Conditions: Fallopian Tube Clear Cell Adenocarcinoma Ovarian Clear Cell Adenocarcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
This phase II trial studies how well cabozantinib-s-malate works in treating patients with ovarian, fallopian tube, or primary peritoneal cavity cancer that has come back or is growing, spreading, or getting worse. Cabozantinib-s-malate may stop the growth of tumor cells by blocking the growth of new blood vessels necessary for tumor growth and also by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the anti-tumor activity of cabozantinib (XL184) (cabozantinib-s-malate) in women with persistent or recurrent clear cell ovarian cancer, based on the proportion of patients who survive progression-free for at least 6 months and the proportion who have objective tumor response (complete or partial).

SECONDARY OBJECTIVES:

I. To determine the nature, frequency and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 for cabozantinib (XL184).

II. To determine the progression free survival (PFS) and overall survival (OS) for patients with persistent or recurrent clear cell ovarian cancer treated with cabozantinib (XL184).

TERTIARY OBJECTIVES:

I. To examine the expression of phosphatase and tensin homolog gene (PTEN), phosphorylated v-akt murine thymoma viral oncogene homolog 1 (pAKT), cyclin E, and met proto-oncogene (MET) in formalin-fixed, paraffin-embedded tumor.

II. To examine MET amplification (fluorescence in situ hybridization) in tumor specimens and the relationship to response.

OUTLINE:

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

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

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

Interventions: intervention 1: Cabozantinib S-malate intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Optional correlative studies

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #:NRG-GY001 
 
Version Date: February 17, 2017 
 
 
i 
 
This amendment is being submitted in response to a Request for Rapid Amendment for XL184 
(Cabozantinib s-malate, NSC 761968) from Dr. John Wright  
 
SUMMARY OF CHANGES 
For Protocol Amendment #3 
NCI Protocol #: NRG-GY001 
Local Protocol #: NRG-GY001 
 
NCI Version Date: February 17, 2017 
Protocol Date: February 17, 2017 
# 
Section 
Page(s) 
Comments 
1. 
Title 
Page 
1 
NCI Version date has been updated. 
Document History has been updated. 
Revised has been added to the footer. 
3. 
9.1.13 
54-58 
CAEPR for Cabozantinib has been updated. 
 
 
 
 
 


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NRG ONCOLOGY  
 
NRG-GY001  
(ClinicalTrials.gov NCT #02315430) 
 
TITLE 
A Phase II Trial of Cabozantinib (XL-184) (NSC #761968) in Women with Recurrent, Clear 
Cell Carcinoma of the Ovary, Fallopian Tube, or Peritoneum 
NCI Version Date: February 17, 2017 
 
Lead Organization: NRG / NRG Oncology  
 
 
 
  
 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center 
1600 JFK Blvd., Suite 1020 
Philadelphia, Pa 19103 
 
Study Team  
Principal Investigator/Study Chair’s Name/Modality 
John H Farley, MD 
St Joseph Hospital and Medical Center 
Obstetrics and Gynecology  
500 W. Thomas Road 
Suite 600 
Phoenix AZ 85013(602) 406-7730/ (602) 406-7424 
john.farley@dignityhealth.org 
 
Other Study Chairs/Co-Chairs 
Panagiotis Konstantinopoulos, MD, PhD  
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Yawkey 1424 
Boston MA 02215  
(617) 632-2334/ (617) 632-3479 
panagiotis_konstantinopoulos@dfci.harvard.edu 
 
Correlative Scientist 
Michael Birrer, MD 
Massachusetts General Hospital 
Yawkey 9072 
Participating Organizations  
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 


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55 Fruit Street 
Boston MA 02114  
(617) 724-4800/ (617) 724-6898 
mbirrer@partners.org 
 
Statistician 
William Brady, PhD 
NRG Statistics and Data Management Center – Buffalo Office 
Roswell Park Cancer Center 
Elm and Carlton Streets 
Buffalo NY 14263 
(716) 845-5702/ (716) 845-8393 
bradyb@nrgoncology.org 
 
Protocol Coordinator 
Samuel DiBernardo 
NRG Oncology 
Four Penn Center 
1600 JFK Blvd., Suite 1020 
Philadelphia, Pa 19103 
(215) 854-0770/ (215) 854-0716 
dibernardos@nrgoncology.org 
 
Data Manager and Data Operations Center  
Rachelle Dutka 
NRG Statistics and Data Management Center – Buffalo Office 
Roswell Park Cancer Institute 
Elm & Carlton Streets 
Buffalo NY 14263 
(716) 845-2394/ (716) 845-8393 
dutkar@nrgoncology.org 
 
Translational Scientist  
Heather A Lankes, PhD, MPH 
NRG Statistics and Data Management Center – Buffalo Office 
Roswell Park Cancer Institute 
Elm & Carlton Streets 
Buffalo NY 14263 
(716) 845-8508 / (716) 845-8393 
lankesh@nrgoncology.org 
 
 
 
Research Nurse 
Christin Whalen, RN 
Dana Farber Cancer Institute  
450 Brookline Ave 
Boston, MA 02215 


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(617) 632-7738/ (617) 582-7921 
Christin_whalen@dfci.harvard.edu 
 
Study Pathologist 
William Rodgers, MD, PhD. 
New York Hospital Queens 
Pathology 
56-45 Main Street 
Flushing, NY 11355 
(718)670-1141/ (718)670-1374 
whr9001@nyp.org 
 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Cabozantinib 
 DCTD/CTEP 
761968 
116059 
DCTD, NCI 
 
 
 
 
 
 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 3 
February 17, 2017 
 
Closure 
May 25, 2016 
October 31, 2016 
Amendment 2 
May 25, 2016 
July 5, 2016 
Update 
 
 
Temporary Closure 
July 30, 2015 
November 30, 2015 
Amendment 1 
July 30, 2015 
September 8, 2015 
Update 
 
 
Activation 
January 30, 2015 
March 30, 2015 
Pre-Activation 
 
 
 
 
 
 
  
 
OPEN TO PATIENT ENTRY APRIL 1, 2015; REVISED SEPTEMBER 8, 2015; TEMPORARILY 
CLOSED TO PATIENT ENTRY NOVEMBER 30, 2015; REVISED JULY 5, 2016; CLOSED TO 
PATIENT ENTRY OCTOBER 31, 2016; REVISED
This protocol was designed and developed by NRG Oncology. It is intended to be used only in 
conjunction with institution-specific IRB approval for study entry.  No other use or reproduction is 
authorized by NRG Oncology nor does NRG Oncology assume any responsibility for unauthorized 
use of this protocol. 


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NRG ONCOLOGY 
 
NRG-GY001  
 
TITLE 
A Phase II Trial of Cabozantinib (XL-184) (NSC #761968) in Women with Recurrent Clear Cell 
Carcinoma of the Ovary, Fallopian Tube, or Peritoneum 
NCI Version Date: February 17, 2017 
 
CONTACT INFORMATION  
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.o
rg (for submitting regulatory 
documents only) 
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_SYS
TEM/ 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 section of the 
protocol 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. 
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.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU Website is located at https://www.ctsu.org. 
 


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TABLE OF CONTENTS 
NRG-GY001 ....................................................................................................................................8 
SCHEMA .........................................................................................................................................8 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objective ....................................................................................................9 
1.2 
Secondary Objectives...............................................................................................9 
1.3 
Translational Science Objectives .............................................................................9 
2. 
BACKGROUND ...............................................................................................................10 
2.1 
Clinical Research Background ...............................................................................10 
2.2 
Cabozantinib (XL184) ...........................................................................................13 
2.3 
Inclusion of Women and Minorities ......................................................................20 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA .................21 
3.1 
Patient Selection Guidelines ..................................................................................21 
3.2 
Eligibility Criteria ..................................................................................................21 
3.3 
Ineligibility Criteria ...............................................................................................23 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........24 
5. 
TREATMENT PLAN/Regimen description......................................................................26 
5.1 
Chemotherapy ........................................................................................................26 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................27 
5.3 
Duration of Therapy ...............................................................................................29 
6. 
TREATMENT MODIFICATIONS/managEment.............................................................29 
6.1 
Cabozantinib (XL184)-Related Adverse Event Management ...............................29 
6.2 
Diarrhea, Nausea, Vomiting,  Stomatitis, and Mucositis .......................................32 
6.3 
Hepatobiliary Disorders .........................................................................................32 
6.4 
Pancreatic Conditions ............................................................................................34 
6.5 
Skin Disorders ........................................................................................................35 
6.6 
Embolism and Thrombosis ....................................................................................37 
6.7 
Hypertension ..........................................................................................................38 
6.8 
Proteinuria ..............................................................................................................39 
6.9 
Guidelines for the Prevention of Hemorrhagic Events ..........................................40 
6.10 
Rectal and Perirectal Abscess ................................................................................41 
6.11 
Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula 
Formation ...............................................................................................................41 
6.12 
Wound Healing and Surgery ..................................................................................42 
6.13 
Endocrine Disorders...............................................................................................42 
6.14 
Guidelines for Prevention of Osteonecrosis of the Jaw .........................................42 
6.15 
Guidelines for Management of Treatment-Emergent Corrected QT (QTc) 


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Prolongation ...........................................................................................................43 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................44 
7.1 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL 
AGENT ..................................................................................................................44 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ..............48 
8.1 
Investigator Registration Requirements .................................................................48 
8.2 
Site Registration Requirements..............................................................................48 
8.3 
Pre-registration Requirements ...............................................................................49 
8.4 
RT-Specific Pre-Registration Requirements..........................................................49 
8.5 
Patient Enrollment .................................................................................................49 
9. 
DRUG INFORMATION ...................................................................................................51 
9.1 
Cabozantinib (XL184) (NSC 761968) ...................................................................51 
10. 
Pathology ...........................................................................................................................58 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL studies ..............................................59 
11.1  Reimbursement ......................................................................................................59 
11.2 
Translational Science .............................................................................................59 
11.3 
Quality of Life........................................................................................................61 
12. 
DATA AND RECORDS ...................................................................................................61 
12.1 
Data Management/Collection ................................................................................61 
12.2 
NRG Data Management Forms (09/08/15)............................................................62 
12.3 
Summary of Data Submission ...............................................................................64 
12.4 
Global Reporting/Monitoring ................................................................................64 
13. 
STATISTICAL CONSIDERATIONS...............................................................................64 
13.1 
Study Design .........................................................................................................64 
13.2 
Study Endpoints .....................................................................................................65 
13.3 
Primary Objectives Study Design ..........................................................................65 
13.4 
Study Monitoring of Primary Objectives ...............................................................69 
13.5 
Accrual Considerations ..........................................................................................70 
13.6 
Dose Level Guidelines ...........................................................................................70 
13.7 
Secondary or Exploratory Elements (including correlative science aims) ............70 
13.8 
Exploratory Hypothesis and Endpoints .................................................................71 
13.9 
Gender/Ethnicity/Race Distribution.......................................................................71 
14. 
Publication Information and Administrative Agreements .................................................72 
15. 
EVALUATION CRITERIA ..............................................................................................72 
15.1 
Antitumor Effect – Solid Tumors ..........................................................................72 
REFERENCES ..............................................................................................................................80 


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APPENDIX I - General Chemotherapy Guidelines: .....................................................................83 
APPENDIX II - CRADA ...............................................................................................................84 
APPENDIX III - Congestive Heart Failure – New York Heart Association Classification ..........86 
APPENDIX IV - PATIENT’S PILL DIARY: Cabozantinib ........................................................87 
APPENDIX V - Translational Science ..........................................................................................88 
APPENDIX VI - ECOG PERFORMANCE SCALE (09/08/15) ..................................................91 
 


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Patients with recurrent or persistent clear cell ovarian cancer 
Cabozantinib (XL184) 60 mg once a day continuously, repeated in 4 week 
cycles until disease progression or adverse effects prohibit further therapy 
 
 
 
NRG-GY001 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 


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1. OBJECTIVES 
1.1 
Primary Objective 
To evaluate the anti-tumor activity of cabozantinib (XL184) in women with persistent or 
recurrent clear cell ovarian cancer, based on the proportion of patients who survive 
progression-free for at least 6 months and the proportion who have objective tumor 
response (complete or partial). 
 
1.2 
Secondary Objectives 
1.2.1 To determine the nature, frequency and maximum degree of toxicity as assessed by 
CTCAE v4 for cabozantinib (XL184) 
 
1.2.2 To determine the PFS and OS for patients with persistent or recurrent clear cell ovarian 
cancer treated with cabozantinib (XL184) 
 
1.3 
Translational Science Objectives 
1.3.1 To examine the expression of PTEN, pAKT, cyclin E, and MET in formalin-fixed, 
paraffin-embedded tumor. 
1.3.2 To examine MET amplification (fluorescence in situ hybridization) in tumor specimens 
and the relationship to response. 
 
 
 


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2. BACKGROUND 
 
2.1 
Clinical Research Background 
Ovarian cancer is the most lethal gynecologic malignancy (Siegel, 2012)  In 2014 we 
could expect 21,980 cases of ovarian cancer and 14,270 deaths. Standard therapy for 
ovarian cancer includes surgical debulking of any primary tumor followed by adjuvant 
chemotherapy with carboplatin and paclitaxel when needed. Patients with advanced stage 
disease have a 5-year survival of only 29% (Siegel, 2012), (Christensen, 2005) Epithelial 
ovarian cancer is considered a chemoresponsive tumor with response rates of 80% to 
standard therapy of platinum and a taxane (Siegel, 2012), (Bhoola, 2006), (Cannistra, 
2004), (Piccart, 2003), (Tummala, 2005) Unfortunately most patients develop recurrent 
disease, chemoresistant disease and the patients are essentially incurable.  In the United 
States, ovarian clear cell carcinoma (OCCC) accounts for approximately 4-9.5% of 
ovarian tumors, whereas in Japan, the rate is upwards of 15-25%. 
  
Age, performance status, tumor histology, and residual disease volume have been found 
to be statistically significant prognostic factors for advanced stage epithelial ovarian 
cancer in multivariate analyses (Winter, 2007) Clear-cell histology has been generally 
accepted as an unfavorable histology. Clear-cell epithelial ovarian carcinomas are 
associated with a worse PFS and OS when compared with serous histology. In a study of 
similarly treated advanced epithelial ovarian cancer patients clear cell tumors had a 
decreased median OS of 24 months compared to 45 and 56 months for serous and 
endometrioid histologies, respectively. 
 
Expression profiling of epithelial ovarian cancer of varying histologies has afforded the 
elucidation of genes which contribute to the biological and clinical features seen in the 
four major histological types of ovarian carcinoma (Bonome, 2008), (Zorn, 2005) When 
clear cell ovarian cancer was compared with non–clear cell ovarian cancer (serous and 
endometrioid ovarian cancer grouped together), 171 differentially expressed genes were 
identified (Bonome, 2008)  For clear cell tumors in general; there is a small set of 
differentially expressed genes common to tumors from all organs, ovary, endometrium 
and kidney. These genes include TFPI2 (tissue factor pathway inhibitor), ANXA4 
(Annexin), UGT1A1 (UDP glycosyltransferase1family, polypeptideA1), FXYD2 (FXYD 
domain containing ion transport regulator 2), GLRX (Glutaredoxin), KIAA1922 
(KIAA1922 protein), MAP3K5 (Mitogen-activated protein kinase kinase kinase 5), 
CXADR (Coxsackie virus and adenovirus receptor), and RFX5 (Regulatory factor X, 5). 
(Zorn, 2005) This over expression of certain types of genes in the clear cell histotype 
provides insights into their disproportionately poor prognosis relative to other types of 
ovarian cancer. Two of these genes have intriguing associations with chemotherapy 
response: ANXA4 has been associated with paclitaxel resistance, whereas UGT1A1 
detoxifies the active metabolite of irinotecan (Pal, 2012), (Gibney, 2013) The sum total 
clinical and biological effect of these genes is to increase anti-apoptotic signals 
(ASK1/GLRX), inhibit cellular proliferation (TFP12), and increase resistance to 
chemotherapeutic agents (ANXA4 and UGT1A1), which is consistent with the slow 


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growth and relative chemoresistance of clear cell tumors.  
 
