 
indinavir5 
irinotecan  
itraconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
cimetidine 
conivaptan 
crizotinib 
cyclosporine  
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
mifepristone 
nilotinib 
verapamil 
alprazolam 
amiodarone 
amlodipine 
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
ciprofloxacin 
cyclosporine 
fosaprepitant 
fluvoxamine 
isoniazid 
nicardipine 
propofol 
quinidine 
ranolazine 
 
 
 
armodafinil 
barbiturates 
bosentan 
carbamazepine 
deferasirox 
echinacea 
efavirenz 
etravirine 
fosphenytoin 
glucocorticoids2 
modafinil 
nafcillin 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin 
rifampin 
rifapentin 
ritonavir 
St. John’s wort 
topiramate 
 

  
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Page 91 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
modafinil 
montelukast 
nefazodone 
nilotinib 
nisoldipine5 
omeprazole 
ondansetron 
paclitaxel 
pazopanib 
quetiapine5 
quinidine4  
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sunitinib 
tacrolimus4,5  
telaprevir 
tamoxifen 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.1.4.3 regarding use of corticosteroids. Dexamethasone is considered a weak CYP3A4 inducer. 
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is concentration-
, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates 
 
 
 
 
 

  
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Page 92 
APPENDIX III:  XL184 PATIENT DIARY 
COG Patient ID_________________  Patient Initials________  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. You 
will take the tablet with a large glass of water on an empty stomach. Do not eat 2 hours before or 1 hour 
after each dose of XL184. Do not crush or break the tablet. Furthermore, do not take a missed dose within 
12 hours of the next dose. Do not eat grapefruit or drink grapefruit juice while being treated with XL184. 
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 after 
each treatment cycle. Your institution will upload this document into RAVE 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 IV. 
 
EXAMPLE 
WEEK 1 
Date 
Time 
20 mg 
60 mg 
Comments 
Day 1: 
Friday 
5/27/16 8:30 
AM / PM 
# prescribed: 3 
 
# taken:  3 
 
# prescribed: 0 
 
# taken:  0 
 
He felt nauseated an 
hour after taking the drug 
but did not vomit. 
 
 
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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Page 93 
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:   
 
 
Day 21 
 
 
 
AM / PM 
# prescribed:  
 
# taken:   
 
# prescribed:  
 
 
# taken:   
 
 
 

  
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Page 94 
 
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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Version Date: 04/16/19 
 
 
Page 95 
APPENDIX IV: XL184 DOSING NOMOGRAM  
If a patient’s dose is reduced due to toxicity, any future XL184 total weekly dose should not exceed 
a previously un-tolerated dose.  
 
See Section 5.11 for the XL184 dose reduction table. 
 
XL184 
(Cabozantinib) 
40 mg/m2/day 
BSA (m2) 
Weekly Dose/ Schedule for Initial Dosing 
0.35 – 0.39 
100 mg = 20 mg M, W, Th, Sat, Sun (or Day 1, 3, 4, 6, 7 of each week) 
0.40 – 0.45 
120 mg =20 mg M, T, W, F, Sat, Sun (or Day 1, 2, 3, 5, 6, 7 of each week) 
0.46 – 0.55 
140 mg =20 mg Daily 
0.56 – 0.64 
160 mg = 40 mg M, W, F, Sun (or Day 1, 3, 5, 7 of each week) 
0.65 – 0.78 
200 mg = 40 mg M, W, Th, Sat, Sun (or Day 1, 3, 4, 6, 7 of each week) 
0.79 – 0.90 
240 mg = 40 mg M, T, W, F, Sat, Sun (or Day 1, 2, 3, 5, 6, 7 of each week) 
0.91 – 1.09 
280 mg = 40 mg Daily 
1.10 – 1.17 
300 mg = 60 mg M, W, Th, Sat, Sun (or Day 1, 3, 4, 6, 7 of each week) 
1.18 – 1.36 
360 mg = 60 mg M, T, W, F, Sat, Sun (or Day 1, 2, 3, 5, 6, 7 of each week) 
1.37 – 1.65 
420 mg = 60 mg Daily 
1.66 – 1.85 
480 mg = 80 mg M, T, W, F, Sat, Sun (or Day 1, 2, 3, 5, 6, 7 of each week) 
1.86 – 2.07 
560 mg = 80 mg Daily 
≥ 2.08 
600 mg = 100 mg M, T, W, F, Sat, Sun (or Day 1, 2, 3, 5, 6, 7 of each week) 
 
