Clinical trial NCT01935934
Conditions: Endometrial Adenosquamous Carcinoma Endometrial Clear Cell Adenocarcinoma Endometrial Mixed Cell Adenocarcinoma Endometrial Serous Adenocarcinoma Metastatic Endometrioid Adenocarcinoma Recurrent Uterine Corpus Cancer Stage IV Uterine Corpus Cancer AJCC v7 Stage IVA Uterine Corpus Cancer AJCC v7 Stage IVB Uterine Corpus Cancer AJCC v7 Uterine Corpus Carcinosarcoma
Sponsor: National Cancer Institute (NCI)
Start date: 2013-05-08; Completion date: 2024-10-24
Enrollment: 102 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well cabozantinib s-malate works in treating patients with endometrial cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine efficacy of single agent cabozantinib s-malate (cabozantinib) in women previously receiving one line of chemotherapy for metastatic endometrial cancer or with progression within 12 months of completing adjuvant therapy, with co-primary endpoints of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and progression-free-survival at 12 weeks (PFS).

SECONDARY OBJECTIVES:

I. Correlation of clinical response with baseline molecular status of archival tumor (hepatocyte growth factor receptor \[c-met\] amplification \& mutation status) and overall survival.

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 4 weeks or every 6 months.

Arms: arm 1: Patients receive 60 mg cabozantinib s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cabozantinib S-malate intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
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NCI Protocol #: 9322 
Local Protocol #: PHL-086 
 
Protocol Date: 
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from Sukhi Brah to Oulu Zhu.  
 
Rationale: To update to current Data Manager and contact 
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Changes (highlighted text inserted): 
 
Grade 4 febrile neutropenia: In this case, upon recovery of ANC 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. 
 
Rationale: To clarify the term of the corresponding AE. 
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Changes (highlighted text inserted, strikethrough text deleted): 
 
ENDOCRINE DISORDERS – Endocrine disorders, Other 
(hHypopituitarism) 
GASTROINTESTINAL DISORDERS – Gastrointestinal disorders, 
Other (aAnal fissure) 
INVESTIGATIONS – Investigations, Other (bBlood lactate 
dehydrogenase increased); Investigations, Other (eosinophil count 
increased Eosinophilia); Investigations, Other (glucose urine present 
Glucosuria) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS – Musculoskeletal and connective tissue disorders, 
Other (oOsteonecrosis); Musculoskeletal and connective tissue 
disorders, Other (rRhabdomyolysis) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 
(INCL CYSTS AND POLYPS) – Neoplasms benigh, malignant and 
unspecified (incl cysts and polyps), Other (tTumor hemorrhage) 
NERVOUS SYSTEM DISORDERS – Nervous system disorders, 
Other (sSpinal cord compression) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
– Respiratory, thoracic and mediastinal disorders, Other 


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(oOropharyngeal pain) 
 
 
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CTCAE term (AE description) and grade:  The descriptions and 
grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
AE reporting until March 31, 2018 for AE reporting.  CTCAE 
version 5.0 will be utilized for AE reporting beginning April 1, 2018. 
All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.04.0.  A copy of the CTCAE version 5.04.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/c
tc.htm.   
 
Rationale: CTCAE version has been updated as per CTEP request 
letter dated 12-Jan-2018 
 
6 Section 
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https://ctep.cancer.gov 
 
Rationale: Links to CTEP Website updated as the previous address 
did not work. 


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NCI Protocol #: 
9322 
Local Protocol #: 
PHL-086 
 
TITLE:  A Phase 2 Study of XL184 (Cabozantinib) in Recurrent or Metastatic  
Endometrial Cancer 
 
Coordinating Center: 
 
 
The Princess Margaret Hospital Phase II Consortium (PMHC) 
 
*Principal Investigator: 
Dr. Neesha Dhani 
 
610 University Avenue 
 
Princess Margaret Cancer Center 
 
Toronto Ontario M5G2M9 
 
Phone: 416-946-2000 
 
Fax: 416-946-4467 
 
 neesha.dhani @uhn.ca 
 
Co-Investigators: 
Dr. Amit Oza 
 
610 University Avenue 
 
Princess Margaret Cancer Centre 
 
Toronto Ontario M5G2M9 
 
Phone: 416-946-2818 
 
Fax: 416-946-4467 
 
amit.oza @uhn.ca 
 
 
Dr. Katia Tonkin 
 
11560 University Ave 
 
Cross Cancer Institute 
 
Edmonton Alberta T6G 1Z2 
 
Phone: 780-432-8514 
 
Fax: 780-432-8888 
 
Katia.Tonkin@albertahealthservices.ca 
 
 
Dr. Hal Hirte 
 
Juravinski Cancer Centre  
 
 
 