MET. MET has a number of purported roles in the pathogenesis of RCC. Over a 
decade ago, germ line and somatic mutations were identified in the tyrosine kinase 
domain of MET in patients with papillary RCC 8. MET plays a critical role in clear cell 
RCC. Inactivation of VHL may actually cause constitutive activation of the moiety, and 
VHL null RCC cell lines appear to be exquisitely sensitive to MET shRNA. (Zorn, 2005) 
c-Met protein expression was determined by automated quantitative analysis (AQUA) on 
a Tissue microarray (TMA) data incorporating 330 unique RCC specimens c-Met 
expression and selective inhibition with SU11274 and ARQ 197 were also studied in 
clear cell RCC cell lines. (Pal, 2012) Higher c-Met expression was detected in all RCC 
subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in 
papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met 
expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% 
confidence interval (CI) 1.08-1.74; P = 0.0091] and was an independent predictor of 
survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell 
lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197. 
They concluded that c-Met is associated with poor pathologic features and prognosis in 
RCC. Additionally, c-Met inhibition demonstrates in vitro activity against clear cell RCC.  
Deregulation of the c-Met-HGF/SF (hepatocyte growth factor/scatter factor) signaling 
axis has been identified as a contributing factor to tumorigenesis and tumor progression 
in numerous cancers. (Zillhardt, 2011) This pathway has also been shown to show a 
critical role in the pathogenesis of ovarian cancer (Gibney, 2013), (Zillhardt, 2011). An 
examination of approximately 170 candidate genes/regions in a multistage analysis based 
initially on 312 Mayo Clinic ovarian cancer cases revealed the strongest initial mortality 
association was associated with HGF (hepatocyte growth factor). (Zillhardt, 2011) 
Analysis of TCGA data revealed consistent findings and suggested a potential genotype 
correlation with reduced HGF mRNA levels. In analysis of the Mayo Clinic TMAs, 
protein levels of phospho-MET were associated with reduced mortality. They concluded 
that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely 
that HGF genetic variation plays a major role in ovarian cancer mortality.  
Perturbation of the c-Met-HGF/SF pathway in ovarian cancer carcinogenesis has been 
demonstrated in the laboratory. Evaluation of a multikinase inhibitor of c-Met and 
vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) was performed in 
a genetic mouse model. In the genetic mouse model, treatment with foretinib prevented 
the progression of primary ovarian tumors to invasive adenocarcinoma. (Gibney, 2013) 
Invasion through the basement membrane was completely blocked in treated mice, 
whereas in control mice, invasive tumors entirely replaced the normal ovary. In two 
xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced 
overall tumor burden. The mechanism of inhibition by foretinib involved (a) inhibition of 
c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, 
(c) a block in migration and invasion, (d) reduced proliferation mediated by a G2–M cell-
cycle arrest, and (e) induction of anoikis. (Gibney, 2013) This study shows that a 
multikinase inhibitor of c-Met and VEGF-2 blocks tumorigenesis and reduces invasive 
tumor growth in different models of ovarian cancer by affecting several critical tumor 


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functions. These observations provide a rationale for the further clinical development of 
c-Met inhibitors for the treatment of ovarian cancer.  
An additional study demonstrated that, among ovarian carcinomas, amplification of the 
MET gene and overexpression of MET specifically and commonly occur in clear-cell 
adenocarcinoma histology12,1314. Low-level (≥3 MET copies in ≥10% and ≥4 MET copies 
in 10-40% of tumor cells) gain of MET was detected in 4 (40%) of the 10 atypical 
endometrioses and 1 of the 2 borderline CCAFs. Moreover, high-level (≥4 MET copies in 
≥40% of tumor cells) gain of MET were detected in five (50%) of the atypical 
endometrioses. In 4 (31%) of the 13 cases enrolled, intratumoral heterogeneity for MET 
gain was documented in invasive carcinoma components, wherein all the relatively 
differentiated carcinoma components showed low-level gain of MET and all the 
corresponding poorly differentiated carcinomas showed high-level gain. The overall 
incidence of MET overexpression gradually increased from the ovarian clear cell 
carcinoma precursors of non-atypical form (0%), through those of atypical form (67%) 
and the relatively differentiated carcinoma components (92%), to the poorly 
differentiated carcinoma components (100%). These results suggest that accumulative 
MET gene copy number alterations causing MET overexpression are associated with 
higher tumor grade ovarian clear cell carcinomas and might drive the development and 
progression of the MET amplification-positive ovarian clear-cell adenocarcinoma. 
(Goode, 2011), (Yamamoto, 2012) Also, in patients with early stage (stage I and 2) clear 
cell ovarian cancer, Met gene amplification is associated with worse survival (Yamashita 
et al. PLoS One. 2013; 8(3):e57724). Overexpression of the IL6-STAT3-HIF pathway 
commonly occurs in ovarian clear cell cancer and this pathway is known to activate MET 
promoter which contains hypoxia inducible factor-1 (HIF-1) binding sites and thus 
upregulate MET expression (Anglesio, 2011) (Anglesio et al. Clin Cancer Res. 2011 Apr 
15; 17(8):2538-48).  IL6 levels are also elevated in women with endometriosis. Therefore 
deregulation of IL6 expression seems to be an early event in the development of ovarian 
clear cell carcinoma. IL6 signals via STAT3 and activates expression of downstream 
genes including PTHLH and HIF1A. Strong expression of activated pSTAT3 in tumors 
and cell lines and nuclear HIF1A in TMA, were observed and consistent with autocrine 
activation of the pathway. Finally, in a phase II randomized discontinuation trial of 
cabozantinib in advanced ovarian cancer patients, there were 3 patients with clear cell 
ovarian cancer: one had a RECIST PR, one had a close to-PR response and the third had 
stable disease with decrease in her CA125 level (Buckanovich et al. ASCO 2011 
meeting, J Clin Oncol 29: 2011 (suppl; abstr 5008). Cabozantinib (NSC# 761968). 
Cabozantinib (NSC# 761968), is an orally bioavailable inhibitor of multiple receptor 
tyrosine kinases (RTKs) including c-Met and vascular endothelial growth factor receptor 
2 (VEGFR2).  
Mechanism of Action 
Cabozantinib is a potent inhibitor of MET and VEGFR2. Cabozantinib strongly inhibited 
several kinases that have also been implicated in tumor pathobiology, including KIT, 
RET, AXL, TIE2, and FLT3. Cabozantinib did not potently inhibit kinases such as RON, 
EGFR, IGFR1, and EphA4/B4. In cellular assays, cabozantinib inhibited phosphorylation 
of MET and VEGFR2, as well as KIT, FLT3, and AXL. (Yakes, 2011) 


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The dual VEGFR2/MET targeting agent, cabozantinib, has recently shown 
unprecedented activity in the setting of metastatic castration resistant prostate cancer 
(mCRPC), causing regression of metastases visualized on bone scan in 56 of 65 evaluable 
patients (86%) enrolled in a randomized, phase II study. (Smith, 2013) Patients received 
100 mg of cabozantinib daily. One hundred seventy-one men with CRPC were enrolled. 
Random assignment was halted early based on the observed activity of Cabozantinib. 
Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of 
evaluable patients had improvement on bone scan, including complete resolution in 12%. 
The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. 
Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS 
was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with Cabozantinib and 5.9 weeks (95% CI, 
5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Cabozantinib had clinical 
activity in men with CRPC, including reduction of soft tissue lesions, improvement in 
PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and 
narcotic use (Zorn, 2005), (Smith, 2013), (Vaishampayan, 2013)  Early experiences with 
cabozantinib also indicate substantial activity in ovarian cancer and medullary thyroid 
carcinoma (Vaishampayan, 2013), (Kurzrock, 2011)_ENREF_29. Given these promising 
preliminary results, the further development plan for cabozantinib in OCCC is eagerly 
anticipated. 
 
2.2 
Cabozantinib (XL184) 
 
Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor 
growth, metastasis, and angiogenesis (Investigator’s Brochure, 2011).  The primary 
targets of cabozantinib are MET (c-MET) and vascular endothelial growth factor receptor 
2 (VEGFR2); additional targets include RET, AXL, KIT, and TIE-2.  Both c-Met and 
VEGFR2 are important mediators of tumor growth and tumor angiogenesis, and in vivo 
pharmacodynamic activity of Cabozantinib against c-Met and VEGFR2 has been 
demonstrated in both preclinical and clinical studies.  
 
RTKs regulate many processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair (Christensen, 2005)  Dysregulation of RTKs by 
mutation, gene rearrangement, gene amplification, and overexpression of both receptor 
and ligand have been implicated as causative factors in the development and progression 
of numerous human cancers. 
 
The RTK c-Met, encodes the high-affinity receptor for hepatocyte growth factor (HGF) 
or scatter factor (SF) (Christensen, 2005) c-Met and HGF are each required for normal 
mammalian development and have been shown to be important in cell migration, 
morphogenic differentiation, and organization of three-dimensional tubular structures 
(e.g., renal tubular cells, gland formation, etc.), as well as cell growth, angiogenesis, and 
tumor invasiveness and metastasis.  Upregulation of MET is found in a wide range of 
malignancies including thyroid, prostate, ovarian, lung, and breast cancers, and is 
associated with more aggressive and invasive phenotypes of cancer cells in vitro and 
metastases in vivo (Investigator’s Brochure, 2011). c-Met-driven metastasis may be 
exacerbated by a number of factors, including tumor hypoxia caused by selective 


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inhibition of the VEGF pathway. 
 
Evidence linking c-Met and HGF as causative or progression factors in human cancers 
include:  (1) the overexpression of both receptor and ligand in neoplasms relative to 
surrounding tissues; (2) the correlation of receptor and ligand overexpression with 
disease severity and outcome; (3) genetic alteration of c-Met by mutation of gene 
amplification in multiple cancer types; (4) introduction of c-Met and HGF (or mutant c-
Met) into cell lines, conferred the properties of tumorgenicity and metastatic propensity 
on engineered cells; (5) introduction of c-Met or HGF as transgenes into the germline of 
mice resulted in primary and secondary neoplasms; and (6) the inhibition of c-Met or 
HGF function with dominant-negative receptors, antibody antagonists (both Met and 
HGF), and biologic antagonists (e.g., NK4) have reversed cancer-associated phenotypes 
such as motility, invasion and proliferation of tumor cells, and tumor growth and 
dissemination in vivo (Christensen, 2005). 
 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, 
demonstrate dysregulated c-Met activity (Liu, 2010), either by means of c-Met kinase 
overexpression (Comoglio, 2008), activating c-Met gene mutations and/or amplification 
(Comoglio, 2008), (Jeffers, 1997), (Schmidt, 1997), or increased autocrine and/or 
paracrine secretion of the c-Met ligand, HGF/SF (Birchmeier, 2003), (Bocaccio, 2006).  
These alterations have been implicated in tumor progression and metastasis, and a high 
constitutive activation of c-Met has been correlated with poor clinical prognosis 
(Birchmeier, 2003). 
 
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, 
proliferation, survival, and enhanced vascular permeability (Kurzrock, 2011).  Increased 
expression of VEGFR2, often in combination with VEGFR3, has been observed in the 
tumor vascular endothelium in most common human solid tumor types, on tumor cells in 
melanoma and hematological malignancies, and in colitis-associated colon cancer 
(Tugues, 2011).  High VEGFR2 expression is an unfavorable prognostic biomarker in 
hepatocellular carcinoma (HCC), and correlated with triple-negative (i.e., therapy-
resistant) breast cancer and poor survival. 
 
Nonclinical Development of Cabozantinib   
 
In Vivo Activity 
Inhibition of VEGF signaling pathway was previously shown to result in more invasive 
tumors in the transgenic RIP-Tag2 mouse model of pancreatic neuroendocrine cancer that 
spontaneously develops aggressive tumors (Paez-Ribes, 2009).  In RIP-Tag2 transgenic 
mice, tumors treated with cabozantinib were smaller (P <0.05) than in mice treated with 
vehicle or an anti-VEGF antibody, but were also less invasive (P <0.05) and had no liver 
metastases (Sennino, 2009).  All mice treated with cabozantinib (n = 6) survived until 20 
weeks, but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) reached that 
endpoint.  Tumor vascularity decreased after treatment, with reductions ranging from 
67% at 3 mg/kg to 83% at 30 mg/kg for 7 days (You, 2011).  Tumors were 35% smaller 
after cabozantinib treatment than corresponding values for vehicle control mice.  c-Met 


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protein expression in tumors was slightly decreased, but phosphorylated c-Met was 
markedly reduced after treatment for 7 days.   
 
Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered four 
oral doses of 100 mg/kg (Yakes, 2011).  Cabozantinib increased tumor hypoxia (13-fold) 
and apoptosis (TUNEL; 2.5-fold) at 8 and 4 hours after the first and second doses, 
respectively, when compared to vehicle-treated tumors.  In addition, Cabozantinib 
disrupted tumor vasculature by inducing endothelial cell death that negatively affected 
tumor viability.  Cabozantinib treatment resulted in significant tumor growth inhibition of 
MDA-MB-231 tumors (P <0.001) at all doses (1, 3, 10, 30, or 60 mg/kg) when compared 
to vehicle-treated tumors.  Dose-dependent inhibition was observed for the 3 and 10 
mg/kg doses (P <0.01), and complete inhibition was observed at the 30 and 60 mg/kg 
doses.  A single 100 mg/kg dose resulted in sustained MDA-MB-231 tumor growth 
inhibition for ~8 days after which tumors began growing at a rate similar to vehicle-
treated control tumors.  In addition, cabozantinib inhibited tumor growth (P <0.001) in 
the MET-expressing rat C6 glioma cell line for all doses (1, 3, 10, 30, or 60 mg/kg) when 
compared with vehicle-treated tumors.  The 3 mg/kg and 10 mg/kg doses resulted in 
significant tumor regression (62% and 85%, P <0.0001) when compared with predose 
tumor weights.  Subchronic administration of cabozantinib was well tolerated in mice and 
rats with no signs of toxicity, as determined by stable and/or increasing body weights 
during the treatment period. 
 
ARCaP-M is a human prostate cancer model which expresses both c-Met and VEGF co-
receptor NP-1 used in a human prostate tumor xenograft study in mouse bone (Zhang, 
2010). ARCaP-M cells were injected into the tibia of nude mice on Day 1, and on Day 31 
animals with established bone lesions were randomized to receive Cabozantinib or 
vehicle daily (qd) for 7 weeks of treatment(Investigator’s Brochure, 2011).  Tibiae from 
vehicle-treated animals exhibited both osteoblastic and osteolytic lesions, whereas tibiae 
from Cabozantinib treated animals appeared mostly normal.  Thus, Cabozantinib 
treatment blocked both osteoblastic and osteolytic progression of ARCaP-M xenograft 
tumors in bone. 
 
Nonclinical Pharmacodynamics 
In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at 
well tolerated doses of Cabozantinib and at plasma exposures comparable to exposure 
observed in clinical trials (Investigator’s Brochure, 2010).  Cabozantinib produced 
prolonged inhibition of receptor phosphorylation, such as sustained inhibition of c-Met 
and VEGFR2 for 10 hours after administration of a single dose of cabozantinib.  This 
extended inhibition occurred in a manner that was generally predicted by plasma 
exposure, i.e., inhibition was diminished when plasma levels fell below approximately 20 
μM for c-Met, 5 μM for VEGFR2, and 23 μM for TIE-2. 
 
Once daily administration of cabozantinib resulted in significant inhibition of c-Met 
phosphorylation in TT tumors, relative to tumors from vehicle control-treated mice, with 
maximal inhibition of 70% seen at 60 mg/kg (Investigator’s Brochure, 2010).  Dose-
dependent inhibition of phosphorylation of c-Met and RET was observed among the 3, 


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10, and 30 mg/kg dose groups as well.   
 
c-Met phosphorylation was inhibited by a single 100 mg/kg oral dose of Cabozantinib, 
2–8 hours post dose in H441 tumors (human lung papillary adenocarcinoma) that harbor 
constitutively phosphorylated c-Met (Yakes, 2011). This effect was reversible, as c-Met 
phosphorylation returned to basal levels by 48 hours after treatment.   
 
Nonclinical Pharmacokinetics 
In the various xenograft models, plasma exposures were similar and plasma 
concentrations in the range of 3 to 27 μM were associated with efficacy (Investigator’s 
Brochure, 2010).  In rats, plasma concentrations in the range of 5 to 15 μM were 
associated with maximal anti-tumor activity.  Despite the apparent requirement for high 
peak concentrations, trough concentrations as low as 0.1 μM were observed at highly 
efficacious doses in mice.  These results were consistent with in vivo target modulation 
studies in mice which demonstrated long (4- to 10-hour) durations of action, and 
indicated that continuous high exposure was not required to maintain efficacy.   
 
Dose proportional increases in exposure occurred at oral doses of 3–100 mg/kg in mice 
and at 3–30 mg/kg in rats (Investigator’s Brochure, 2010).  In rats, the oral bioavailability 
of cabozantinib dosed as a solid was approximately 100% of cabozantinib dosed as a 
liquid.  In comparison, oral bioavailability was much lower in dogs (20%) and monkeys 
(18%) for the solid versus liquid dosage forms. 
 
Systemic drug exposure parameters (maximum plasma concentration [Cmax] and area 
under the time-concentration curve from 0 to t hours post-dose [AUC0-t] values) 
associated with single cabozantinib  oral doses in rats increased less than dose-
proportionally with increasing dose (100–900 mg/kg) (Investigator’s Brochure, 2010).  
With repeat daily oral dosing in rats, systemic exposure (AUC0-t values) increased 
generally dose-proportionally following 14 and 178 dosing days (dose ranges 1–15 
mg/kg/day and 0.1–1 mg/kg/day, respectively).  The Cmax and AUC0-t values in rats 
administered 100 mg/kg were approximately 2-fold and 3-fold higher, respectively, than 
for dogs given 2000 mg/kg; therefore, the higher systemic exposure to cabozantinib in 
rats correlated with the greater toxicity observed in this species at lower administered 
doses. 
 
Systemic drug exposure parameters (Cmax and AUC0-t values) associated with single 
cabozantinib oral doses in dogs increased less than dose-proportionally with increasing 
Cabozantinib dose (400–2000 mg/kg), suggesting possible saturation of systemic 
absorption (Investigator’s Brochure, 2011).  With repeat daily dosing, exposure (Cmax and 
AUC0-24 values) both increased greater than dose-proportionally from 10 to 100 mg/kg 
and less than dose proportionally from 100 to 1000 mg/kg following 14 dosing days.   
 
Toxicology 
In rodents and non-rodents, histopathological changes associated with cabozantinib 
administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid 
tissues, kidney, and adrenal and reproductive tract tissues (Investigator’s Brochure, 


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2011).  Histopathological changes present in the bone and pancreas were considered 
secondary to cabozantinib administration. Adverse effects following oral exposure to 
cabozantinib were generally dose-related, clinically monitorable, and self-resolving upon 
discontinuation of dosing. In 6-month chronic toxicity studies, treatment-related changes 
were present only in kidney (rats) and reproductive tissues (dog).  In 
reproductive/developmental toxicity studies, Cabozantinib administration resulted in 
decreased fertility in male and female rats, in embryotoxicity when given to pregnant 
rats, and in a visceral tissue malformation (small spleen) when given to pregnant rabbits. 
The no-observable-adverse-effect-levels (NOAELs) for the chronic toxicity and 
reproductive/developmental toxicity studies occurred at plasma exposures (AUC) below 
steady-state values measured in subjects with solid tumors administered 175 mg 
Cabozantinib capsule form daily (Study XL184-001). 
 
In definitive genotoxicity bioassays, Cabozantinib was negative in an S. 
typhimurium/E.coli bacterial mutagenicity study, an in vitro chromosome aberration 
study using human peripheral blood lymphocytes, and an in vivo mouse bone marrow 
micronucleus study (Investigator’s Brochure, 2010).  In safety pharmacology studies, no 
adverse effects occurred on neurobehavioral or respiratory functions in Cabozantinib-
treated rats or on cardiovascular function in Cabozantinib-treated dogs. 
 