 
 

  
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Page 96 
APPENDIX V:  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 5.1.1 for definition of dose limiting hypertension, Section 5.5 for management and grading of 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 97 
 
 
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 5.1.1 for definition of dose limiting hypertension, Section 5.5 for management and grading of 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 98 
APPENDIX VI: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
You should purchase or will be given a prescription for loperamide to have available to 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.  
 
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__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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Page 99 
 
 
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 (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half 
teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours. During the night, 
the patient may take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL 
oral solution) every 4 hours. Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per 
day. 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [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 (5 mL 
[one teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours. During the night, 
the patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 mL oral solution) 
every 4 hours. Do not exceed 6 mg (30 mL or 6 teaspoonfuls) per day. 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [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 (5 mL [one 
teaspoonful] of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours. 
During the night, the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 
mL oral solution or 1 capsule or tablet) every 4 hours. Do not exceed 8 mg (40 mL 
or 8 teaspoonfuls) per day. 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [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 (5 mL [one 
teaspoonful] of the 1 mg/5 mL oral solution or one-half tablet) every 2 hours. 
During the night, the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 
mL oral solution or 1 capsule or tablet) every 4 hours. Do not exceed 12 mg (60 
mL or 12 teaspoonfuls) per day. 
Over 43 kg 
Take 4 mg (20 mL [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 (10 mL [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 (20 mL [4 teaspoonfuls] of the 1 mg/5 
mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 16 mg 
(80 mL or 16 teaspoonfuls) per day. 

  
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Page 100 
APPENDIX VII:  UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-
ENZYME INDUCING ANTICONVULSANTS 
 
 
 
Recommended Non-enzyme inducing 
anticonvulsants 
 
Clonazepam 
Diazepam 
Ethosuximide 
Ezogabine 
Gabapentin 
Lacosamide 
Lamotrigine 
Levetiracetam  
Lorazepam 
Perampanel 
Tiagabine 
Topiramate 
Valproic Acid 
Zonisamide 
 
Unacceptable Enzyme inducing anticonvulsants 
 
Carbamazepine 
Felbamate 
Phenobarbital 
Fosphenytoin 
Phenytoin 
Primidone 
Oxcarbazepine 

  
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Page 101 
APPENDIX VIII: MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
 
The use of the following medications should be avoided during protocol therapy if reasonable alternatives 
exist. This is not an inclusive list. Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references. For the most current list of medications, please 
refer to the following reference: 
Woosley, RL and Romero, KA,  www.Crediblemeds.org,  QTdrugs List, Accession Date December 2nd, 
2016, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ  85755 
 
 
Medications that prolong QTc 
Amiodarone 
Flecainide 
Anagrelide 
Fluconazole 
Arsenic trioxide 
Haloperidol 
Azithromycin 
Ibutilide 
Chloroquine 
Methadone 
Chlorpromazine 
Moxifloxacin 
Ciprofloxacin 
Ondansetron 
Citalopram 
Pentamidine 
Clarithromycin 
Pimozide 
Disopyramide 
Procainamide 
Dofetilide 
Propofol 
Domperidone 
Quinidine  
Droperidol 
Sevoflurane 
Dronedarone 
Sotalol 
Erythromycin 
Thioridazine  
Escitalopram 
Vandetanib  
 