699 Concession St. 
 
Hamilton Ontario L8V 5C2 
 
Phone: (905) 387-9495 
 
Fax: (905) 575-6326 
 
 
 
Hal.hirte@jcc.hhsc.ca 
 
Dr. Jim Biagi 
Cancer Centre of Southeastern Ontario at Kingston 
25 King Street West 
Kingston Ontario K7L 5P9 
Phone: (613) 544-2630 
Fax: (613) 546-8209 


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Version Date: 09Feb2018 
 
2 
jim.biagi@krcc.on.ca  
 
Dr. Stephen Welch 
London Regional Cancer Program 
790 Commissioners Road East 
London Ontario N6A 4L6 
Phone: (519) 685-8640 
Fax: (519) 685-8624 
Stephen.welch@lhsc.on.ca 
 
Dr. Johanne Weberpals 
Ottawa Regional Cancer Centre 
501 Smyth Road 
Ottawa Ontario K1H 8L6 
Phone: 613-737-8899 
Fax: 613-737-8828 
jwebserpals@ottawahospital.on.ca 
 
Dr. Angela Jain 
Fox Chase Cancer Center 
333 Cottman Ave, Room C307 
Philadelphia Pensylvannia 19111-2497 
Phone: (215)728-2871 
Fax: (215)728-3639 
Angela.Jain@fccc.edu 
 
Dr. Prafull Ghatage  
Tom Baker Cancer Centre  
1331-29th Street, NW  
Calgary Alberta T2N 4N2  
Phone: (403) 521-3721  
Fax: (403) 521-3593  
Prafull.Ghatage@albertahealthservices.ca 
 
Chicago Consortium  
Dr. Gini Fleming  
University of Chicago Medical Center  
5841 South Maryland Ave., MC 2115  
Chicago, IL 60637  
Telephone: (773) 702-6712  
Fax: (773) 702-0963  
gfleming@medicine.bsd.uchicago.edu 
 
Jean A. Hurteau MD 
Division of Gynecologic Oncology 
North Shore University Health System Evanston Hospital 
2650 Ridge Avenue, Walgreen Building, Suite 1507 


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3 
Evanston, Illinois 60201 
Clinical Professor and Co-director,  
Gynecologic Oncology Fellowshiop 
University of Chicago Pritzker School of Medicine 
Phone: 847-570-2639 
FAX: 847-733-5358 
E-mail: jhurteau@uchicago.edu 
 
Carolyn Johnston, MD, MD 
University of Michigan  
1500 East Medical Center Drive/CC5219 
Ann Arbor, MI 48109 
Phone: (734) 936-6886 
Fax: (734) 764-7261 
Email:johnstob@umich.edu 
 
Bert O’Neil 
IU Simon Cancer Center 
535 Barnhill Drive, Suite 130D 
Indianapolis, IN 46202-5289 
Phone: 317-278-0320 
Fax:317-274-8022 
Email: bhoneil@iu.edu 
 
James L. Wade III, M.D.  
Decatur Memorial Hospital  
2300 N. Edward St. 
Decatur, IL 62526  
Ph: (217) 876-6600 
JLWADE3@sbcglobal.net      
 
Krishna Rao, M.D.    
Southern Illinois University School of Medicine 
315 West Carpenter Street 
Springfield, IL  62702 
Phone: 217-545-5817 
Fax: 217-545-1141 
krao@siumed.edu 
 
California Consortium: 
Sidney Scudder, MD 
University of California, Davis Cancer Center 
4501 X Street, Room 3016 
Sacramento, CA, USA 95817 
Tel: (916) 734-3772 
Fax: (916) 734-7946 
Email: sidney.scudder@ucdmc.ucdavis.edu 