Clinical Experience 
 
As of May 4, 2011, 1003 patients have been studied in 12 ongoing Exelixis-sponsored 
clinical trials with Cabozantinib treatment 1) as a single agent at does ranging from 0.08 
to 11.52 mg/kg on an intermittent dosing schedule, 2) from 25 to 265 mg (19.7-209 mg 
freebase equivalent weight) on a fixed daily dosing schedule and 3) in combination with 
temozolomide (TMZ) and radiation therapy (RT), or with erlotinib (Exelixis 
Communication, 2011).  The maximum tolerated dose (MTD) on once daily (qd) by 
mouth (PO) dosing schedule was determined to be 175 mg L-malate salt (or 
approximately 138 mg freebase equivalent weight). 
 
Detailed information for each of these studies, including pharmacokinetic data, can be 
found in the Investigator’s Brochure (2011).  Safety and efficacy information, from the 
2011 Investigator’s Brochure, is summarized below.  
 
Phase 2 Studies 
 
In a phase 2 study, XL184-201, subjects with progressive or recurrent GB in first or 
second relapse were enrolled to receive cabozantinib qd as a single agent.  Group A 
received an initial dose of 175 mg (Group A), subsequent cohorts (Groups B and C) 
received an initial dose of 125 mg.  Forty-six subjects were enrolled in Group A, and a 
total of 176 subjects were enrolled in Groups B/C.  Fifty-seven subjects experienced one 
or more serious adverse events (SAEs) that were assessed to be related to treatment, 
including five fatal related. 
 
Study XL184-203 is a phase 2 randomized discontinuation trial.  Subjects are enrolled 


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into one of nine tumor-specific cohorts: breast cancer, gastric/gastroesophageal (GEJ) 
cancer, hepatocellular carcinoma (HCC), melanoma, NSCLC, ovarian cancer, pancreatic 
cancer, prostate cancer, and small cell lung cancer (SCLC).  Eligible subjects with 
advanced solid tumors receive open-label cabozantinib at starting dose of 100 mg qd for 
12 weeks.  Of the 531 subjects enrolled in this study as of May 2011, 92 experienced one 
or more SAEs that were assessed to be related to treatment with cabozantinib, including 
seven fatal related SAEs. 
 
Study XL184-205 is a randomized phase 2 trial for subjects with grade IV astrocytic 
tumors in first or second relapse.  Subjects received one of four regimens: 25 mg qd (Arm 
1) continuously, 75 mg qd (Arm 2) continuously, 125 mg qd for 2 weeks followed by 50 
mg qd continuously (Arm 3), and 125 mg qd on an intermittent 3 week on/1 week off 
schedule (Arm 4).  A total of 19 subjects were accrued before the study was terminated.  
Three subjects were rolled over to maintenance Study XL184-900.  One subject 
experienced an SAE assessed to be related to treatment with cabozantinib.  
 
Study XL184-301 is a blind trial for subjects with unresectable, locally advanced or 
metastatic MTC, randomized 2:1 to cabozantinib or placebo.  SAEs reported in Study 
XL184-301 are: one grade 4 reversible posterior leukoencephalopathy syndrome (RPLS), 
one grade 5 cardiac arrest following asystolic vagal reaction after aspiration on study 
medication, and three SAEs of acquired trachea-esophageal fistula (two grade 3, one 
grade 5). 
 
Study GOG-0186K is a phase II trial for subjects with persistent or recurrent ovarian, 
fallopian tube, or primary peritoneal cancer.  The study demonstrated a low rate of Grade 
3 and 4 toxicities with only 1 bowel perforation among 52 patients who received 
Cabozantinib.  
 
Adverse Events 
The clinical studies with cabozantinib are ongoing and thus the AE data from the clinical 
database as of March 1, 2011 and May 4, 2011 do not yet include all SAEs (Exelixis 
Communication, 2011).  As of March 2011, AE data are available for 913 subjects who 
have been dosed with Cabozantinib (806 in single-agent studies and 107 in combination 
studies of cabozantinib with erlotinib, rosiglitazone, or TMZ ± radiation) (Investigator’s 
Brochure, 2011).  Data from the 806 subjects who received single-agent cabozantinib 
show that the most frequently (>20%) observed AEs regardless of causality were fatigue, 
diarrhea, nausea, decreased appetite, constipation, palmar-plantar erythrodysesthesia 
(PPE) syndrome, vomiting, dysphonia, and hypertension.  Effects that may be related to 
the inhibition of VEGF, including hypertension, thromboembolic events, GI perforation, 
fistula formation, hemorrhage, wound dehiscence, and proteinuria, have been observed in 
the single-agent and combination cabozantinib studies.  The most commonly reported 
SAEs that were assessed as related to study treatment with cabozantinib (as a single-
agent or combination) were pulmonary embolism (PE), diarrhea, dehydration, deep vein 
thrombosis (DVT), vomiting, nausea, thrombocytopenia, fatigue, wound dehiscence, and 
PPE syndrome. 
 


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There have been 15 grade 5 AEs related to study treatment: GI hemorrhage (two 
subjects), PE (two subjects), respiratory failure (two subjects), respiratory disorder (one 
subject), hemoptysis (one subject), death due to unknown cause (two subjects), 
intracranial hemorrhage (one subject), intestinal perforation (one subject), 
enterocutaneous fistula (one subject), hemorrhage (presumed to be hemoptysis; one 
subject), and diverticular perforation, peritonitis (one subject) (Investigator’s Brochure, 
2011). 
 
Pharmacokinetics 
Pharmacokinetic analysis of 74 patients in trial XL184-001 showed dose proportional 
increases in maximum plasma concentration (Cmax) and AUC both for PIB (dose range 
0.08-11.52 mg/kg) and the capsule formulation (dose range: 125 to 175 mg) (Kurzrock, 
2011).  Terminal-phase half-life (t1/2,z) values were 59.1 to 136 hours (Investigator’s 
Brochure, 2011).  After repeat dosing, t1/2,z values (mean ± standard deviation) for 
cabozantinib were 91.3 ± 33.3 hours (n = 23), and apparent steady-state plasma levels 
were reached by Day 15 18.  Steady-state clearance for the 175 mg capsule dose derived 
from repeat dose data was 4.2 ± 1.5 L/h.  Patients who received 175 mg capsules had 
four- to five-fold higher steady-state exposure (AUC) compared with Day 1 (7.68 ± 2.85 
mcg∙h/mL; n = 23 vs. 41.6 ± 15.3 mcg∙h/mL; n = 23), indicating that cabozantinib 
accumulated with repeat daily dosing.  There was no significant difference in exposure 
between patients with MTC and those without MTC. 
 
Based on the preliminary PK data from 23 subjects in XL184-005 who completed both 
treatments, after a single oral dose of cabozantinib at 100 mg, the terminal t1/2, z of 
cabozantinib appeared to be similar for both tablet and capsule formulations, with 
approximately mean values of 110 hours (Exelixis Communication, 2012).  The median 
time to the maximum plasma concentration (tmax) was 4 hours for the tablet formulation 
and 5 hours for the capsule formulation.  High inter-subject variability for Cmax and the 
area under the plasma drug concentration time curve (AUC) values were observed for 
both formulations (coefficient of variation [CV]% Cmax: 51% for the tablet formulation, 
61% for the capsule formulation; CV% for the AUC from time zero to the last 
quantifiable timepoint or to infinity [AUC0-last or AUC0-inf]: 40-43% for the tablet 
formulation, 43% for the capsule formulation).  The geometric mean Cmax of the tablet 
formulation was approximately 39% higher than the value observed for the capsule 
formulation.  The geometric mean AUC0-last and AUC0-inf values for the tablet formulation 
were also higher (15% and 19%, respectively) than those observed for the capsule 
formulation.  However, due to the high within-formulation variability observed, no 
statistical difference in exposure between the two formulations was apparent. 
 
Based on the preliminary PK data from 46 subjects who completed both treatments on 
trial XL184-004, a high-fat meal did not appear to alter the terminal t1/2, z of cabozantinib 
[mean t1/2, z : 131 hours (fed) vs 128 hours (fasted)].  The high-fat meal significantly 
increased the median tmax to 6 hours from 4 hours (fasted).  The high-fat meal also 
significantly increased both the cabozantinib Cmax and AUC values by 39% and 56%, 
respectively.  The geometric mean ratio of Cmax fed/fasted was 1.39 (90% CI: 1.16-1.67), 
and the geometric mean ratio of AUC0-last fed/fasted was 1.56 (90% CI: 1.34-1.80).  


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Based on this result, cabozantinib must be taken on an empty stomach (fasting is required 
2 hours before and 1 hour after each cabozantinib dose). 
 
2.3 
Inclusion of Women and Minorities 
 
The NRG Oncology Group and NRG participating institutions will not exclude potential 
subjects from participating in this or any study solely on the basis of ethnic origin or 
socioeconomic status.  Every attempt will be made to enter all eligible patients into this 
protocol and therefore address the study objectives in a patient population representative 
of the entire serous ovarian and peritoneal population treated by participating institutions. 
 
 


3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the NRG Statistics and Data 
Management Center – Buffalo Office (via the contact list on the NRG web site).  
 
3.1 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential should be willing and able to use medically acceptable 
forms of contraception during the trial. 
 
3.2 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.2.1 A retrospective review of all patients entered will be performed to confirm clear cell 
histology. Patients must have recurrent or, progressive clear cell ovarian cancer not 
solely based on CA-125. Primary tumors must be at least 50% clear cell 
histomorphology in order to be eligible or have a histologically documented recurrence 
with at least 50% clear cell histomorphology. Recurrence should be biopsy proven 
unless the tumor is located in an area deemed unsafe to biopsy by the surgeon. If a 
biopsy can be obtained without significant risk, then biopsy should be obtained 
 
3.2.1.1 
If the primary tumor had at least 50% clear cell histomorphology, a biopsy of the 
recurrent or persistent tumor is not required. The percentage of clear cell 
histomorphology must be documented in the pathology report or in an addendum to 
the original report. If slides of the primary tumor are not available for review due to 
disposal of slides by the histology laboratory (typically 10 years after diagnosis), 
biopsy of recurrent or persistent disease is required. 
 
3.2.1.2 
If slides of the primary tumor are not available for review, a biopsy of the recurrent or 
persistent tumor is required to confirm at least 50% clear cell histomorphology. The 
percentage of involvement must be documented in the pathology report or in an 
addendum to the original report. 
 


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3.2.2 All patients must have measurable disease as defined by RECIST 1.1.  
3.2.3 All patients must submit unstained slides of primary or recurrent tumor for translational 
analysis 
3.2.4 Patients must have at least one “target lesion” to be used to assess response on this 
protocol as defined by RECIST 1.1  
3.2.5 Patients must have had one prior platinum-based chemotherapeutic regimen for 
management of primary disease. Platinum sensitive and resistant patients are eligible. 
3.2.6 Patients are allowed to receive, but are not required to receive, one additional cytotoxic 
regimen for management of recurrent or persistent disease  
3.2.7 Concomitant use of additional anti-neoplastic agents will not be allowed in this study 
3.2.8 Patients may not have received previous therapy with a MET inhibitor. 
3.2.9 Patients must not be eligible for a higher priority (e.g.; Phase II/III), NRG protocol for 
the same population if one exists. 
3.2.10 Patients must be recovered from effects of recent surgery (28 days must elapse between 
surgery and the start of treatment with cabozantinib). 
3.2.11 Patients must have ≥ 4 weeks since prior chemotherapy or radiation (≥ 6 weeks for 
nitrosoureas or mitomycin C). 
3.2.12 Appropriate stage for study entry based on the following diagnostic workup: 
• History/physical examination within 28 days prior to registration 
3.2.13 Age ≥ 18 
3.2.14 The trial is open only to women with recurrent, progressive clear cell carcinoma of the 
ovary. 
3.2.15 Patients must have an ECOG Performance Status of 0, 1, or 2 (Karnofsky ≥ 60% (See 
Appendix VI)  within 28 days prior to registration (09/08/15) 
3.2.16 Adequate hematologic function within 14 days prior to registration defined as follows: 
• Absolute neutrophil count (ANC) >1,500/mcl  
• Platelets greater than or equal 100,000/mcl. 
• Leukocytes ≥3,000/mcL 
• Hemoglobin ≥9 g/dL 
• serum albumin ≥2.8g/dL 
 
3.2.17 Adequate blood coagulation parameters within 14 days prior to registration defined as 
follows:  
• PT such that international normalized ratio (INR) is less than or equal to 1.3 x 
ULN  
• PTT less than or equal to 1.3 x ULN  
 
3.2.18 Adequate renal function within 14 days prior to registration defined as follows: 
• Creatinine less than or equal to 1.5 times the ULN  
OR 
• Creatinine clearance ≥50 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
• The UPCR is derived as follows: protein concentration (mg/dL)/creatinine 


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(mg/dL). Patients must have a UPCR < 1.0 to allow participation in the study 
 
 
3.2.19 Adequate hepatic function within 14 days prior to registration defined as follows: 
• Bilirubin less than or equal to 1.5 ULN. 
• AST and ALT less than or equal to 2.5 times the ULN, unless subjects have liver 
metastasis, in which case both AST and ALT must be less than or equal to 5 times 
the ULN. 
 
3.2.20 Adequate pancreatic function within 14 days prior to registration defined as follows: 
• Lipase less than or equal to 2 x ULN 
• No clinical evidence of pancreatitis 
 
3.2.21 Adequate thyroid function within 28 days prior to registration defined as follows:  
 Patients must have a normal baseline TSH.  A history of hypothyroidism and/or  
hyperthyroidism is allowed. 
 
3.2.22 Women of childbearing potential must have a negative pregnancy test at screening.  
Women of childbearing potential include women who have experienced menarche and 
who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or are not postmenopausal.  Post-menopause is 
defined as amenorrhea ≥12 consecutive months.  Note: women who have been 
amenorrheic for 12 or more months are still considered to be of childbearing potential if 
the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian 
suppression or any other reversible reason. Women should stop breastfeeding while 
participating in this trial. Male partners of women participants should also use 
medically-acceptable forms of contraception during the study 
 
3.2.23 The patient must provide study-specific informed consent prior to study entry. 
 
3.3 
Ineligibility Criteria 
Patients with one or more of the following conditions are NOT eligible for this study. 
3.3.1 HIV positive patients. 
3.3.2 Patients with serious non-healing wound, ulcer, or bone fracture. 
3.3.3 Patients with active bleeding or pathologic conditions that carry high risk of bleeding, 
such as known bleeding disorder, coagulopathy, or tumor involving major vessels. 
3.3.4 The subject requires concomitant treatment, in therapeutic doses, with anticoagulants 
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or 
antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤81 mg/day), low-dose warfarin 
(≤1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted. 
 


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3.3.5 Patients with history or evidence upon physical examination of CNS disease, including 
primary brain tumor, seizures not controlled with standard medical therapy, any brain 
metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic 
attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment 
on this study. 
3.3.6 Patients with clinically significant cardiovascular disease. This includes: 
3.3.6.1 
Poorly controlled hypertension (>140 mm Hg and > 90 mm Hg  for systolic and 
diastolic BP) are ineligible. 
3.3.6.2 
Myocardial infarction or unstable angina within 6 months prior to registration; New 
York Heart Association (NYHA) Grade II or greater congestive heart failure (see 
Appendix III) 
3.3.6.3 
Cardiac arrhythmia requiring medication 
3.3.7 Grade II or greater peripheral vascular disease based on NCI CTC; e.g. ischemic rest 
pain, minor tissue loss, and ulceration or gangrene 
3.3.8 Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid 
function in the normal range with medication are ineligible. Patients with a history of 
hypothyroidism are eligible provided they are currently euthyroid. 
3.3.9 Patients who have a major surgical procedure, or significant traumatic injury within 28 
days prior to the first date of treatment on this study, or anticipation of need for major 
surgical procedure during the course of the study; patients with placement of vascular 
access device or core biopsy within 7 days prior to the first date of treatment on this 
study. 
3.3.10 Patients with other invasive malignancies, with the exception of non-melanoma skin 
cancer, who had (or have) any evidence of other cancer present within the last 5 years or 
whose previous cancer treatment contraindicates this protocol therapy. 
3.3.11 Patients must not be eligible for a higher priority NRG clear cell protocol (GOG-0283). 
Rare patients ineligible for GOG-0283 may be eligible for this trial without prior 
treatment on dasatinib therapy (e.g. they have been deemed allergic to dasatinib). 
3.3.12 Patients who cannot swallow pills 
 
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
PRE-TREATMENT ASSESSMENTS (07/05/16) 
Assessments 
Prior to Registration 
 (within specified number of 
calendar days prior to study 
therapy) 
History & Physical  
28 
Performance Status 
28 
Height 
28 
Weight 
28 
Vital Signs (blood pressure, 
heart 
rate and temperature) 
28 
Toxicity Assessment 
28 
CBC, differential, 
14 


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hemoglobin, platelets, 
Electrolytes, BUN, 
Creatinine, UPC, Ca, Mg, 
PO4, Bilirubin, AST/SGOT, 
ALT/SGPT, Alkaline 
Phosphatase, Amylase, 
Lipase, Urine 
protein/creatinine ratio 
 
PT, INR, PTT 
14 
Pregnancy test 
3 
TSH 
28 
CA125 
14 
Chest Imaging (CT of Chest) 
28 
Radiographic disease 
assessment 
28 
Electrocardiogram 
28 
Review of medications 
28 
 
ASSESSMENTS DURING TREATMENT 
Assessments 
During Adjuvant 
Chemotherapy 
History & Physical  
Prior to each treatment cycle 
Performance Status 
Prior to each treatment cycle 
Height 
 
Weight 
Prior to each treatment cycle 
Vital Signs (blood pressure, 
heart 
rate and temperature) 
Prior to each treatment cycle 
Toxicity Assessment 
Prior to each treatment cycle 
CBC, differential, 
hemoglobin, platelets, 
Electrolytes, BUN, 
Creatinine, UPC, Ca, Mg, 
PO4, Bilirubin, AST/SGOT, 
ALT/SGPT, Alkaline 
Phosphatase, Amylase, 
Lipase, Urine 
protein/creatinine ratio 
Prior to each treatment cycle 
Within 4 days prior to 
retreatment 
 
PT, INR, PTT 
Prior to each treatment cycle 
Within 4 days prior to 
retreatment 
CA125 
Prior to each treatment cycle 
Chest Imaging (CT of Chest) 
After second cycle  then every 
8 weeks 
Radiographic disease 
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assessment 
8 weeks 
Patient diary documenting 
cabozantinib dosing 
Prior to each treatment cycle 
Within 4 days prior to 
retreatment 
 
ASSESSMENTS IN FOLLOW UP 
Assessments 
Example: From end of Chemotherapy: q3 
mos. x 2 yrs.; q6 mos. x 3 years; then 
annually, unless otherwise indicated 
History & Physical  
X 
Performance Status 
X 
Height 
X 
Weight 
X 
Vital Signs (blood pressure, heart 
rate and temperature) 
X 
Routine blood tests 
X 
CT scan or MRI of Abdomen and pelvis to 
measure detectable tumor 
X 
 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
 
5.1 
Chemotherapy  
 
Institutional participation in chemotherapy studies must be in accordance with the 
Medical Oncology Quality Control guidelines stated in the NRG Oncology 
Procedures Manual. 
 