 
Medications that MAY prolong QTc 
Aripiprazole 
Lapatinib 
Bortezomib 
Lenvatinib 
Bosutinib 
Leuprolide 
Ceritinib 
Mirtazapine 
Clomipramine 
Nicardipine 
Crizotinib 
Nilotinib 
Dabrafenib 
Olanzapine 
Dasatinib 
Osimertinib 
Degarelix 
Pazopanib 
Desipramine 
Promethazine 
Dolasetron 
Risperidone 
Eribulin mesylate 
Sorafenib 
Famotidine 
Sunitinib 
Foscarnet 
Tacrolimus 
Gemifloxacin 
Vemurafenib 
Granisetron 
Venlafaxine 
Isradipine 
Vorinostat 

  
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Page 102 
 
APPENDIX IX: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1622 
(for children from 7 through 12 years of age) 
A study of the drug XL184 (cabozantinib) in children with a cancer that has come back after treatment or 
is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already 
but the cancer did not go away or it came back after treatment or you have a cancer that is difficult 
to treat.  
 
2. We are asking you to take part in a research study because your cancer has come back or is hard to 
treat. A research study is when doctors work together to try out new ways to help people who are 
sick. In this study, we are trying to learn more about how to treat the kind of cancer that you have. 
We will do this by trying a new medicine to treat your cancer.  
 
3. Children who are part of this study will be treated with a cancer-fighting medicine called XL184. 
You will also have regular tests and exams done more often while you are in this study. The doctors 
want to see if XL184 will make children with your type of cancer get better. We don’t know if 
XL184 will work well to get rid of your cancer. That is why we are doing this study.  
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that XL184 may 
cause your cancer to stop growing or to shrink for a period of time but we don’t know for sure if 
there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have more problems, or side 
effects, from XL184 than other treatments. Other things may happen to you that we don’t yet know 
about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood. We want to see how your body handles 
XL184. Some of these samples are collected when you may not need to have a blood sample taken 
and may require extra needle sticks. You can still take part in this study even if you don't allow us 
to collect some of the extra blood samples for research. We are also asking your permission to keep 
some of the tumor tissue that may have been removed during your diagnosis and/or earlier treatment 
and any that is removed with procedures that happen while you are on this study. We would like to 
save the tumor tissue for tests in the future. 
 
 
 
 

  
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Page 103 
INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1622 
(for teens from 13 through 17 years of age) 
A study of the drug XL184 (cabozantinib) in children with a cancer that has come back after treatment or 
is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment or you have a cancer that is difficult to treat.  
 
2. We are asking you to take part in a research study because your cancer has come back or is hard to 
treat. A research study is when doctors work together to try out new ways to help people who are sick. 
In this study, we are trying to learn more about how to treat the kind of cancer that you have. 
 
3. Children and teens who are part of this study will be given a cancer-fighting medicine called XL184. 
XL184 blocks pathways that are involved in the growth of tumors and blood vessels that supply tumors. 
XL184 has been approved by the Food and Drug Administration (FDA) for another illness, but not for 
your cancer. The dose of XL184 used in this study was found to be well tolerated in children and teens. 
 
4. You will take XL184 every day. You may continue to receive XL184 for as long as you do not have 
bad effects from it and your cancer does not get any worse. You will also have exams and tests done 
that are part of normal cancer care. But, the exams and tests will be done more often while you are 
being treated with XL184. The doctors want to see if XL184 will make children and teens with your 
type of cancer get better. We don’t know if XL184 is better than other medicines. That is why we are 
doing this study.  
 
5. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that XL184 may cause 
your cancer to stop growing or to shrink for a period of time but we don’t know for sure if there is any 
benefit of being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you may have more problems, or side effects, 
from XL184 than other treatments. Other things may happen to you that we don’t yet know about. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. There may be other treatments for your illness that your doctor can 
tell you about. Make sure to ask your doctors any questions that you have.  
 