NCI Protocol #: 9322 
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Mihaela Cristea, MD 
City of Hope 
1500 E. Duarte Road. 
Duarte, CA 91010 
Telephone: 626-256-4673 
Fax: 626-930-5461 
Email:  mcristea@coh.org 
 
Koji Matsuo, MD 
University of Southern California / Norris Comprehensive 
Cancer Center 
1441 Eastlake Avenue, Rm. 3440Los Angeles, CA, USA 
90033 
Tel: (323) 226-3416 
Fax: (323) 865-0061 
Email: Koji.Matsuo@med.usc.edu 
 
Dr. Madeleine Courtney-Brooks 
Magee Women’s Hospital 
300 Halket Street 
Pittsburgh, PA 15213 
Tel:  412-641-5418 
Email: courtneybrooksmb@upmc.edu  
 
Robert Morris, MD, PhD 
4100 john R, HP07GO 
Detroit, MI 48201 
Phone: 313-576-9435 
Fax: 313-993-8857 
Email:  rmorris@med.wayne.edu 
 
Stephen Koehler, MD 
City of Hope Medical Group, Inc. 
209 Fair Oaks Avenue 
South Pasadena, CA  91030 
Phone: 626-396-2900 
Fax: 626-396-2770 
Email: Skoehler@cohmg.com 
 
 
 
 
 
 
 


NCI Protocol #: 9322 
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Statistician: 
 
Manager: 
Lisa Wang 
 
 
 
 
Chantale Blattler 
Princess Margaret Cancer Centre  
 
 
 
Princess Margaret Cancer Centre 
610 University Avenue 
 
 
 
 
700 University Avenue 
Toronto Ontario M5G 2M9 
 
 
 
 
Toronto Ontario M5G 1X6  
Phone: 416-946-4501 ext. 4883  
 
 
 
Phone: 416-946-4501 ext. 3692 
Fax: 416-946-2048 
 
 
 
 
Fax: 416-946-2016 
lisawang@uhnres.utoronto.ca  
chantale.blattler@uhn.ca 
 
Responsible Data Managers: 
Oulu Zhu 
 
Anjali Mehta 
Princess Margaret Cancer Centre  
 
 
 
Princess Margaret Cancer Centre 
700 University Avenue 
 
 
 
 
700 University Avenue 
Toronto Ontario M5G 1X6  
 
 
 
 
Toronto Ontario M5G 1X6 
Phone: 416-946-4501 ext. 3452  
 
 
 
Phone: 416-946-4501 ext 5618 
Fax: 416-946-2016 
 
 
 
 
Fax: 416-946-2016 
Oulu.Zhu@uhn.ca 
Anjali.Mehta@uhn.ca 
 
NCI Supplied Agent:  XL184 (cabozantinib) (NSC # 761968; IND # 116059) 
 
Protocol Date: 
Initial / 20November2012 
 
Amendment 1/ 29April2013 
 
Amendment 2/ 27Aug2013 
 
Amendment 3/ 28January2014 
 
Amendment 4 / 14April2014 
 
Amendment 5/ 15September2014 
 
Amendment 6/ 12Aug2015 
 
Amendment 7/ 23February2016 
 
Amendment 8/11May2016 
 
Amendment 9/14Dec2016 
 
Amendment 10/10Feb2016 
 
Amendment 11/19Apr2017 
 
Amendment 12/09Feb2018 
 
 
 


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6 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Metastatic Endometrial Cancer <1 prior chemo for metastatic disease 
Measureable Disease 
ECOG 0-2 
Archival biopsy tissue 
Progression 
Off Tx 
Stage I: 18 patients per histological cohort 
Experimental Cohort: 
 Histological Cohort 1 (serous) 
Histological Cohort 2 (endometriod) 
Exploratory Cohort (clear cell, carcinosarcoma, adenosquamous, mixed) 
Cabozantinib (XL-184) daily, 28-day cycle 
>2/18 PR or >6/18 PFS>12weeks
Response / Stable 
Continue Tx 
Stage II: 18 patients per histological cohort 
Imaging RECIST 1.1 CT at end of cycle 3, then every 2 cycles; patients on study 
for two years or longer, every 3 cycles. 