See the General Chemotherapy Guidelines (Appendix I). 
 
5.1.1  Cabozantinib (XL184) 60 mg once a day continuously , repeated in 4 week cycles until 
disease progression or adverse effects prohibit further therapy 
 
5.1.1.1 
One cycle equals 28 days. 
 
5.1.2 Patients will be given a Patient Medication Calendar to complete daily (Appendix IV).  
The Patient Medication Calendar should be reviewed prior to the start of each cycle. 
 
5.1.3 Cabozantinib must be taken on an empty stomach.  Patients must fast for 2 hours before 
and 1 hour following each dose of Cabozantinib. 
 


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5.2 
General Concomitant Medication and Supportive Care Guidelines 
5.2.1 Because there is a potential for interaction of cabozantinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must 
capture the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies.  The Principal Investigator should be alerted if the patient is taking 
any agent known to affect or with the potential to affect selected CYP450 isoenzymes.   
 
5.2.2 Concomitant Medications and Therapies 
 
5.2.2.1 
Anticancer Therapy 
 
If a subject requires additional systemic anticancer treatment, study treatment must be 
discontinued.  Local intervention is discouraged unless medically unavoidable.  
 
5.2.2.2 
Other Medications 
 
Subjects must be instructed to inform the investigators of the current or planned use 
or all other medications during the study (including prescription medications, over-
the-counter medications, vitamins and herbal and nutritional supplements).  It is the 
responsibility of the investigator to ensure that details regarding all medications are 
documented. 
 
Bisphosphonates started prior to screening activities or initiated during the course of 
the study to control bone pain may be used with caution. 
 
Colony stimulating factors (e.g., erythropoietin and granulocyte colony-stimulating 
factors) and pain medications administered as dictated by standard practice are 
acceptable while the subject is enrolled in the study.  However, colony stimulating 
factors should not be administered prophylactically prior to the first dose of study 
treatment.  
 
No concurrent investigational agents are permitted. 
 
5.2.2.3 
Potential Drug Interactions 
 
CYP450 isozymes: 
In vitro, XL184 is a substrate of CYP3A4 and a weak substrate of CYP2C9. Co-
administration of ketoconazole, a strong inhibitor of CYP3A4, increases XL184 AUC (37%) 
and rifampin, a strong inducer of CYP3A4, reduces XL184 AUC (77%) . Therefore, avoid 
chronic use of strong CYP3A4 inducers such as rifampin, dexamethasone, phenytoin, 
carbamazepine, rifabutin, rifampentin, phenobarbital, and St. John’s Wort while taking 
XL184. Avoid chronic use of strong CYP3A4 inhibitors such as ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir. Use alternative medications. 
 
[Note: Use caution when discontinuing medication that is a strong inducer of CYP3A4 in 
patients who has been on a stable dose of XL184, as this could significantly increase the 
exposure to XL184.] 
 


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XL184 is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of 
both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive 
inhibitor of CYP3A4 (estimated Kiapp = 282 μM) in human liver microsomal (HLM). IC50 
values >20 μM were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes. XL184 is an 
inducer of CYP1A1 mRNA in human hepatocyte incubations, 
 
Avoid grapefruit/ grapefruit juice and Seville oranges while participating in this trial. 
 
P-glycoprotein/ MRP2: 
In vitro data indicate that XL184 is unlikely to be a substrate but may be an inhibitor of P-
glycoprotein transport activity (IC50 = 7.0 μM). 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 substrates (e.g., 
fexofenadine, aliskiren, ambrisentan, digoxin, colchicine, maraviroc, posaconazole, tolvaptan, 
etc.). In an in vitro assay, XL184 has shown to be 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, delavirine, efavirenz, emtricitabine. 
 
Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, 
and inhibitors of selected CYP450 isozyme pathways. Table available at (Flockhart 
2007; http://medicine.iupui.edu/clinpharm/ddis/table.aspx).  
 
Protein bound: 
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). Avoid administration of warfarin with XL184 as warfarin is highly protein-
bound and has a very narrow therapeutic index. 
 
Antacids, H2-blockers, PPIs: 
Co-administration of gastric pH modifying drugs such as PPI, H2-blockers or antacids has no 
clinically-relevant effect on XL184 plasma PK in healthy volunteers; thus, concomitant use 
of these drugs with XL184 is allowed. 
 
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 itmay increase XL184 plasma 
concentrations. Refer to the protocol for QTcF criteria. 
 
 
 
5.2.3  
Participation in Other Trials  
• Patients must not be eligible for a higher priority NRG clear cell protocol (GOG-
0283). Rare patients ineligible for GOG-0283 may be eligible for this trial without 
prior treatment on dasatinib therapy (e.g. they have been deemed allergic to 
dasatinib). 
 


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5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
▪ 
Disease progression, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), 
▪ 
Patient decides to withdraw from the study, or 
▪ 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
 
6.1 
Cabozantinib (XL184)-Related Adverse Event Management 
 
Subjects will be monitored continuously for AEs throughout the study. Subjects must be 
instructed to notify their physician immediately for any and all toxicities. 
 
General guidelines for the management of non-hematologic and hematologic toxicities are 
provided in Table 6-1 and Table 6-2, respectively. As a general approach, it is suggested that all 
AEs be managed with supportive care when possible at the earliest signs of toxicity. Calcium, 
magnesium, potassium and phosphorus should be kept above the lower limits of the laboratory 
normal values. For more specific guidelines on gastrointestinal AEs (diarrhea, nausea/vomiting, 
stomatitis/mucositis), hepatobiliary disorders, pancreatic disorders including lipase and amylase 
elevations, skin disorders (PPE), embolism and thrombus, hypertension, proteinurea, 
hemorrhage, rectal and perirectal abscess, gastrointestinal (GI) perforation and GI fistula, non-GI 
fistula, wound healing and surgery, osteonecrosis of the jaw (ONJ),  endocrine disorders and 
management of treatment-emergent prolongation of the QTc interval, refer to the appropriate 
below.  Guidance for the management of fatigue, anorexia, weight loss, eye disorders, 
musculoskeletal and connective tissue disorders, nervous system disorders, 
respiratory/thoracic/mediastinal disorders and congenital, familial and genetic disorders can be 
found in the Cabozantinib Investigator’s Brochure.  
  
 
Dose adjustments for Cabozantinib 
 
 
Cabozantinib Dose 
mg/day 
Initial 
60 
-1 
40 
-2 
20 
 
 
 


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Table 6-1.  General Approach to the Management of Cabozantinib-Related Non-
Hematologic Adverse Events 
CTCAE Version 4 Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level. 
Grade 2: 
Grade 2 AEs considered related to 
cabozantinib that are subjectively 
tolerable or easily managed 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level.  
Grade 2 AEs considered related to 
cabozantinib that are intolerable to the 
subject or deemed unacceptable in the 
investigator’s judgment; or are not 
easily managed or corrected 
Dose reduce 
• 
If the AE dose not resolve to Grade ≤1 or baseline in 7 to 10 days 
or worsens at any time, cabozantinib dosing should then be 
interrupted.  Then upon resolution to baseline or Grade ≤ 1, the 
reduced dose should be restarted. 
• 
If the AE does resolves to resolves to Grade ≤1 or baseline 
without a dose interruption, continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered related to 
cabozantinib which occurred without 
optimal prophylaxis or which is easily 
managed by medical intervention or 
resolved quickly 
• 
Interrupt cabozantinib and add supportive care as indicated 
• 
For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or Grade ≤1 within 24 hours,  
cabozantinib may be resumed at either the same dose or with a 
dose reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
• 
For AEs that require supportive care, the dose should be held 
while supportive care is initiated and optimized.  Then upon 
resolution of the AE to baseline or Grade ≤1,  cabozantinib may be 
resumed at either the same dose or with a dose reduction at the 
discretion of the investigator unless this is a recurring event at 
which time the dose should be reduced 
Grade 3 AEs considered related to 
study treatment that occurred despite 
optimal prophylaxis or is not easily 
managed by medical intervention  
Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and 
resume treatment with a dose reduction 
Grade 4: 
 
Grade 4 AEs considered related to 
study treatment 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor 
but only with sponsor approval. 
Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the 
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Table 6-2.  General Approach to the Management of Cabozantinib-Related Hematologic 
Adverse Events 
CTCAE Version 4 Grade 
Intervention 
Neutropenia 
Grade 3 neutropenia with documented 
infection 
Grade 3 neutropenia ≥ 5 days 
Grade 4 neutropenia  
Interrupt cabozantinib treatment until resolution to Grade ≤1, and 
resume cabozantinib treatment at a reduced dose.  
Thrombocytopenia 
Grade 3 thrombocytopenia with clinically 
significant bleeding or Grade 4 
thrombocytopenia 
Interrupt cabozantinib treatment until platelet count is  
≥100,000/mm3, and resume cabozantinib treatment at a reduced dose 
Febrile Neutropenia 
Grade 3 febrile neutropenia 
Interrupt cabozantinib treatment until recovery of ANC to Grade ≤1 
and temperature to ≤38.0°C and resume cabozantinib treatment at a 
reduced dose. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor 
but only with sponsor approval. 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic toxicities  
other than anemia 
Permanently discontinue study treatment unless determined that the 
subject is clearly deriving clinical benefit. In this case, upon recovery 
to Grade ≤1 or baseline, the subject may be re-treated at a reduced 
dose that is to be determined by the investigator and sponsor and only 
with approval by the sponsor. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not mandated. Dose 
reductions or dose delays for anemia should be applied as clinically 
indicated. Supportive care such as red blood cell transfusions should 
be managed according to institutional guidelines. 
ANC, absolute neutrophil count; LLN, lower limit of normal 
Neutropenia: Grade 1 (LLN ≤ ANC < 1.5  109/L; Grade 2 (1  109/L ≤ ANC <1.5 x 109/L),  
Grade 3 (0.5  109/L ≤ ANC < 1  109/L), Grade 4 (ANC < 0.5  109/L). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
Thrombocytopenia: Grade 1 (Platelet count <LLN – 75 x 109/L); Grade 2 (Platelet count <75.0 – 50.0 x 109/L);  
Grade 3 (Platelet count ≤ 50 - 25  109/L); Grade 4 (Platelet count < 25  109/L). 
 


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6.2 
Diarrhea, Nausea, Vomiting,  Stomatitis, and Mucositis 
 
Diarrhea 
 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements.  Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management.  
Loperamide is recommended as standard first line therapy.  Alternatively, diphenoxylate/atropine 
can be used.  Additional agents to consider in subjects with diarrhea that is refractory to the 
above include deodorized tincture of opium and octreotide (Benson et al., 2004).  Some subjects 
may require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized 
tincture of opium to control diarrhea.  The dose modification guidance in Table 6-1 should be 
followed.  In addition, general supportive measures should be implemented including continuous 
oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high fat meals and alcohol.  
 
Nausea and Vomiting 
 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting.  The dose modification guidance in Table 6-1 should be 
followed.   
 
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists 
and dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and 
glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure.  Caution is also 
recommended with the use of nabilone, which is a weak inhibitor of CYP3A4. Caution is also 
recommended with ondansetron, as ondansetron may result in QTc prolongation when 
administered with cabozantinib.  Ondansetron is a 5-HT3 antagonist. 
 
Stomatitis and Mucositis 
 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated.  Appropriate correction of local factors should 
be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of 
gingivitis.  During treatment with cabozantinib, good oral hygiene and standard local treatments 
such as non-traumatic cleansing, and oral rinses (e.g., with a weak solution of salt and baking 
soda) should be maintained.  The oral cavity should be rinsed and wiped after meals, and 
dentures should be cleaned and brushed often to remove plaque. Local treatment should be 
instituted at the earliest onset of symptoms.  When stomatitis interferes with adequate nutrition 
and local therapy is not adequately effective, dose reduction or temporary withholding of 
cabozantinib should be considered. 
 
6.3 
Hepatobiliary Disorders 
 
Elevations of transaminases have also been observed during treatment with cabozantinib.  In 
general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more 


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frequent laboratory monitoring of these parameters.  If possible, hepatotoxic concomitant 
medications and alcohol should be discontinued in subjects who develop elevated transaminases.  
Since subjects may enter the study with elevations of AST/ALT at baseline, the following 
guideline should be used for dose modifications: 
 
 
 
Transaminase elevation 
CTCAE v4.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at 
least 4 weeks. Then resume the standard protocol-defined monitoring of LFTs. 
Grade 2 
Continue cabozantinib with at least twice weekly monitoring of LFTs for 2 weeks. 
Then weekly for 4 weeks.  If LFTs continue to rise within Grade 2, interrupt 
cabozantinib treatment.   Then continue with at least weekly LFTs until resolution 
to Grade ≤ 1.  Study treatment may then be resumed at a one-dose-level reduction 
of cabozantinib 
Grade 3  
Interrupt cabozantinib treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Cabozantinib may then be resumed at a one-dose-level reduction.  
Grade 4 
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.   If the subject 
was unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose of cabozantinib as determined by the investigator and 
sponsor but only with sponsor approval. 
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline   
≥ 1.5 fold increase of AST or 
ALT AND both AST and 
ALT are ≤ 5.0 x ULN 
Continue cabozantinib treatment with at least twice weekly monitoring of LFTs 
for 4 weeks and weekly for 4 weeks.  If LFTs continue to rise, interrupt study 
treatment.   Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib 
≥ 1.5 fold increase of AST or 
ALT and at least one of 
AST or ALT is Grade 3 (i.e. 
AST or ALT > 5.0 but ≤ 
20.0 x ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.  If the subject 
was unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose as determined by the investigator and sponsor but only 
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Cabozantinib treatment should also be interrupted when transaminase increases are accompanied 
by progressive elevations of total bilirubin, and/or elevations of coagulation tests (e.g., 
International Normalized Ratio [INR]).  Monitoring of transaminases should be intensified (2–3 
times per week) and cabozantinib should be held until the etiology of the abnormalities is 
determined and these abnormalities are corrected or stabilize at clinically acceptable levels (INR 
< 1.5  ULN, total bilirubin < 1.5  ULN, aminotransferases ≤ baseline grade).  
 
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation >2 ULN), in the 
absence of evidence of biliary obstruction (i.e., significant elevation of alkaline phosphatase) or 
some other explanation of the injury (e.g., viral hepatitis, alcohol hepatitis), as the combined 
finding (i.e., Hy’s Law cases) represents a signal of a potential for the drug to cause severe liver 
injury. 
 
All subjects who develop isolated bilirubin elevations of Grade 3 should have study treatment 
held until recovered to Grade ≤1 or baseline (or lower).  If this occurs within 6 weeks of the 
dosing delay, study treatment may continue at a reduced dose. In subjects without biliary 
obstruction and Grade 4 bilirubin elevation, or with recurrence of Grade 3 bilirubin elevation 
after a dose reduction, study treatment must be discontinued.  
 
6.4 
Pancreatic Conditions 
 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib.  The 
clinical significance of asymptomatic elevations of enzymes is not known but in general have not 
been associated with clinically apparent sequelae.  It is recommended that subjects with lipase 
elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of lipase 
and/or amylase (2-3 times per week). Subjects with symptomatic pancreatitis should be treated 
with standard supportive measures. 
 


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Asymptomatic Lipase or Amylase Elevations 
 
Asymptomatic Lipase or Amylase  Elevations 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is recommended 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted 
at the same dose or at a reduced dose provided that this occurs within 6 
weeks. 
• 
If retreatment following Grade 3 lipase or amylase elevation is at the 
same dose and Grade 3 or Grade 4 elevations recur, then treatment must 
be interrupted again until lipase and amylase  levels have resolved to 
Grade ≤1 or baseline and retreatment must be at a reduced dose. 
Grade 4 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline and if resolution occurred 
within 4 days, cabozantinib may be restarted at the same dose or a 
reduced dose.  If resolution took more than 4 days, the dose must be 
reduced upon retreatment provided that resolution occurred within 6 
weeks. 
• 
If retreatment following Grade 4 lipase or amylase elevation is at the 
same dose and Grade 3 or 4 elevations recur, then treatment must be 
interrupted again until lipase and amylase have resolved to Grade ≤1 or 
baseline and retreatment must be at a reduced dose. 
 