8. We are asking your permission to collect additional blood. We want to see how your body handles 
XL184. Some of these samples are collected when you may not need to have a blood sample taken and 
may require extra needle sticks. You can still take part in this study even if you don't allow us to collect 
the extra blood samples for research. We are also asking your permission to keep some of the tumor 
tissue that may have been removed during your diagnosis and/or earlier treatment and any that is 
removed with procedures that happen while you are on this study. We would like to save the tumor 
tissue for tests in the future. 
 
 

  
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ADVL1622 
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Page 104 
APPENDIX X: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD  
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug, XL184 (cabozantinib). This clinical trial is sponsored by the National Cancer Institute. This form 
is addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know:  
XL184 (cabozantinib) interacts with a certain specific enzyme in your liver, a certain transport protein 
that helps move drugs in and out of cells, and the heart’s electrical activity (QTc prolongation) .  
 
• 
The enzyme in question is CYP 3A4. XL184 (cabozantinib) is metabolized by CYP3A4 and may be 
affected by other drugs that inhibit or induce this enzyme.  
• 
The protein in question are P-glycoprotein (P-gp) and MRP2. XL184 (cabozantinib) is an inhibitor 
of P-gp and may be affected by other drugs that are “substrates.” XL184 is also a substrate of MRP2 
and may be affected by other drugs that are “inhibitor” or “inducers” of MRP2.  
• 
XL184 (cabozantinib) may affect the heart’s electrical activity causing QTc prolongation. The study 
doctor may be concerned about QTc prolongation and any other medicine that is associated with 
greater risk for having QTc prolongation.  
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.  
XL184 (cabozantinib) may interact with other drugs which can cause side effects. For this reason, it is 
very important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines, or if 
you start taking a new medicine while you take part in this study. When you talk about your current 
medications with your doctors, include medicine you buy without a prescription (over-the-counter 
remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles 
or an updated medication list with you.  
Many health care providers can write prescriptions. You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
XL184 (cabozantinib) must be used very carefully with other medicines that use certain liver enzyme, 
transport proteins to be effective or to be cleared from your system or that may affect your heart’s 
electrical activity. Before you enroll onto the clinical trial, your study doctor will work with your regular 
health care providers to review any medicines and herbal supplements that are considered “strong 
inducers/inhibitors of CYP3A4, substrate of P-gp, or any medicine associated with greater risk for 
having QTc prolongation.”  
 
• 
Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• 
Do not drink or eat grapefruit/juice or Seville oranges.  
• Your regular health care provider should check a frequently updated medical reference or call your 
study doctor before prescribing any new medicine or discontinuing any medicine.  
• Your study doctor’s name is _____________________________________ and he or she can be 
contacted at _____________________________________.  
• 
 

  
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Page 105 
XL184 (cabozantinib) must be used very carefully with other 
medicines that interact with CYP3A4 enzyme, transporter proteins 
(P-gp) and MRP2, or drugs that may trigger your heart’s electrical 
activity (QTc prolongation). 
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inducers/inhibitors CYP3A4; P-gp substrates; or drugs that cause 
risks for QTc prolongation.” 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor. 
 Your study doctor’s name is ___________________________and 
can be contacted at____________________________________. 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental study 
drug XL184 (cabozantinib). This clinical trial is sponsored by the 
NCI. XL184 (cabozantinib) may interact with drugs that are 
processed by your liver, or use certain transport proteins in your 
body or affect the electrical activity of your heart. Because of this, 
it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Page 106 
APPENDIX XI: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
> ULN- ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3.0 x ULN 
Grade 3: 
> 3.0 x ULN -10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
> 45 U/L - ≤ 135 U/L 
Grade 2: 
136 U/L - 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for SGOT is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L - ≤ 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN - 5.0 x ULN 
Grade 3: 
> 5.0 x ULN -20.0 x ULN 
Grade 4: 
> 20.0 x ULN 
 
 
 
 
  
 

  
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Page 107 
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