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Study Summary 
 
This is a single arm phase II study to evaluate the activity of the multi-targeted inhibitor 
cabozantinib (with activity against MET, VEGFR2, TIE2, RET, AXL and KIT) in endometrial 
cancer (with a dual primary endpoint of improved response rate and 12-week progression-free-
survival (PFS)). Cabozantinib co-mines the simultaneous targeting of epithelial cell growth 
factor signaling and angiogenic support from stromal compartments. Correlative studies include 
evaluation of mutational profiles and met amplification status as baseline molecular predictors of 
response. 
 
Eligible patients include those with serous or endometroid histology endometrial cancer with 
radiographic disease progression after one line of cytotoxic therapy for metastatic disease or with 
progression within 12 months of completing adjuvant chemotherapy. Chemotherapy and 
radiation administered in the adjuvant setting will be allowed as well as prior hormonal 
manipulation. In addition, a separate cohort of patients with unusual histology endometrial 
cancer (including clear cell, carcinosarcoma) will also be accrued applying same eligibility 
criteria. The statistical plan to assess efficacy will only apply to the experimental cohort (serous 
and endometroid histology patients).  
 
Dosing of cabozantinib will be continuous (7 days a week) on a 28 day cycle, with response 
evaluation performed, at the end of cycle 3, then every 2 cycles with CT tumour measurements 
by RECIST (Study Schema). 
 
Statistical plan is based on efficacy in serous and endometroid histology endometrial cancer. A 
modified Simon two-stage design is planned with a maximum accrual of 36 patients per 
histological cohort (i.e. 72 patients in total) to discriminate between co-primary endpoints of 
tumor response rates of 30% vs. 10% and 12-week progression-free-survival (PFS) rates of 55% 
vs. 30% (corresponding to median PFS of 3.4 vs. 1.7 months). Stage I has a planned accrual of 
18 patients per histological group. If no more than 2 objective responses (no more than 11%), 
and no more than 6 instances of 12-week PFS (no more than 33%), are observed among the 
initial 18 patients, that cohort would be terminated early and declared negative but the other 
cohort can continue to accrue and will be analyzed separately. Otherwise study will proceed to 
Stage II accrual to a maximum of 36 patients per histological cohort. If at least 8 objective 
responses (at least 22%), or at least 16 instances of 12-week PFS (at least 44%) are observed 
among the 36 evaluable patients, this agent would be considered worthy of further testing in that 
particular histological subgroup of endometrial cancer. 
 
Adverse events will be graded using CTCAE v 5.0. 


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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................6 
1. 
OBJECTIVES ....................................................................................................................10 
 
Primary Objectives.................................................................................................10 
 
Secondary Objectives.............................................................................................10 
2. 
BACKGROUND ...............................................................................................................10 
 
Endometrial Cancer: Epidemiology and Contemporary Management ..................10 
 
Relevance of Histopathology and Molecular Characterization .............................11 
 
XL-184 (Cabozatinib) ............................................................................................12 
 
Rationale for Targeting HGF and Angiogenesis in Endometrial Cancer ..............19 
 
Correlative Studies Background ............................................................................21 
3. 
PATIENT SELECTION ....................................................................................................21 
 
Eligibility Criteria ..................................................................................................21 
 
Exclusion Criteria ..................................................................................................23 
 
Inclusion of Women and Minorities ......................................................................26 
4. 
REGISTRATION PROCEDURES ...................................................................................27 
 
General Guidelines.................................................................................................27 
 
Registration Process ...............................................................................................28 
5. 
TREATMENT PLAN ........................................................................................................28 
 
Agent Administration.............................................................................................29 
 
General Concomitant Medication and Supportive Care Guidelines ......................29 
 
Duration of Therapy ...............................................................................................32 
 
Duration of Follow Up ...........................................................................................33 
 
Criteria for Removal from Study ........................... Error! Bookmark not defined. 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................34 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................48 
 
Adverse Event Characteristics ...............................................................................52 
 
Expedited Adverse Event Reporting ......................................................................53 
 
Routine Adverse Event Reporting .........................................................................56 
 
Secondary Malignancy...........................................................................................56 
 
Second Malignancy ................................................................................................56 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................56 
 
CTEP IND Agent: Cabozantinib (XL 184) ...........................................................56 
9. 
ANCILLARY & EXPLORATORY ANALYSES ............................................................59 
 
Baseline Mutational Profiling of Archival Samples ..............................................59 
 