Pancreatitis 
 
Pancreatitis 
Grade 2 and asymptomatic 
• 
Continue at current dose level. More frequent monitoring of lipase and 
amylase and radiographic evaluation is recommended. 
Grade 2 symptomatic and 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline , cabozantinib may be restarted 
at a reduced dose if resolution occurred within 6 weeks 
Grade 4 
Permanently discontinue treatment.  However, if the subject was unequivocally 
deriving benefit from cabozantinib therapy, treatment may resume at a reduced 
dose agreed to by the investigator and sponsor but only with sponsor approval. 
 
 
 
6.5 
Skin Disorders 
 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin 
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and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been 
reported in cabozantinib-treated subjects.  All subjects on study should be advised to use 
prophylactic measures for skin care.  These measures includes the use of hypoallergenic 
moisturizing creams, ointment for dry skin, sunscreen with SPF ≥30; avoidance of exposure of 
hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; and use of 
thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects 
with skin disorders should be carefully monitored for signs of infection (e.g., abscess, cellulitis, 
or impetigo). 
 
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild 
hyperkeratosis.  Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles.  The lateral sides of the fingers or periungual zones may also be affected.  
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas.  Aggressive management of symptoms 
is recommended, including early dermatology referral. 
 
Treatment guidelines for PPE related to study treatment are presented in the table below. 
 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent.  
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  
 


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Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose if tolerable or reduce to the next lower 
dose if intolerable. Start urea 20% cream twice daily AND clobetasol 0.05% 
cream once daily. Assess subject at least weekly for changes in severity.  
Subjects should be instructed to notify investigator immediately if severity 
worsens.  If severity worsens at any time or if there is no improvement after 2 
weeks, proceed to the management guidelines for Grade 2 PPE 
Grade 2 
Reduce cabozantinib dose to next lower level and/or interrupt dosing. 
Start/continue urea 20% cream twice daily AND clobetasol 0.05% cream once 
daily. Add analgesics for pain control with NSAIDs/GABA agonists/narcotics if 
needed.. Assess subject at least weekly for changes in severity.  Subjects should 
be instructed to notify investigator immediately if severity worsens.  If severity 
worsens at any time, or affects self-care, or if there is no improvement after 2 
weeks, proceed to the management guidelines for Grade 3 PPE.  If the dose was 
only reduced but not interrupted, treatment may continue at the reduced dose.  If 
the dose was only interrupted but not reduced, then treatment may be restarted 
upon resolution to Grade 0 or Grade 1 at one dose level lower. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0.  Start/continue 
urea 20% cream twice daily AND clobetasol 0.05% cream once daily.  Pain 
control with NSAIDs/GABA agonists/narcotics.  Treatment may restart at one 
dose level lower when reaction decreases to Grade 1 or 0.  Permanently 
discontinue subject from study if reactions worsen or do not improve within 6 
weeks.  
GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia 
 
6.6 
Embolism and Thrombosis  
 
Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; including 
fatal events (please refer to the IB).  Subjects who develop a PE or DVT should have study 
treatment held until therapeutic anticoagulation with heparins is established.  Study treatment 
may be resumed with a one dose-level reduction in subjects who have uncomplicated PE or DVT 
and are deriving clinical benefit from study treatment.  During treatment with anticoagulants, 
subjects need to be monitored on an ongoing basis for bleeding risk and signs of bleeding.  
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 Sponsor.  Venous filters (e.g. vena cava filters) are not 
recommended due to the high incidence of complications associated with their use.  Once a 
subject is fully anticoagulated, treatment can be restarted per investigator judgment at one dose 
lower.  Subjects should permanently discontinue after a second thrombotic event.  Although 
routine prophylactic anticoagulation is not necessary for all subjects, prophylactic 
anticoagulation is allowed for individual subjects at the discretion of the investigator. 
 


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Arterial thrombotic events (e.g., transient ischemic attack, myocardial infarction) have been 
observed rarely in studies with cabozantinib.  Cabozantinib should be discontinued in subjects 
who develop an acute MI or any other clinically significant arterial thromboembolic 
complication. 
 
6.7 
Hypertension 
 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has 
been observed in cabozantinib clinical studies. 
 
Decisions to decrease or hold the dose of study treatment must be based on BP readings taken by 
a medical professional and must be confirmed with a second measurement at least 5 minutes 
following the first measurement.  Subjects with known hypertension should be optimally 
managed prior to study entry.  Clinical judgment should be used in deciding whether new or 
worsened hypertension emerging during treatment with cabozantinib requires immediate therapy, 
or whether therapeutic intervention can be delayed in order to confirm the finding of new or 
worsened hypertension at a second visit before taking new therapeutic action.  It is recommended 
that this second visit occur within 1 week.  Blood pressure should be monitored in a constant 
position visit to visit, either sitting or supine.  Cabozantinib dosing should be interrupted in 
subjects with severe hypertension (180 mm Hg systolic or 120 mm Hg diastolic; or sustained 
≥160 mm Hg systolic or ≥110 diastolic) who cannot be controlled with medical interventions and 
discontinued in subjects with hypertensive crises or hypertensive encephalopathy (see next Table 
below). 
 


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Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 140 mm Hg (systolic) and < 160 mm Hg 
OR 
> 90 mm Hg (diastolic) and < 110 mm Hg 
 
 
• Increase antihypertension therapy  (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
• Maintain dose of cabozantinib 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, or if the subject is symptomatic, the dose of 
cabozantinib should be reduced. 
≥ 160 mm Hg (systolic) and < 180 mm Hg 
OR 
≥ 110 mm Hg (diastolic) and < 120 mm Hg 
• Reduce cabozantinib by one dose level. 
• Increase antihypertension therapy  (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
• Monitor subject closely for hypotension. 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, dose of cabozantinib should be reduced further. 
≥ 180 mm Hg (systolic) OR 
≥ 120 mm Hg (diastolic ) 
• Interrupt treatment with cabozantinib Add new or additional 
anti-hypertensive medications and/or increase dose of 
existing medications. 
• Monitor subject closely for hypotension. 
• When SBP < 140 and DBP < 90, restart cabozantinib 
treatment at  one dose level lower 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, dose of cabozantinib should be reduced further. 
Hypertensive crisis or hypertensive 
encephalopathy 
Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE:  If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
 
 
 
6.8 
Proteinuria 
 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib.  Any level of proteinuria diagnosed by dipstick should be quantified by a UPCR 
(mg/dL protein / mg/dL creatinine).  When a UPCR exceeds 1, a repeat UPCR or a 24-hour urine 
protein and creatinine should be performed to confirm the result. Cabozantinib should be 
discontinued in subjects who develop nephrotic syndrome (proteinuria >3.5 g/day in 
combination with hypoalbuminemia, edema and hyperlipidemia) or any other relevant renal 
disease.  Also, given the nephrotoxic potential of bisphosphonates, these agents should be used 


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with caution in patients receiving treatment with cabozantinib.  Details of management are 
described in the next Table below. 
 
Management of Treatment Emergent Proteinuria 
 Urine Protein/Creatinine Ratio 
Action To Be Taken 
≤ 1 
• 
No change in treatment or monitoring 
> 1 and < 3.5 
 
• 
No change in study treatment required  
• 
Consider confirming with a 24-hour protein excretion within 7 
days 
• 
Repeat UPCR within 7 days and once every week. If UPCR is < 
1 on two consecutive readings, then UPCR monitoring can revert 
to protocol specific time points. (The second reading is a 
confirmatory reading and can be done within 1 week of the first 
reading.). 
≥ 3.5 
 
• 
Hold cabozantinib immediately and confirm with 24 hour urine 
protein excretion.  
• 
Evaluate for nephrotic syndrome. If present, discontinue 
cabozantinib treatment permanently, and monitor subject for 
resolution of nephrotic syndrome.  
• 
If proteinuria of ≥ 3.5 g/24 hours is confirmed without diagnosis 
of nephrotic syndrome, continue to hold cabozantinib and 
monitor UPCR weekly. If UPCR decreases to < 1.5, restart 
cabozantinib at a reduced dose.  Continue monitoring UPCR 
once every week until two consecutive readings are < 1, then 
revert to UPCR monitoring frequency specified in the protocol. 
UPCR, urine protein/urine creatinine ratio 
 
6.9 
Guidelines for the Prevention of Hemorrhagic Events 
 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well 
as with cabozantinib.  As preventive measures, subjects should be evaluated for potential 
bleeding risk factors prior to initiating cabozantinib treatment and monitored for bleeding events 
with serial complete blood counts and physical examination while on study.  Risk factors for 
hemorrhagic events may include (but may not be limited to) the following: 
 
• Tumor lesions with cavitations or tumor lesions which invade, encase, or abut major blood 
vessels.  The anatomic location and characteristics of primary tumors or metastases as well as 
the medical history should be carefully reviewed in the selection of subjects for treatment 
with cabozantinib. 
• Recent or concurrent radiation to the thoracic cavity.  
• Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases. 
• Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in clotting 
factors and/or platelet function, or thrombocytopenia). 


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• Concomitant medication with anticoagulants or other drugs which affect normal hemostasis. 
• History of clinically significant hemoptysis. 
 
 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥0.5 teaspoon (2.5mL) of red blood).  Treatment with cabozantinib 
should be interrupted if less severe forms of clinically significant hemorrhage occur and may be 
restarted after the cause of hemorrhage has been identified and the risk of bleeding has subsided 
at a dose agreed to by the sponsor and the investigator.  Therapy of bleeding events should 
include supportive care and standard medical interventions.  
 
Furthermore, subjects who develop tumors abutting, encasing, or invading a major blood vessel 
or who develop cavitation of their pulmonary tumors while on study treatment must be 
discontinued from cabozantinib treatment. 
 
6.10 
Rectal and Perirectal Abscess 
 
Rectal and perirectal abscesses have been reported, sometimes in subjects with concurrent 
diarrhea. These should be treated with appropriate local care and antibiotic therapy. Cabozantinib 
should be held until adequate healing has taken place.  
 
6.11 
Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula Formation 
 
GI perforation/fistula and Non-GI fistula formation have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of 
abdominal pain, especially in subjects with known risk factors for developing GI 
perforation/fistula or non-GI fistula, to allow for early diagnosis. Such risk factors include (but 
may not be limited to) the following: 
 
GI-perforation/fistula: 
 
• Intra-abdominal tumor/metastases invading GI mucosa.  
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, 
cholecystitis or symptomatic cholangitis, or appendicitis . 
• History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
• Prior GI surgery (particularly when associated with delayed or incomplete healing). 
Complete healing following abdominal surgery or resolution of intra-abdominal abscess must 
be confirmed prior to initiating treatment with cabozantinib. 
 
Additional risk factors include concurrent chronic use of steroid treatment or non-steroidal 
anti-inflammatory drugs.  Constipation indicative of bowel obstruction should be monitored and 
effectively managed.  
 
Non-GI fistula: 
 


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• Radiation therapy has been identified as a possible predisposing risk factor for non-GI fistula 
formation in subjects undergoing treatment with drugs that inhibit VEGF pathways.  In 
addition, subjects who have undergone extensive surgery may be at increased risk of 
developing a fistula of the involved organs Non-GI fistula should be ruled out as appropriate 
in cases of onset of mucositis after start of therapy. 
  
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI 
perforation/fistula. 
 
6.12 
Wound Healing and Surgery 
 
VEGF inhibitors can cause wound healing complications and wound dehiscence which may 
occur even long after a wound has been considered healed. Therefore, surgical and traumatic 
wounds must have completely healed prior to starting cabozantinib treatment and be monitored 
for wound dehiscence or wound infection while the subject is being treated with cabozantinib.  
 
Treatment with cabozantinib must be interrupted for any wound healing complication which 
needs medical intervention. Treatment with cabozantinib can be resumed once wound healing 
has occurred unless otherwise prohibited in specific protocols. Cabozantinib should be 
discontinued in subjects with serious or chronic wound healing complications. 
 
The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing 
complications has not been determined. In general, cabozantinib should be stopped at least 
3 weeks (5 half-lives) prior to elective surgery.  
 
6.13 
Endocrine Disorders 
 
Prospective studies of markers of thyroid functions are currently ongoing in two single-agent 
studies to characterize the effects of cabozantinib on thyroid function. Preliminary data indicate 
that cabozantinib affects thyroid function tests (TFTs) in a high number of subjects (see 
Cabozantinib Investigator’s Brochure).  Routine monitoring of thyroid function and assessments 
for signs and symptoms associated with thyroid dysfunction is recommended for subjects treated 
with cabozantinib. Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) 
should follow accepted clinical practice guidelines. 
 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of subjects.  Monitoring with standard laboratory 
tests for endocrine disorders and clinical examination prior to initiation and during treatment 
with cabozantinib is required.  Cabozantinib should be discontinued in subjects with severe or 
life-threatening endocrine dysfunction. 
 
6.14 
Guidelines for Prevention of Osteonecrosis of the Jaw 
 
Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and 
bisphosphonates and denosumab in cancer patients.  Additional risk factors for ONJ have been 
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smoking, dental or orofacial surgery procedures, and cancer disease itself.  Cases of 
osteonecrosis have been reported in subjects treated with cabozantinib, the details of which are 
provided in the current version of Investigator’s Brochure.  As a preventive measure, invasive 
dental procedures should be avoided if possible in subjects who have previously been treated 
with or concomitantly receive bisphosphonates or denosumab. In cases where dental procedures 
are unavoidable, the risks and benefits of a dental procedure and the extent of the procedure as 
well as the risk of developing osteonecrosis of the jaw need to be considered when deciding on 
the duration of a temporary treatment interruption of cabozantinib.  If clinically possible, 
treatment with cabozantinib should be held for at least 2 weeks prior to a dental procedure and 
resumed after complete wound healing occurred. 
 
Subjects with any documented case of osteonecrosis should have study treatment interrupted, 
and appropriate clinical management should be initiated.  Re-initiation of study treatment must 
be discussed with and approved by the Sponsor on a case by case basis. 
 
6.15 
Guidelines for Management of Treatment-Emergent Corrected QT (QTc) 
Prolongation 
 
Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval.  
Other factors which may contribute to QTc prolongation include 
• Treatment with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org). 
• Treatment with CyP 3A4 inhibitors (which may increase cabozantinib drug levels) 
• Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia). 
• Medical conditions which can alter electrolyte status e.g., severe or prolonged diarrhea. 
 
Subjects having any of these additional risk factors while on cabozantinib must have ECGs 
performed approximately one week after the onset of these factors. 
 
If at any time on study there is an increase in QTc interval to an absolute value >500 msec, two 
additional ECGs should be performed within 30 minutes after the initial ECG with intervals not 
less than 3 minutes apart.  If the average QTcF from the three ECGs is >500 msec, study 
treatment must be withheld and the following actions should be taken: 
 
• Check electrolytes, especially potassium, magnesium and calcium.  Correct abnormalities 
as clinically indicated. 
• If possible, discontinue any QTc-prolonging concomitant medications. 
•  Repeat ECG triplets hourly until the average QTcF is ≤500 msec or otherwise 
determined by consultation with a cardiologist. 
 
The Sponsor should be notified immediately of any QTc prolongation event.  
 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation has resolved.  Cardiology consultation is recommended for evaluation and subject 
management.  Symptomatic subjects must be treated according to standard clinical practice.  No 
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subject has been thoroughly evaluated, and further treatment has been agreed to by the Sponsor.  
If any additional study treatment is given (e.g., after correction of electrolyte abnormalities and 
normalization of QTcF), it will be at a reduced dose as agreed to by the investigator and the 
Sponsor. 
 
 
 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT 
   
7.1.1 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease that occurs in a 
patient administered a medical treatment, whether the event is considered 
related or unrelated to the medical treatment.  
 
CTCAE term (AE description) and grade:  The descriptions and 
grading scales found in the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE 
reporting.  The CTCAE version 4.0 is identified and located on the CTEP 
website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. 
 
The CTCAE Manual is also available on the NRG member web site 
(http://www.gog.org under MANUALS). 
 
7.1.2 Reporting Expedited Adverse Events 
 
Depending on the phase of the study, use of investigational agents, and 
role of the pharmaceutical sponsor, an expedited AE report may need to 
reach multiple destinations.  For patients participating on a NRG trial, all 
expedited AE reports should be submitted by using the CTEP automated 
system for expedited reporting (CTEP-AERS).  All CTEP-AERS 
submissions are reviewed by NRG before final submission to CTEP.  
Submitting a report through CTEP-AERS serves as notification to NRG, 
and satisfies the NRG requirements for expedited AE reporting.  All 
adverse reactions will be immediately directed to the Study Chair for 
further action. 
 
The requirement for timely reporting of AEs to the study sponsor is 
specified in the Statement of Investigator, Form FDA-1572.  In signing the 
FDA-1572, the investigator assumes the responsibility for reporting AEs 


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to the NCI.  In compliance with FDA regulations, as contained in 21 CFR 
312.64, AEs should be reported by the investigator. 
 
 
7.1.3 
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/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS 
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 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 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 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
Note:  All deaths on study require both routine and expedited reporting regardless  
of causality.   
Attribution to treatment or other cause must be provided. 
 


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• 
Expedited AE reporting timelines defined: 
➢ “24 hours; 3 calendar days” – The investigator must initially report the AE via CTEP-AERS within 24 
hours of learning of the event followed by a complete CTEP-AERS report within 3 calendar days of 
the initial 24-hour report. 
➢ “7 calendar days” - A complete CTEP-AERS report on the AE must be submitted within  
7 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or prolongation 
of existing hospitalization) must be reported regardless of attribution and designation as expected or 
unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth 
defects must be reported via CTEP-AERS if the event occurs following treatment with an agent under a 
CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all 
reports. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 2 and 3 Trials 
Utilizing an Agent under a CTEP-IND: 
 
• 
Grades 2-4 myelosuppression (including neutropenia, anemia, and thrombocytopenia) that do not require 
hospitalization are exempt from expedited reporting 
 
7.1.4 Procedures for Expedited Adverse Event Reporting  
 
7.1.4.1 CTEP-AERS Expedited Reports: Expedited reports are to be 
submitted using CTEP-AERS available at http://ctep.cancer.gov. 
The CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements for expedited adverse event reporting requirements 
are also available at this site.  
 
AML/MDS events must be reported via CTEP-AERS (in addition 
to your routine AE reporting mechanisms). In CTCAE v4.0, the 
event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) 
Treatment related secondary malignancy. 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
 In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to NCI by telephone at: 301-897-7497.  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. Please note that all paper 
CTEP-AERS forms have been removed from the CTEP website 
and will NO LONGER be accepted. 
 
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unexpected events are those not listed in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER). The SPEER is a 
subset of AEs within the Comprehensive Adverse Event and 
Potential Risks List (CAEPR). This list of events is based on 
CTEP’s clinical experience with this agent and defines “expected” 
Grade 2 and 3 AEs not requiring hospitalization as exempt from 
expedited reporting. The CAEPR is a complete list of reported 
and/or potential AEs associated with an agent under a CTEP IND. 
For questions or comments regarding the SPEER or CAEPR, 
please contact the CTEP-AERS MD Help Desk at CTEP-
AERSmd@tech-res.com. 
 
Secondary Malignancy:  
 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following 
treatment with an agent under an NCI IND/IDE be reported via 
AdEERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol.  
 
Second Malignancy:  
 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting via CDUS 
unless otherwise specified. “ 
 
 
 
 
 
7.1.5 Routine Adverse Event Reporting  
 
For studies using investigational agents, the NRG Statistical and Data 
Center (SDC) routinely reports adverse events electronically to the CTEP 
Clinical Data Update System (CDUS Version 3.0).  The SDC submits this 
data quarterly.  The AEs reported through CTEP-AERS will also be 
included with the quarterly CDUS data submissions. 


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8. REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
Access requirements for OPEN, Medidata Rave: Site staff will need to be registered with 
CTEP and have a valid and active CTEP Identity and Access Management (IAM) account. 
This is the same account (user id and password) used for the CTSU members' web site. To 
obtain an active CTEP-IAM account, go to https://eapps-ctep.nci.nih.gov/iam.  
 
8.1 
Investigator Registration Requirements  
8.1.1 This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Lead Protocol Organization.  Each investigator must have an NCI 
investigator number and must maintain an “active” investigator registration status 
through the annual submission of a complete investigator registration packet (FDA Form 
1572 with original signature, current CV, Supplemental Investigator Data Form with 
signature, and Financial Disclosure Form with original signature) to the Pharmaceutical 
Management Branch (PMB), CTEP, DCTD, NCI.  These forms are available on the 
CTSU Member web site or by calling the PMB at 240-276-6575 Monday through Friday 
between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
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 enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
 
All site staff (Lead Group and CTSU Sites as applicable) 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. 
 
8.2 
Site Registration Requirements  
Requirements for NRG-GY001 site registration: 
• CTSU IRB Certification 
• CTSU IRB/Regulatory Approval Transmittal Sheet 
In addition to the requirements noted above, ALL institutions must fax copies of the 
documentation below to the CTSU Regulatory Office (215-569-0206); study-related 
regulatory documentation also may be e-mailed to the CTSU at 
CTSURegulatory@ctsu.coccg.org. This must be done prior to registration of the 
institution’s first patient: 
• 
IRB/REB approval letter 
• 
IRB/REB approved consent (English and native language versions*) 


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*Note: Institutions must provide certification/verification of IRB/REB 
consent translation to NRG Headquarters (described below IRB/REB 
registration number renewal information as appropriate. 
 
8.2.1 Non-English Speaking Canadian and International Institutions: 
 
 Not Applicable 
 
8.2.2 Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
Not Applicable 
 
8.2.3 Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
Not Applicable 
 
 
 
8.3 
Pre-registration Requirements 
 
8.3.1 Surgeon Credentialing  
Not Applicable. 
 
8.3.2 Neurocognitive Function Testing Certification (09/08/15) 
Not Applicable 
 
8.4 
RT-Specific Pre-Registration Requirements  
Not Applicable 
 
 
 
8.5 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
 
8.5.1 Oncology Patient Enrollment Network (OPEN) 
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. All site staff 
(NRG and CTSU Sites) 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’ web site 
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. Site 
staff should use the registration forms provided on the group or CTSU web site as 
a tool to verify eligibility. 


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• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
Access requirements for OPEN: 
• See beginning of Section 8 for information on obtaining a CTEP-IAM account.  
• To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster.  
• To perform registrations on protocols for which you are a member of the NRG, 
you must have an equivalent 'Registrar' role on the NRG roster.  Role assignments 
are handled through the Groups in which you are a member.  
• To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations) you must have the role of Registrar on the CTSU roster. 
Site and/or Data Administrators can manage CTSU roster roles via the new Site 
Roles maintenance feature under RSS on the CTSU members' web site. This will 
allow them to assign staff the "Registrar" role. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records. [Add if 
applicable: Additionally, a transmittal form to be used when faxing the signed consent 
form to the NRG Biostatistical Center will be provided.  If it is necessary to reprint the 
randomization confirmation or the transmittal form, they can be reprinted through 
Coordinator Online via the View a Patient Entry Report under Patient Entry.] 
 
Further instructional information is provided on the OPEN tab located on the CTSU 
members' web site at https://www.ctsu.org or at https://open.ctsu.org. For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: [email to come] or call the NRG 
Registration Desk at [phone number to come], Monday through Friday, 8:30 a.m. to 5:00 
p.m. ET. The registrar will ask the site to fax in the eligibility checklist and will need the 
registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration 
system (e.g. drug shipment and confirmation of registration) will occur.  


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9. DRUG INFORMATION  
 
9.1 
Cabozantinib (XL184) (NSC 761968) 
 
9.1.1 Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate  
 
Other Names: Cabozantinib, EXEL-7184, EXEL-02977184  
 
Classification: Receptor Tyrosine Kinases Inhibitor (RTK) 
 
CAS Registry Number: 1140909-48-3  
 
Molecular Formula: 
C28H24FN3O5.C4H6O5  
 
M.W.: 635.6  
 
9.1.2 Mode of Action: Cabozantinib (XL184) inhibits multiple RTKs implicated in tumor 
growth, metastasis, and angiogenesis, and targets primarily MET and VEGFR2.  Other 
targets are RET, AXL, KIT, TIE-2, and FLT-3.  
 
9.1.3 How Supplied:  Cabozantinib (XL184) is supplied by Exelixis and distributed by the 
DCTD.  Cabozantinib (XL184) is available in 20 mg and 60 mg tablet.  The tablets are 
yellow film coated containing cabozantinib malate equivalent to 20 mg and 60 mg of 
cabozantinib.  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 bottle.  
 
Cabozantinib (XL184) should be dispensed in its original container.  Cabozantinib tablets 
are stable for up to 24 hours when dispensed in an open container, such as in a pill cup, 
and are stable for up to 7 days when dispensed in a closed container, such as a pharmacy 
dispensing bottle. 
 


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Cabozantinib (XL184) 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
 
9.1.4 Storage:  Store intact bottles at controlled room temperature, 200 to 250C. 
  
9.1.5 Stability:  Stability testing of the intact bottles is on-going.  cabozantinib is stable up to 
24 hours when dispensed in an open container such as a pill cup, and up to 7 days when 
dispensed in a closed container such as a pharmacy bottle other than the original 
container.  
 
9.1.6 Route of Administration: Oral. 
 
9.1.7 Method of Administration: Take cabozantinib on an empty stomach; i.e., do not eat 2 
hours before or 1 hour after each dose of cabozantinib.  Do not crush or chew.  Do not take 
missed dose within 12 hours of the next dose. 
 
9.1.8 Potential Drug Interactions:  
CYP450 isozymes: 
In vitro, XL184 is a substrate of CYP3A4 and a weak substrate of CYP2C9. Co-administration of 
ketoconazole, a strong inhibitor of CYP3A4, increases XL184 AUC (37%) and rifampin, a strong 
inducer of CYP3A4, reduces XL184 AUC (77%). Therefore, avoid chronic use of strong 
CYP3A4 inducers such as rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, 
rifampentin, phenobarbital, and St. John’s Wort while taking XL184. Avoid chronic use of strong 
CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, 
nelfinavir, and ritonavir. Use alternative medications. 
 
[Note: Use caution when discontinuing medication that is a strong inducer of CYP3A4 in patients 
who has been on a stable dose of XL184, as this could significantly increase the exposure to 
XL184.] 
 
XL184 is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of both 
CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor of 


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CYP3A4 (estimated Kiapp = 282 μM) in human liver microsomal (HLM). IC50 values >20 μM 
were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes. XL184 is an inducer of CYP1A1 
mRNA in human hepatocyte incubations, 
 
Avoid grapefruit/ grapefruit juice and Seville oranges while participating in this trial. 
 
P-glycoprotein/ MRP2: 
In vitro data indicate that XL184 is unlikely to be a substrate but may be an inhibitor of P-
glycoprotein transport activity (IC50 = 7.0 μM). 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 substrates (e.g., fexofenadine, aliskiren, 
ambrisentan, digoxin, colchicine, maraviroc, posaconazole, tolvaptan, etc.). In an in vitro assay, 
XL184 has shown to be 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, 
delavirine, efavirenz, emtricitabine. 
 
Protein bound: 
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). Avoid administration of warfarin with XL184 as warfarin is highly protein-bound 
and has a very narrow therapeutic index. 
 
Antacids, H2-blockers, PPIs: 
Co-administration of gastric pH modifying drugs such as PPI, H2-blockers or antacids has no 
clinically-relevant effect on XL184 plasma PK in healthy volunteers; thus, concomitant use of 
these drugs with XL184 is allowed. 
 
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. 
 
9.1.9 Potential Food Effect 
The effect of food on the bioavailability of cabozantinib was evaluated in healthy adult 
subjects in a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover study (Study XL184-004). Based on the preliminary PK data, a high fat meal did 
not appear to alter the terminal t1/2 but significantly increased the median tmax to 6 hours 
from 4 hours (fasted). The high fat meal also significantly increased both the cabozantinib 
Cmax and AUC values by 41% and 57%, respectively. Based on this result, cabozantinib 
should be taken on an empty stomach (fasting is required 2 hours before and 1 hour after 
each cabozantinib dose). 
 
9.1.10 Patient Care Implications:   Do not take grapefruit/ grapefruit juice or Seville oranges 
while participating in this trial.  Inform physician and study healthcare team about current 
medications including over the counter drugs, herbals, or natural medicines.  Refer to the 
protocol for management of adverse events 
 


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9.1.11 Availability 
 
Cabozantinib (XL184) is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Cabozantinib (XL184) is provided to the NCI under a Collaborative Agreement between 
the Pharmaceutical Collaborator and the DCTD, NCI (see Appendix I). 
 
9.1.12 Agent Ordering and Agent Accountability (09/08/15) 
 
NCI supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained.)  The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx 
>.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance 
of an “active” account status and a “current” password.   For questions about drug orders, 
transfers, returns, or accountability, call (301) 496-5725 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the 
NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 
 
 
9.1.13 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
XL184 (Cabozantinib s-malate, 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 


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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 2438 patients. Below is the CAEPR for XL184 
(Cabozantinib s-malate). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
      Version 2.3, October 4, 20161 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
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 
 
  


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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Musculoskeletal and 
connective tissue disorders - 
Other (muscle spasms) 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
 Pneumothorax6 
  
 
 
 Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
Voice alteration 
 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 3) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (hair color 
changes) 
 
 Skin and subcutaneous tissue 
disorders - Other (hair color 
changes) (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 


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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. 
 
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC.  
 
9Thromboembolic event includes pulmonary embolism which may be life-threatening. 
 
 
Adverse events reported on XL184 (Cabozantinib s-malate) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that XL184 (Cabozantinib 
s-malate) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Febrile neutropenia; Hemolytic uremic syndrome 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac arrest; Chest pain - 
cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Myocarditis; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - 
Other (hypopituitarism); Endocrine disorders - Other (thyroiditis); Endocrine disorders - Other 
(thyrotoxicosis); Hyperthyroidism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Anal ulcer; Cheilitis; Colitis; 
Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; Esophagitis; Flatulence; 
Gastric ulcer; Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other 
(gastroenteritis); Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other 
(pneumoperitoneum); Hemorrhoids; Ileus; Pancreatitis; Rectal pain; Rectal ulcer 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Fever; Gait 
disturbance; General disorders and administration site conditions - Other (implant site inflammation); 
Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other 
(cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other 
(hepatitis toxic); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - 
Other (tendon injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Cardiac 


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troponin I increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Investigations - Other (blood lactate dehydrogenase increased); Investigations - Other (D-
dimer); Investigations - Other (eosinophil count increased); Investigations - Other (glucose urine present); 
Investigations - Other (urine ketone body present); Lymphocyte count decreased; Neutrophil count 
decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders 
- Other (failure to thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Flank pain; 
Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorders - Other (muscle hemorrhage); Musculoskeletal and connective tissue disorders - Other 
(osteonecrosis); Musculoskeletal and connective tissue disorders - Other (rhabdomyolysis); Myalgia; 
Neck pain; Osteoporosis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity cancer); 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor 
pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory 
impairment; Nervous system disorders - Other (cerebral hematoma); Nervous system disorders - Other 
(hemiparesis); Nervous system disorders - Other (spinal cord compression); Nervous system disorders - 
Other (vocal cord paralysis); Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; 
Seizure; Somnolence; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; 
Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Renal and urinary disorders - 
Other (azotemia); Renal and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - 
Other (scrotal ulcer/erythema/edema); Vaginal fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Aspiration; Atelectasis; Hypoxia; Laryngeal edema; Pharyngeal mucositis; Pleural 
effusion; Pneumonitis; Productive cough; Pulmonary hypertension; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (nasal septum perforation); Respiratory, thoracic and 
mediastinal disorders - Other (oropharyngeal pain); Respiratory, thoracic and mediastinal disorders - 
Other (pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Pruritus; Rash acneiform; 
Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and erythema); Skin and 
subcutaneous tissue disorders - Other (psoriasis); Skin and subcutaneous tissue disorders - Other 
(splinter hemorrhages); Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders 
- Other (bleeding varicose vein); Vasculitis 
 
Note: XL184 (Cabozantinib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
10. 
PATHOLOGY   
 
Patients must have recurrent or, progressive clear cell ovarian cancer not solely based on CA-
125. A retrospective review of all patients entered will be performed to confirm clear cell 
histology. Primary tumors must be at least 50% clear cell histomorphology in order to be 
eligible or have a histologically documented recurrence with at least 50% clear cell 
histomorphology.  
 
 


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Stained pathology slides are required for central review by the NRG Pathology Committee to 
confirm eligibility for the protocol.  At least one representative H&E stained slide (or slides) 
demonstrating primary site, histologic cell type, and grade, and one H&E stained slide 
showing the most advanced stage of disease will be required. When submitting pathology 
material to the NRG Statistics and Data Center individual slides must be labeled with NRG 
Patient ID, patient initials and the surgical / pathology accession number (e.g., S08-2355) and 
block identifier (e.g., A6).  Do not label the slides with disease site (e.g., right ovary) or 
procedure date.  Pack the labeled slides into plastic slide cassette(s).  Tape plastic slide 
cassettes shut and wrap in bubble wrap or another type of padded material prior to shipping.  
Please include the NRG Patient ID, patient initials, and protocol number on all pages of the 
pathology report and black out the patient’s name.  Ship stained pathology slides and the 
official pathology report in your own shipping containing using postal mail at your own 
expense directly to the Pathology Materials Coordinator at the NRG Statistics and Data 
Center, Roswell Park Cancer Institute, Research Studies Center, Carlton and Elm 
Streets, Buffalo, New York, 14263; phone (716) 845-5702.Please see section 13.2 for 
additional requirements and instructions. 
 
11. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
11.1  Reimbursement 
See the Reimbursement and Case Credit Schedule found on the NRG web site (link to 
come). 
 
11.2 
Translational Science 
 
Note: Testing of banked specimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. 
 
11.2.1 Specimen Requirements (09/08/15) 
 
If the patient gives permission to participate in this optional study component, then 
participating sites within the United States are required to submit the patient’s specimens 
as outlined below. 
 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
FFPE Primary Tumor (FP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to all treatment 
NRG Oncology 
Biospecimen Bank-
Columbus within 8 weeks of 
registration1 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to all treatment (Optional if 
FP01, FRP01, FRM01, FPP01, or 
FPM01 is submitted) 
FFPE Recurrent Primary Tumor 
(FRP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRM01, FPP01, or 
FPM01 is submitted) 


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FFPE Recurrent Metastatic Tumor 
(FRM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01, FPP01, or 
FPM01 is submitted) 
FFPE Persistent Primary Tumor 
(FPP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01, FRM01, or 
FPM01 is submitted) 
FFPE Persistent Metastatic Tumor 
(FPM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01, FRM01, or 
FPP01 is submitted) 
*A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the NRG Oncology 
Biospecimen Bank-Columbus. 
1 NRG Oncology Biospecimen Bank-Columbus/ Protocol NRG-GY001, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH    
   43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
 
11.2.2 Specimen Procedures 
 
A detailed description of specimen procedures can be found in Appendix V. 
 
11.2.3 Laboratory Testing 
 
Details regarding the distribution of translational science specimens to investigators can 
be found in Appendix V. 
 
11.2.3.1 
Immunohistochemical Analysis 
 
Unstained sections of formalin-fixed, paraffin-embedded (FFPE) tumor will be batch 
shipped upon trial completion to Dr. Michael Birrer (address below) for (1) 
immunohistochemical analysis of PTEN, pAKT, and cyclin E, and (2) fluorescence in 
situ hybridization analysis of MET amplification. 
 
Dr. Michael Birrer 
Massachusetts General Hospital 
55 Fruit St, Yawkey 9072 
Boston, MA 02114 
Phone: 617-724-4800 
Email: mbirrer@partners.org 
 
Unstained sections of FFPE tumor will be batch shipped upon trial completion to Dr. 
Panagiotis Konstantinopoulos (address below) for immunohistochemical analysis of 
MET. 
 