Peripheral Blood Collection ...................................................................................60 
10. STUDY CALENDAR .............................................................................................................61 


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11.  MEASUREMENT OF EFFECT.............................................................................................62 
 
Antitumor Effect – Solid Tumors ..........................................................................62 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................69 
 
Data Reporting .......................................................................................................69 
 
CTEP Multicenter Guidelines ................................................................................69 
 
Collaborative Agreements Language .....................................................................70 
13. 
STATISTICAL CONSIDERATIONS...............................................................................71 
 
Study Design/Endpoints.........................................................................................71 
13.2 
Sample Size/Accrual Rate ......................................................................................72 
13.3 
Analysis of Secondary Endpoints ..........................................................................72 
13.4 
Reporting and Exclusions ......................................................................................72 
REFERENCES ..............................................................................................................................73 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................77 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ....................................................78 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................80 
APPENDIX D 
DATA MANAGEMENT GUIDELINES ..................................................82 
APPENDIX E 
PATIENT’S STUDY DRUG DIARY .......................................................84 
 
 


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1. OBJECTIVES 
 
 
Primary Objectives 
 
Determine efficacy of single agent cabozatinib in women previously receiving one line of 
chemotherapy for metastatic endometrial cancer or with progression within 12 months of 
completing adjuvant therapy, with co-primary endpoints of  
 
• objective response rate by RECIST 1.1 
• progression-free-survival at 12 weeks (PFS) 
 
 
Secondary Objectives 
 
Correlation of clinical response with:  
 
• baseline molecular status of archival tumour (c-met amplification & mutation status) 
• overall survival 
 
2. BACKGROUND 
 
 
Endometrial Cancer: Epidemiology and Contemporary Management 
 
Endometrial cancer is the highest incidence gynecologic malignancy and remains the 4th most 
common cancer diagnosis in North American women less frequent only to diagnoses of breast, 
lung and colorectal cancer. In 2012, approximately 5600 more women will be diagnosed with, 
and 900 will die of this disease in Canada. US statistics parallel those of Canada with an 
approximately 10-fold difference [1, 2]. 
 
The main risk factor for the development of endometrial cancer continues to be prolonged 
exposure to unopposed estrogen. Other identified risk factors (nulliparity, use of taxomifen, 
hormone replacement therapy etc) are likely relevant due to the pathology-promoting imbalance 
of estrogen/progesterone they create. The ever growing obesity epidemic with its consequent 
metabolic syndromes is yet another factor promoting estrogenic imbalances in women and is 
likely a major contributing factor to the burden of disease we currently see related to endometrial 
cancer. 
 
Uterine cancer is predominantly a disease of older women who present with aberrant post-
menopausal bleeding as the first symptom of their disease. The majority of women are diagnosed 
with early stage disease and have a relatively good prognosis, with 5-year disease-free survivals 
of greater than 80%. Surgery continues to be the mainstay of management; however both 
chemotherapy and radiation have demonstrated utility at reducing the risk of local and distant 
disease recurrence and have now become standard practice. Unfortunately a not insignificant 
percentage of women with early stage disease are at a greater risk of developing disease 
recurrence. Factors like age > 60, depth of invasion, involvement of lower uterine segment, non-
endometroid histology and the presence of lymphovascular invasion or aneuploidy, have 
demonstrated importance in identifying those at a particularly high risk of failing primary 


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11 
therapy [3, 4]. These women, together with those with more advanced disease at initial 
presentation have a relatively poor prognosis, and in contrast with the high 5-year disease free 
survival in early stage disease, women with stage IV disease can expect about a 20% chance of 
the same. There is significant heterogeneity within this group as patients with endometroid 
histology cancer tend to have more slow-growing disease that may respond to hormonal 
manipulation while patients with high grade serous cancers follow a more aggressive course and 
benefit from a limited number of cytotoxic therapies. The best responses are to agents like 
doxorubicin and cisplatin which are still modest and in the range of 20 to 40% and where noted 
are transient in duration [3, 5]. Although combination regimens have demonstrated higher 
response rates, given their increased toxicities and unclear impact on survival their use in the 
palliative setting of these patients is unclear [6]. 
 