Dr. Panagiotis Konstantinopoulos 
Dana-Farber Cancer Institute 


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450 Brookline Ave, Yawkey 1424 
Boston, MA 02215 
Phone: 617-632-2334 
Email: panagiotisa.konstantinopoulos@dfci.harvard.edu 
 
11.2.3.2 
MET Pathway Gene Expression 
 
Unstained sections of FFPE tumor will be batch shipped upon trial completion to Dr. 
Michael Birrer (address above) for MET pathway gene expression analysis. 
 
11.2.4 Banking Specimens for Future Research 
 
Details regarding the banking and use of specimens for future research can be found in 
Appendix V. 
 
11.3 
Quality of Life 
 
Not applicable. 
 
12. DATA AND RECORDS 
 
12.1 
Data Management/Collection 
Data collection for this study will be done exclusively through Medidata Rave®. Access 
to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS (Regulatory Support System). To access iMedidata/Rave, see 
beginning of Section 8. 
 
Each person responsible for data entry must be on the NRG roster in order to receive 
access to Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata 
(iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Once an account is activated, eLearning modules will 
be available for Rave RDC instructions.  Please note, site users will not be able to access 
the study in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be listed in the upper right pane of the iMedidata screen. 
  
Users that have not previously activated their iMedidata/Rave accounts also will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-


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mail at ctsucontact@westat.com. 
 
 
12.2 
 
NRG Data Management Forms (09/08/15) 
 
The following forms must be completed and submitted to the Statistical and Data 
Monitoring Center (SDMC) in accordance with the schedule below.  NRG 
electronic case report forms must be submitted through the Medidata Rave 
Electronic Data Entry System (www.imedidata.com).    All amendments to forms 
must also be submitted through Medidata Rave.   The pathology reports can be 
sent to the NRG SDMC via postal mail or uploaded in Medidata Rave. The 
upload option is an alternative method for submitting paper reports. 
 
 
 
 
 
Form 
Comments 
Baseline Folder  
(Forms due within 2 weeks of registration) 
 
Baseline/History Forms: 
- 
Visit Information – Baseline Form 
- 
Registration Form 
- 
History Information Form 
- 
Primary Surgery Form 
- 
Chemotherapy Information Form 
- 
Pre-Treatment Summary Form 
- 
Specimen Consent 
- 
Concomitant Medications form 
- 
ECG Information form 
 
Solid Tumor Evaluation Forms: 
- 
Target Lesions Form 
- 
Non-Target Lesions Form 
 
The appropriate forms will load in the Baseline 
Folder based on the answers reported on the 
corresponding Baseline Visit Information form. 
 
Visit Folder 
(Forms due within 2 weeks of the completion of each cycle) 
 
Cycle Information and Treatment Forms: 
- 
Visit Information Form 
- 
Cycle Drug Information Form  
- 
Labs and Chemistries Form 
- 
Vitals Form 
- 
ECG Information Form 
- 
Bio-Marker Information form 
 
The appropriate forms will load in the Visit Folder 
based on the answers reported on the corresponding 
Visit Information forms. 
 
 
 


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Toxicity Forms: 
- 
Section 1 Form 
- 
Adverse Event Form 
- 
Adverse Event Grades 
 
Solid Tumor Evaluation Forms: 
- 
Target Lesions Form 
- 
Non-Target Form 
- 
New Target Lesions Form 
- 
Status and Response Form 
 
Form 
Comments 
Pathology Folder 
(Reports and slides due within 6 weeks of registration) 
      Primary disease:  
   Pathology Report 
   Stained Slides 
 
     Recurrent or Persistent Disease: 
  Pathology Report 
  Stained Slides 
 
 
Submit stained slides with two copies of the pathology report 
to SDC via postal mail or upload the pathology report online 
via RAVE. 
 
Stained pathology slides are required for central review by the 
GOG Pathology Committee. See Section 10 for Pathology 
eligibility. All stained slides MUST be submitted via postal 
mail. 
 
  
 
Form 
Comments 
Translational Research Folder 
TR Forms: 
- FFPE Primary Tumor (FP01) 
- FFPE Metastatic Tumor (FM01) optional 
- FFPE Recurrent Primary Tumor (FRP01) 
optional 
- FFPE Recurrent Metastatic Tumor 
(FRM01) optional 
- FFPE Persistent Primary Tumor (FPP01) 
optional 
- FFPE Persistent Metastatic Tumor 
(FPM01) optional 
An electronically completed copy of Form TR must 
accompany each specimen shipped to the NRG Oncology 
Biospecimen Bank-Columbus. Handwritten forms will not be 
accepted. 
 
FP01, FM01, FRP01, FRM01, FPP01, and FPM01 are due 8 
weeks from registration. 
Treatment Completion Folder 
(Forms due within 2 weeks of treatment completion) 
Treatment Completion Form 
 
Follow-up Visit Folder 
(Forms due within 2 weeks of follow-up visits, disease progression or death) 


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Visit Information Follow-Up Form 
- 
Bio-Marker Information form 
 
Follow-Up Form 
 
Vitals form 
 
Follow-Up Period Adverse Event: 
- 
Reporting Form – Part 1 
- 
Reporting Form – Part 2 
 
Solid Tumor Evaluation: 
- 
Target Lesions Form 
- 
Non-Target Form 
- 
New Target Lesions Form 
- 
Status and Response Form 
Follow-up visits should be scheduled quarterly for 2 years, 
semi-annually for 3 more years, and annually thereafter. 
 
The appropriate forms will in the Follow-up Visit Folder 
based on the answers reported on the corresponding Follow-up 
Visit Information forms. 
 
12.3 
Summary of Data Submission 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Sections 7.1.4 and 7.1.5 for information about expedited and 
routine reporting.   
 
For reporting of secondary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is 
required. 
 
Summary of Data Submission: Refer to the NRG website [Insert weblink to data 
submission summary]  
 
 
12.4 
Global Reporting/Monitoring 
This study will be monitored by the Complete Clinical Data Update System (CDUS) 
version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic 
means. Reports are due January 31, April 30, July 31, and October 31. 
 
13. STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
The primary objective of this study is to assess the anti- tumor activity of cabozantinib 
(XL184) in women with persistent or recurrent clear cell ovarian cancer. The primary 
measures of efficacy will be objective response and whether the patient survived 
progression-free for at least 6 months. 
 
This is a single-arm, Phase II clinical trial that will use a flexible, bivariate, three-stage 
design.  


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13.1.1 Stratification 
This is a single-arm, trial with no randomization and thus no stratification. 
 
13.1.2 Randomization 
This is a single-arm, trial with no randomization. 
 
13.1.3 Total Accrual 
If the trial enters all three stages, the total accrual target will be 31 patients but will be 
allowed to range from 27 to 34 (due to the difficulty in accruing precise numbers of 
patients in a multicenter trial). 
 
13.1.4 Justification of Design:  
The biologic mechanism of the study agent is expected to impede the growth of tumors 
already present and inhibit the development of new metastases.  Therefore, the endpoint 
includes progression-free survival at 6 months, which is capable of detecting stabilization 
of disease.  In addition, there is also interest in objective tumor response as a primary 
measure of efficacy.  So the design of the study will use both endpoints to formally draw 
conclusions about the activity of the drug.  In particular, if either endpoint indicates 
activity, the drug will be considered clinically interesting and worthy of further 
investigation. 
 
13.2 
Study Endpoints 
Primary endpoints: 
• Progression-free survival at six months 
• Complete or partial objective tumor response 
 
Secondary endpoints: 
• Nature, frequency and maximum degree of toxicity as assessed by CTCAE v4 
• Progression-free survival 
• Overall survival. 
 
 
13.3 
Primary Objectives Study Design 
13.3.1 Primary Hypothesis and Endpoints 
The primary hypothesis of this study tests the proportion of patients with objective tumor 
response (complete or partial) (πr) and the proportion of patients surviving progression 
free for at least six months (πs).  Based on the historical data shown below, the null 
hypothesis is that the proportion of patients with objective tumor response will be ≤10% 
and the proportion of patients surviving progression free for at least six months (πs) will 
be ≤15%, i.e.,: 
 
H0: πr ≤ 0.10 and πr ≤ 0.15. 
 
The alternative hypothesis is the complement of the null parameter space, and the study is 
powered to detect the following points in the alternative space: πr = .3 or πs = .4. 


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The primary analysis will include all eligible patients who receive study drug. 
 
The guiding principle in selecting the design for this study is to limit the number of 
patients treated with clinically ineffective therapies but to estimate efficacy with 
reasonable precision for those agents that are clinically active.  Strict adherence to a 
planned sample size is not practical because the accrual is complicated by the logistics of 
managing a multi-center phase II study.  Instead, a flexible sample size will be used in 
which once the targeted sample size is attained, those patients who have already been 
approached will be permitted to register. 
 
Historical Data and Design Parameters 
The design parameters for this study arise from considering the results of three series of 
protocols: GOG-0126, GOG-0146, and GOG-0170.  The patients entered on GOG-0126 
were required to have platinum resistant disease (i.e. a platinum free interval of less than 
6 months) while the patients entered on GOG-0146 were required to be GOG platinum 
sensitive (i.e. a platinum-free interval between 6 and 12 months).  Both of these patient 
populations were allowed in GOG-0170 and will be allowed to enter the current protocol.  
Selected GOG protocols from these series are listed in Table 13.1 and were selected for 
historical controls because the population is similar to the current protocol and the agents 
investigated in the selected protocols were deemed to have minimal activity.  
 
Table 13.1: Measures of Efficacy by Protocol and Section for All Patients and for Clear Cell Patients in the 
GOG 0126, 0146, and 0170 Series of Protocols Restricted to Studies with Agents Deemed Inactive or 
Minimally Active 
Section 
Evaluable 
(All, Clear Cell) 
Response,  
n (%) 
PFS at 6 Months, 
n (%) 
N 
All 
Clear Cell 
All 
Clear Cell 
GOG-126 Series 
B 
26, 3 
 3  (12%) 
 1 (33%) 
 4 (15%) 
 1 (33%) 
C 
33, 0 
 3 
(9%) 
 0 
(0%) 
 9 (27%) 
 0 
(0%) 
D 
27, 5 
 2 
(7%) 
 0 
(0%) 
 5 (19%) 
 0 
(0%) 
E 
58, 7 
 5 
(9%) 
 0 
(0%) 
10 (17%) 
 1 (14%) 
G 
27, 2 
 1 
(4%) 
 0 
(0%) 
 2 
(7%) 
 0 
(0%) 
H 
26, 1 
 1 
(4%) 
 0 
(0%) 
 1 
(4%) 
 0 
(0%) 
K 
23, 2 
 1 
(4%) 
 0 
(0%) 
 5 (22%) 
 0 
(0%) 
GOG-146 Series 
B 
28, 0 
 3 (11%) 
 0 
(0%) 
 6 (21%) 
 0 
(0%) 
E 
23, 4 
 1 
(4%) 
 1 (25%) 
 3 (13%) 
 1 (25%) 
F 
28, 1 
 2 
(7%) 
 0 
(0%) 
 8 (29%) 
 0 
(0%) 
H 
54, 3 
 1 
(2%) 
 0 
(0%) 
 7 (13%) 
 0 
(0%) 
J 
30, 2 
 0 
(0%) 
 0 
(0%) 
 2 
(7%) 
 0 
(0%) 
L 
21, 0 
 2 (10%) 
 0 
(0%) 
10 (48%) 
 0 
(0%) 
N 
55, 0 
 3 
(5%) 
 0 
(0%) 
11 (20%) 
 0 
(0%) 
GOG-170 Series 
C 
27, 0 
 1 
(4%) 
 0 
(0%) 
 4 (15%) 
 0 
(0%) 


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E 
57, 0 
 1 
(2%) 
 0 
(0%) 
10 (18%) 
 0 
(0%) 
G 
26, 0 
 0 
(0%) 
 0 
(0%) 
 2 
(8%) 
 0 
(0%) 
H 
27, 1 
 1 
(4%) 
 0 
(0%) 
 2 
(7%) 
 0 
(0%) 
 
13.3.2 Definitions of Primary Endpoints and How These Will Be Analyzed 
To evaluate the hypothesis stated above, we will utilize a modification of the bivariate 
two-stage design of Sill, et al (2012), which uses the numbers of patients progression-free 
at 6 months and the number with objective responses to make inferences about the 
efficacy of the study drug. We will add an additional stage to the study—preceding the 
Sill design.  In the first stage, if all patients have increasing disease (progression) at their 
first scan (which will be done after 2 cycles or 8 weeks), the trial will be stopped, and the 
agent will be not considered worthy of further investigation in this patient population.  
The trial will be suspended for this first stage decision; however, if at any point, any of 
these patients do not have increasing disease, it would not be necessary to suspend the 
trial.   
 
If the trial enters the second stage and third stage, the following decision rules will be 
applied where 
• Xr(1) is the number of patients with objective tumor responses (partial or complete) 
within four months of starting treatment in stage 1, 
• Xs(1) is the number of patients progression-free at 6 months after stage 1, 
• Xr(2) is the number of patients with objective tumor responses after stage 2, 
• Xs(2) is the number of patients progression-free at 6 months after stage 2, 
• Xr is the cumulative number of patients with objective tumor responses after 
stage 3, 
• Xs is the cumulative number of patients progression-free at 6 months after stage 3, 
• Cr(1) is the critical value for Xr(1), 
• Cr(2) is the critical value for Xr(2), 
• Cs(2) is the critical value for Xs(2), 
• Cr is the critical value for Xr, and 
• Cs is the critical value for Xs. 
Decision Rules:  
1) If Xr(1) > Cr(1) after the first stage, then the study will open to a second stage of accrual 
to further evaluate the activity of the drug, 
a. or if Xs(1) > Cs(2), the trial will open to the third stage of accrual (because the 
number of patients with PFS≥6 months in the first stage will be greater than that 
required in the second stage). 
2) If either Xr(2) > Cr(2) or Xs(2) > Cs(2) after the second stage, then the study will open to a 
third stage of accrual to further evaluate the activity of the drug.   
3) If either Xr > Cr or Xs > Cs after the third stage and clinical judgment indicates, then 
the agent will be deemed clinically interesting and worthy of further investigation. 


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13.3.3 Sample Size and Power Calculations 
The targeted accrual for the first stage will be 12 eligible and treated patients but will be 
permitted to range from 10 to 14. If all patients have increasing disease on their first scan, 
the trial will be terminated for futility.   The cumulative targeted accrual for the second 
stage will be 19 eligible and evaluable patients but permitted to range from 15 to 22 for 
administrative reasons.  The cumulative targeted accrual for the third stage will be 31 
eligible and evaluable patients.  Critical values for each stage are provided in Table 13.2, 
Table 13.3, and Table 13.4, respectively. 
We acknowledge that a three-stage trial may lengthen the trial beyond what is normally 
expected; therefore, we will follow the following plan for the first stage.  After eight 
patients have been followed for response for four months (which is required for the Xr(1) 
endpoint), if no responses have been seen, we will suspend the trial; otherwise, we will 
continue to stage 2.  If the trial is suspended, we will then follow any additional patients 
for the response endpoint; given the anticipated accrual rate of 1/month, this should be 
approximately four or less.  If no responses are seen, the trial will end. 
The operating characteristics of each stage’s decision rules are provided in Table 13.5 
and Table 13.6 under the assumption of independence of response and PFS and under an 
assumption of a high association between response and PFS, respectively.  To assess the 
operating characteristics when the two primary endpoints are not independent, the 
probability calculations (carried out as outlined above) were done with the assumption 
that the joint probability (11) of response and PFS at 6 months is equal to 0.90 ∙ min{πr, 
πs}, which would carry a fairly high degree of association. 
 
Table 13.2: Stage 1 critical values for the number of patients with objective responses 
within four months of starting treatment 
n1 † 
10 
11 
12 
13 
14 
Cr(1) 
0 
0 
0 
0 
0 
† n1 is the sample size for the first 
stage of accrual. 
 
Table 13.3: Stage 2 critical values for the number of patients with objective responses 
and the number who survive progression-free for 6 months 
 
n2 † 
 
15 
16 
17 
18 
19 
20 
21 
22 
Cr(2) 
1 
1 
2 
2 
2 
2 
2 
2 
Cs(2) 
3 
3 
3 
3 
4 
4 
4 
5 
† n2 is the cumulative sample size for the second 
stage of accrual 
 
Table 13.4: Stage 3 critical values for the number of patients with objective responses 
and the number who survive progression-free for 6 months 
Stage 3 
(Cr, Cs) 
n2 † 
n‡ 


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27 
28 
29 
30 
31 
32 
33 
34 
15 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
16 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
17 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
18 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
19 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
20 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
21 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
22 
(4,7) 
(5,7) 
(5,7) 
(5,8) 
(5,8) 
(5,8) 
(6,8) 
(6,9) 
† n2 is the cumulative sample size for the second stage of accrual 
‡ n is the cumulative sample size after the third stage of accrual. 
 
 
 
 
Table 13.5: Average power of testing procedure when accrual guidelines are met and 
under the assumption that response and surviving progression-free for 6 
months are independent events 
Scenario (probabilities) 
Probability of† 
 
r 
s 
Stopping at 
Stage 1 
Stopping at 
Stage 2 
Rejecting H0 
Null 
0.10 
0.15 
0.260 
0.308 
0.097 
Alternative Response Only 
0.30 
0.15 
0.014 
0.026 
0.906 
Alternative PFS Only 
0.10 
0.40 
0.072 
0.022 
0.867 
Alternative Both 
0.30 
0.40 
0.004 
0.002 
0.989 
† Probabilities are averaged across all possible combinations of n1, n2, and n3; and are 
computed from 10,000 simulations for each sample size combination. 
 
Table 13.6: Average power of testing procedure when accrual guidelines are met and 
under the assumption that response and surviving progression-free for 6 
months are not independent events‡ 
Scenario (probabilities) 
Probability of† 
 
r 
s 
Stopping at 
Stage 1 
Stopping at 
Stage 2 
Rejecting H0 
Null 
0.10 
0.15 
0.284 
0.342 
0.083 
Alternative Response Only 
0.30 
0.15 
0.016 
0.032 
0.900 
Alternative PFS Only 
0.10 
0.40 
0.111 
0.023 
0.833 
Alternative Both 
0.30 
0.40 
0.013 
0.012 
0.954 
‡ Joint probability 11 = 0.90∙min{r, s}. 
† Probabilities are averaged across all possible combinations of n1, n2, and n3; and are 
computed from 10,000 simulations for each sample size combination.  
 
 
13.4 
Study Monitoring of Primary Objectives 
Monitoring of the primary objectives is an inherent part of the three-stage design and is 
described fully in sections 13.3.2 and 13.3.3. 
 


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13.5 
Accrual Considerations 
13.5.1 Accrual Rate 
We expect to accrue approximately one patient per month.  This is based on the accrual 
to study GOG-0254, which accrued 35 patients over 34 months of active accrual in the 
same patient population. 
 
13.5.2 Accrual Goal 
 
Ten patients are required for the first stage, a cumulative target of 19 (allowable range 
15-22) in the second stage, and a cumulative target of 31 (allowable range 27-34) in the 
third stage. 
 
13.5.3 Study Duration 
 
Approximately sixteen months are expected to be required for the first stage, ten months 
for the second stage, and twelve months for the third stage. 
 
13.5.4 Estimated Duration for Completion of Primary Endpoint:  
 
Completion of the primary endpoints is expected approximately 52 months after 
activation. 
 
13.6 
Dose Level Guidelines 
 
Not applicable. 
 
13.7 
Secondary or Exploratory Elements (including correlative science aims) 
If there are secondary or exploratory aims, they must be addressed in the Statistical 
Considerations section. 
 
13.7.1 Secondary Hypotheses and Endpoints:  
 
Below are the secondary objectives and endpoints. These are focused on estimation and 
description; there are no associated hypotheses. 
 
Objective: To determine the nature, frequency and maximum degree of toxicity as 
assessed by CTCAE v4 for cabozantinib (XL184) 
Endpoint: Adverse events based on CTC AE v 4. 
 
Objective: To determine the PFS and OS for patients with persistent or recurrent clear 
cell ovarian cancer treated with cabozantinib (XL184). 
Endpoints: Progression-free Survival and Overall Survival 
 
13.7.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Adverse events are based on CTC AE v 4.  Events will be tabulated using maximum 
grade for each AE term regardless of attribution to study drug. 
 
Overall survival and PFS of patients on this study will be characterized graphically and 
using descriptive statistics such as median survival based on Kaplan-Meier estimates. 
 


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13.7.3 Interim Analysis for All Other Endpoints (Goals): Optional 
No interim analyses are planned for secondary endpoints. 
 
13.7.4 Power Calculations: 
As there are no hypotheses for the secondary endpoints, no power calculations are done. 
 
13.7.5 Expected Sample Size or Patient Cohorts: 
Not applicable. 
 
13.7.6 Data and Safety Monitoring (09/08/15) 
Data sheets from studies on this protocol will be reviewed before each semi-annual 
meeting and will also be reviewed by the Study Chairperson in conjunction with the NRG 
Statistics and Data Management Center (SDMC). In some instances, because of 
unexpectedly severe toxicity, the NRG SDMC may elect, after consultation with the 
Study Chairperson and the Medical Oncology Committee, to recommend early closure of 
a study.  
 
The frequency and severity of all toxicities are tabulated from submitted case report 
forms and summarized for review by the study chairperson, Gynecologic Rare Tumor 
Committee, and NRG Safety Review Committee (SRC) in conjunction with each semi-
annual NRG meeting. For studies sponsored by CTEP of the National Cancer Institute 
(NCI), standardized toxicity reports are also submitted to the drug and disease monitors at 
the Investigational Drug Branch (IDB) and Clinical Investigation Branch (CIB). As this 
is a multi-stage multi-institutional phase II protocol, the initial overall review of toxicity 
is usually performed after completion of the first stage of accrual, at which point accrual 
is generally suspended pending formal analysis of response.  
 
All serious and/or unexpected events are communicated to the Study Chair, sponsor, and 
regulatory agencies as mandated in the protocol. These reports are reviewed by the Study 
Chair (or designated co-chair) within two working days for consideration of investigator 
notification, amendment, or immediate study suspension. All participating institutions 
will then receive notification of the toxicities and reason for study suspension. Under 
these circumstances, accrual cannot be re-activated until the study is reviewed by the 
NRG SRC. However, patients currently receiving treatment may continue to receive 
treatment in accordance with protocol guidelines at the discretion of their physicians, 
unless directed otherwise. 
 
13.8 
Exploratory Hypothesis and Endpoints 
There are no exploratory objectives.  
 
 
13.9 
Gender/Ethnicity/Race Distribution 
The distribution below is based on the maximum, two-stage sample size of 34 patients. 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
2 
0 
2 
Not Hispanic or Latino 
32 
0 
32 


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Gender 
Ethnic Category 
Females 
Males 
Total 
Ethnic Category: Total of all subjects 
34 
0 
34 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
2 
0 
2 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
1 
0 
1 
White 
29 
0 
29 
Racial Category: Total of all subjects 
34 
0 
34 
 
 
14. PUBLICATION INFORMATION AND ADMINISTRATIVE AGREEMENTS 
TBD 
 
15. EVALUATION CRITERIA   
 
15.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  
Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in 
the RECIST criteria. 
 
15.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment on study. 
 
Evaluable for objective response.  Only those patients who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  


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15.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm 
with calipers by clinical exam.  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will 
not be considered measurable unless progression is documented or a 
biopsy is obtained to confirm persistence at least 90 days following 
completion of radiation therapy. Thus, a confirmed biopsy in an irradiated 
area at a date longer than 90 days post-completion of radiation can be 
considered a target lesion to assess progression and response. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no greater than 5 
mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥ 10 to <15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 


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measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 
15.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers.  All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans), but NOT lung.   


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Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  PET-CT scans are not always done with oral and IV 
contrast.  In addition, the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  For these 
reasons, the GOG will not allow PET-CT use for RECIST 1.1 response criteria. 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective 
tumor evaluation is not advised.  However, such techniques may be useful 
to confirm complete pathological response when biopsies are obtained or 
to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
CA125 (Ovarian, fallopian tube and primary peritoneal cancer trials): 
CA125 alone cannot be used to assess response.  If CA125 is initially 
above the upper normal limit, it must normalize for a patient to be 
considered in complete clinical response.  Specific guidelines for CA-125 
response (in recurrent ovarian cancer) have been published [JNCI 96:487-
488, 2004].  In addition, the Gynecologic Cancer Intergroup has 
developed CA-125 progression criteria which are to be integrated with 
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[JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare cases 
(e.g., residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
 
 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of the 
treatment) and progressive disease. 
 
 
 
 
15.1.4 Response Criteria 
 
15.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  
Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. 
 
 
 
 
 
 
 
 
Partial Response (PR): At least a 30% decrease in the sum of 
the diameters of target lesions, taking as reference the baseline 
sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum 
of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is 
the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new lesions 
is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, taking as reference 
the smallest sum diameters while on study. 
 
15.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target 
lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If CA125 is initially above the upper normal limit, it 
must normalize for a patient to be considered in complete 
clinical response. 
 


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Non-CR/Non-PD: Persistence of one or more non-target 
lesion(s) and/or maintenance of CA125 level above the normal 
limits. 
 
Progressive Disease (PD): Appearance of one or more new 
lesions and/or unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease 
status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
  
15.1.4.3 
Progression Based on Serum CA-125 
 
1. Patients with elevated CA-125 pretreatment and 
normalization of CA-125 must show evidence of CA-125 
greater than or equal to two times the upper normal limit on 
two occasions at least one week apart 
OR 
2. Patients with elevated CA-125 pretreatment, which never 
normalizes must show evidence of CA-125 greater than or 
equal to two times the nadir value on two occasions at least one 
week apart 
OR 
3. Patients with CA-125 in the normal range pretreatment must 
show evidence of CA-125 greater than or equal to two times 
the upper normal limit on two occasions at least one week apart 
 
When disease progression is defined by CA-125 criteria 
alone, imaging using the same modality and encompassing 
the same field as in the initial pretreatment evaluation 
should be obtained within 2 weeks that such progression is 
documented. The patient should continue therapy, as per 
protocol, until progressive disease is documented by 
imaging. 
 
15.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from 
the start of the treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The 


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


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progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
15.1.6 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from 
start of treatment to time of progression or death, whichever occurs first. 
 
15.1.7 Survival 
Survival is defined as the duration of time from start of treatment to time 
of death or the date of last contact. 
 


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APPENDIX I - GENERAL CHEMOTHERAPY GUIDELINES: 
 
 
• For 21 or 28 day cycles, a patient will be permitted to have a new cycle of chemotherapy 
delayed up to 7 days (without this being considered to be a protocol violation) for major 
life events (e.g., serious illness in a family member, major holiday, vacation which is 
unable to be re-scheduled). Documentation to justify this decision should be provided.  
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-hour 
window before and after the protocol-defined date” for “Day 1” treatment of 21 or 28 day 
cycles. If the treatment due date is a Friday, and the patient cannot be treated on that 
Friday, then the window for treatment would include the Thursday (1 day earlier than 
due) through the Monday (day 3 past due).  
• For weekly regimens, it will be acceptable for individual chemotherapy doses to be 
delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can be 
delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given on Day 
14, Day 15, or Day 16.  
• Chemotherapy doses can be “rounded” according to institutional standards without being 
considered a protocol violation (most institutions use a rule of approximately +/- 5% of 
the calculated dose).  
• Chemotherapy doses are required to be recalculated if the patient has a weight change of 
greater than or equal to 10%. Patients are permitted to have chemotherapy doses 
recalculated for < 10% weight changes.  
• Maximum body surface area used for chemotherapy dose calculations will be 2.0 m2. For 
chemotherapy dose calculations that use mg/kg, there will be no maximum kilogram 
amount used (doses will be calculated on actual weight in kg).  


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APPENDIX II - CRADA 
 
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: 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study:  
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual should 
sign a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”: 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NIH, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
 


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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. 
 
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 Collaborators confidential 
proprietary information. 
 
 


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APPENDIX III - CONGESTIVE HEART FAILURE – NEW YORK HEART 
ASSOCIATION CLASSIFICATION 
 
Class 
Definition 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even with rest. With any physical activity, 
increased discomfort is experienced. 
 
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964: 
114. 
 
 
 


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APPENDIX IV - PATIENT’S PILL DIARY: CABOZANTINIB  
 
NRG-GY001 – A Phase II Trial of Cabozantinib (XL-184) (NSC #761968) in Women with 
Recurrent Clear Cell Carcinoma of the Ovary, Fallopian Tube, or Peritoneum 
 
Today’s date ________________________________ 
Patient Name_______________________________Patient Study ID ______________________ 
Cycle #__________     (initials acceptable for patient’s name) 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle (28 days). 
2. You will take ___ tablets each morning. 
  Do not eat for at least 2 hours before and at least 1 hour after taking cabozantinib.   
3. Record the date, the number of pills you took, and when you took them.   
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring your pill bottle and this form to your physician when you go for your next appointment. 
6.    If you miss a dose of Cabozantinib, take it as soon as you remember (as long as it is not within 12 hours 
of the time for your next dose).  If it is within 12 hours of the time for your next dose skip the missed 
dose.  Do not take a missed dose within 12 hours of the next dose. Vomited doses will not be made up. 
 
Date 
 
Day 
# pills  and when 
taken: Cabozantinib 
20mg  60 mg        Time 
 
Comments 
 
Date 
 
Day 
# pills and when 
taken: Cabozantinib 
20mg  60 mg       Time 
 
Comments 
 
1 
 
 
 
 
 
15 
 
 
 
 
 
2 
 
 
 
 
 
16 
 
 
 
 
 
3 
 
 
 
 
 
17 
 
 
 
 
 
4 
 
 
 
 
 
18 
 
 
 
 
 
5 
 
 
 
 
 
19 
 
 
 
 
 
6 
 
 
 
 
 
20 
 
 
 
 
 
7 
 
 
 
 
 
21 
 
 
 
 
 
8 
 
 
 
 
 
22 
 
 
 
 
 
9 
 
 
 
 
 
23 
 
 
 
 
 
10 
 
 
 
 
 
24 
 
 
 
 
 
11 
 
 
 
 
 
25 
 
 
 
 
 
12 
 
 
 
 
 
26 
 
 
 
 
 
13 
 
 
 
 
 
27 
 
 
 
 
 
14 
 
 
 
 
 
28 
 
 
 
 
Patient’s Signature: ________________________________________  Date: _________________________ 
 
 


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APPENDIX V - TRANSLATIONAL SCIENCE 
 
I. Obtaining a Bank ID for Translational Science Specimens 
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational science 
specimens and accompanying paperwork must be labeled with this coded patient number. 
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates that 
a patient has agreed to participate in the translational science component. 
 
A Bank ID can also be obtained online via the Tissue Bank Portal link on the NRG Oncology 
website. Obtain the patient’s study ID for all protocols with translational science specimen 
requirements before requesting a Bank ID from the Tissue Bank Portal. Be sure to indicate if 
the patient has a legacy GOG ID when registering. This will ensure the patient is only 
assigned one Bank ID. The GOG ID – Bank ID Lookup on the Tissue Bank Portal can be used to 
search for an existing Bank ID. 
 
Please contact User Support if you need assistance or have assigned more than one Bank ID to a 
patient (Email: support@gogstats.org; Phone: 716-845-7767). 
 
II. Requesting Translational Science Specimen Kits 
Kits are not provided for this protocol. 
 
III. Formalin-Fixed, Paraffin-Embedded Tissue Shipped to the GOG Tissue Bank 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (primary, metastatic, recurrent, persistent). Primary and metastatic tumor should 
be collected prior to all treatment. Recurrent and persistent tumor should be collected prior to 
the study treatment. Recurrent or persistent tumor collected from the site of primary disease 
should be labeled recurrent primary or persistent primary, respectively. Recurrent or 
persistent tumor collected from a site other than the site of primary disease (e.g., lymph node) 
should be labeled recurrent metastatic or persistent metastatic, respectively. Only one block 
may be submitted per tissue type. 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 20 unstained slides (10 charged, 5µm and 10 uncharged, 10 µm) 
should be submitted. All tissue sections should be cut sequentially from the same block.  
 
Note: Stained slides to confirm patient eligibility by central pathology review are required 
for this protocol, but are NOT sent to the GOG Tissue Bank. If these slides will be cut from 
the same block that will be submitted for translational science, your pathology department should 
cut these slides prior to submitting the block for translational science. 
 
The type of specimen (block or slides) should be specified on Form TR. If submitting slides, the 
slide type, thickness, and count should also be specified.  
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 


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Labeling Translational Science Specimens 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG - GY - # # #) 
specimen code (e.g., WB01) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (tissue specimens only) 
block number (tissue specimens only) 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
IV. Submitting Form TR 
An electronically completed copy of Form TR must accompany each specimen shipped to the 
GOG Tissue Bank. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the GOG Tissue Bank if specimens are not collected. 
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@gogstats.org; Phone: 716-
845-7767). 
 
V. Shipping Translational Science Specimens 
An electronically completed copy of Form TR must be included for each translational 
science specimen.  
 
A. FFPE Tissue 
FFPE tissue, an electronically completed copy of Form TR, and a copy of the corresponding 
pathology report should be shipped using your own container at your own expense to: 
 
GOG Tissue Bank / Protocol NRG-GY-001 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: GOGBank@nationwidechildrens.org 
 
Do not ship FFPE tissue for Saturday delivery. 
 
VI. Distributing Translational Science Specimens 
Note: Testing of banked specimens will not occur until an amendment to this treatment protocol 


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(or separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies.  
 
The NRG Oncology Statistics and Data Management Center-Buffalo Office and GOG Tissue 
Bank (or alternate laboratory) will coordinate the distribution of translational science specimens 
to approved investigators. 
 
Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of the translational 
science and for keeping accurate records. 
 
Investigators will ensure the results are linked to the appropriate translational science specimen-
specific identifiers and are responsible for transferring relevant laboratory data to the NRG 
Oncology Statistics and Data Management Center-Buffalo Office. 
 
At the discretion of the Chair of the Translational Science-GYN Committee and the Director of 
the GOG Tissue Bank, investigators may be required to ship any specimens (or by-products) 
remaining after the completion of the translational science to the GOG Tissue Bank. 
 
VII. Banking Translational Science Specimens for Future Research 
Specimens will remain in the GOG Tissue Bank and made available for approved research 
projects if the patient has provided permission for the use of her specimens for future health 
research. The patient’s choices will be recorded on the signed informed consent document and 
electronically via Specimen Consent. At the time of specimen selection for project distribution, 
the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her specimens at any time if 
the patient changes her mind. 
 
If the patient revokes permission to use her specimens, the GOG Tissue Bank will destroy or 
return any remaining specimens. The patient’s specimens will not be used for any further 
research; however, any specimens distributed for research prior to revoking consent cannot be 
returned or destroyed. In addition, the patient cannot be removed from any research that has been 
done with her specimens distributed prior to revoking consent. 
 
Note: If return of specimens is requested, shipping will be at the site’s expense. 
 
 


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APPENDIX VI - ECOG PERFORMANCE SCALE (09/08/15) 
 
GRADE  
KARNOFSKY SCALE  PERFORMANCE  
 
0   
90 & 100   
 
FULLY ACTIVE  
 
 
1  
70 & 80   
 
 RESTRICTED IN PHYSICALLY  
STRENUOUS ACTIVITIES, BUT   
AMBULATORY.  
 
 
2   
50 & 60   
 
AMBULATORY; CAPABLE OF  
 
 
 
 
 
SELF CARE; UNABLE TO WORK;  
UP 50% OF WAKING HOURS.  
 
 
3  
 30 & 40   
 
LIMITED SELF CARE;  
CONFINED TO BED OR CHAIR 50% 
OF WAKING HOURS.  
 
 
4   
10 & 20   
 
COMPLETELY DISABLED;  
NO SELF-CARE