 
Relevance of Histopathology and Molecular Characterization 
 
Endometrial cancers encompass a broad range of tumour histologies. The majority of patients 
close to 80%, are diagnosed with endometroid adenocarcinomas also known as Type I cancers. 
These are the traditional uterine cancers characterized by low grade histology and a relatively 
indolent course, developing in older women possessing the standard risk factors associated with 
unopposed estrogen excess and responsive to therapeutic hormonal manipulation. The Type II or 
non-endometroid histology endometrial cancers follow a very different clinical course. The most 
common histology in this uncommon group is the serous histology cancers which in spite of 
being considered in a similar context to serous ovarian cancers, have demonstrated an inferior 
clinical course matched stage-for-stage. This group also includes clear cell, carcinosarcoma and 
stromal sarcomas albeit at much lower frequencies all with their own unique clinical and 
molecular profiles. In spite of comprising a small proportion of all uterine cancers, non-
endometroid histology cancers account for about 50% cases of recurrent disease and therefore 
represent a significant management challenge [3].  
 
Apart from their distinctive clinical trajectories, the different histologies of endometrial cancer 
also have somewhat divergent molecular backgrounds suggesting a dualistic model of 
endometrial carcinogenesis that is especially relevant in the context of developing rationale 
targeted therapies and combinations thereof. Endometroid cancers tend to be low grade (grade 1) 
occurring on a background of atypical complex hyperplasia. They express both estrogen (ER) 
and progesterone (PR) receptors and demonstrate loss of PTEN tumour suppressor gene (with 
uninhibited activation of the PI3K/Akt pathway), mutation in KRAS and defects in DNA damage 
mismatch repair pathways. Serous endometrial cancers are exclusively high grade arising on a 
background of atrophy, tend to be non-diploid karyotype, ER/PR negative and demonstrating 
loss of p53 and activation of Her2/neu [3]. Molecular profiles of clear cell and carcinosarcoma 
have been less well evaluated and these appear to be a somewhat heterogenous group of diseases 
in their own right [7].  
 
Given the heterogeneity inherent in this patient population with respect to both clinical course 
and therapeutic response, there is optimism that novel approaches aimed specifically at 
differential vulnerabilities within different molecular subgroups of this disease will improve 
outcomes for patients with endometrial cancer. [8] 
 


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XL-184 (Cabozatinib) 
 
Characterization of XL-184 and rationale for HGF targeting in cancer 
 
XL184 (cabozantinib) inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor 
growth, metastasis, and angiogenesis (Investigator’s Brochure, 2011). The primary targets of 
XL184 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 
XL184 against c-Met and VEGFR2 has been demonstrated in preclinical and clinical studies.  
 
RTKs regulate numerous processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair [9]. Dysregulation of RTKs by mutation, gene 
rearrangement, gene amplification, and overexpression of both receptor and ligand have all 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) [9]. 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 inhibition of the VEGF 
pathway. 
 
Evidence linking c-Met and HGF as causative or progression factors in human cancers include: 
(1) Overexpression of both receptor and ligand in neoplasms relative to surrounding tissues; (2) 
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) 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 
[9]. 
 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, demonstrate 
dysregulated c-Met activity [10], either by means of c-Met kinase overexpression [11]; activating 
c-Met gene mutations and/or amplification [11-13]; or increased autocrine and/or paracrine 
secretion of the c-Met ligand, HGF/SF [14, 15]. 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 [14]. 
 


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13 
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, 
proliferation, survival, and enhanced vascular permeability [16]. 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 [17]. 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 XL184   
 
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 et al., 2009). In RIP-Tag2 transgenic mice, tumors 
treated with XL184 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 [18]. All mice treated 
with XL184 (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 [19]. Tumors were 35% 
smaller after XL184 treatment than corresponding values for vehicle control mice. c-Met 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 [20]. XL184 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, XL184 disrupted tumor vasculature by inducing endothelial cell 
death that negatively affected tumor viability. XL184 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, XL184 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 XL184 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 [21] (Zhang et al., 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 XL184 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 XL184 treated animals appeared mostly 


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14 
normal. Thus, XL184 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 XL184 and at plasma exposures comparable to exposure observed in clinical 
trials (Investigator’s Brochure, 2010). XL184 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 XL184. 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 XL184 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, [22]. Dose-dependent inhibition of phosphorylation of c-Met and RET 
was observed among the 3, 10, and 30 mg/kg dose groups as well.  
 
c-Met phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184, 2–8 hours post 
dose in H441 tumors (human lung papillary adenocarcinoma) that harbor constitutively 
phosphorylated c-Met [20]. 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 [22]. 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 XL184 dosed 
as a solid was approximately 100% of XL184 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 
XL184 oral doses in rats increased less than dose-proportionally with increasing dose (100–900 
mg/kg) [22]. 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 XL184 in rats correlated with the greater 
toxicity observed in this species at lower administered doses. 


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Systemic drug exposure parameters (Cmax and AUC0-t values) associated with single XL184 
oral doses in dogs increased less than dose-proportionally with increasing XL184 dose (400–
2000 mg/kg), suggesting possible saturation of systemic absorption [23]. 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 XL184 administration 
were observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, and adrenal 
and reproductive tract tissues [23]. Histopathological changes present in the bone and pancreas 
were considered secondary to XL184 administration. Adverse effects following oral exposure to 
XL184 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, XL184 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 
XL184 capsule form daily (Study XL184-001). 
 
In definitive genotoxicity bioassays, XL184 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 XL184-treated rats or on cardiovascular function in XL184-treated dogs. 
 
Clinical Experience 
 
As of May 4, 2011, 1003 patients have been studied in 12 ongoing Exelixis-sponsored clinical 
trials with XL184 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.  
 


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16 
Phase I Studies 
Study XL184-001 was a phase 1 dose-escalation study in subjects with solid tumors. Eighty-five 
subjects, across 13 dosing levels (DL) ranging from 0.08 mg/kg qd (using powder-in-bottle [PIB] 
suspension on a 5 days on, 9 days off schedule) to 265 qd were enrolled. Capsule dose levels 
were 175mg qd and 250mg qd (using capsules [25 and/or 100mg] for two, 14-day cycles). The 
capsule MTD was determined to be 175 mg qd (Kurzrock et al., 2011). Of the 35 subjects with 
medullary thyroid cancer (MTC) and measureable disease, 10 (29%, 95% CI) had confirmed 
partial responses (cPR) (with a duration up to 48+ months), 17 (49%) had tumor shrinkage of 
≥30%, and stable disease (SD) of at least 6 months was observed in 15/37 (41%) of the MTC 
subjects.  
 
In Study XL184-002, treatment of subjects with newly diagnosed glioblastoma (GB) consisted of 
cabozantinib in combination with TMZ with or without radiation therapy. Enrollment has been 
terminated and no clinical efficacy data is presented in the 2011 Investigator’s Brochure. All 
adverse events (AEs) were assessed with respect to combination treatment and not the individual 
components. Nineteen patients were evaluated for AEs, the most common grade 3 or higher 
included neutropenia (21%), thrombocytopenia (16%), leucopenia (16%), and hypertension 
(11%). Myelosuppression, including prolonged pancytopenia, is a dose-limiting toxicity (DLTs) 
associated with TMZ use. The frequency at which bone marrow toxicity was observed in this 
study is consistent with the TMZ prescribing information.  
 
Study XL184-004 is a Phase 1, open-label, randomized, single-dose, two-treatment, two way 
crossover study to assess the effect of food on the bioavailability of cabozantinib in healthy adult 
subjects. According to a randomization scheme, 56 subjects received single oral doses of the 
assigned treatment of Test (175 mg cabozantinib, dosed as one 100 mg capsule and three 25 mg 
capsules 30 minutes after administration of a high fat breakfast) or Reference (175 mg 
cabozantinib, dosed as one 100 mg capsule and three 25 mg capsules under fasting conditions). 
Blood samples were collected up to 504 hours post dose for each subject after each treatment to 
assess plasma cabozantinib pharmacokinetics. See “Pharmacokinetics” section for results. 
 
Study XL184-005 is a Phase 1, open-label, randomized, single-dose, two-treatment, two way 
crossover comparative bioavailability study of cabozantinib tablet and capsule formulations in 
healthy volunteers. Subjects received single oral doses of the assigned treatment of Test (100 mg 
cabozantinib, dosed as one 100 mg tablet) or Reference (100 mg cabozantinib, dosed as two 50 
mg capsules), according to a randomization scheme. Each dosing was administered under fasting 
conditions, and blood samples were collected up to 504 hours post dose for each subject after 
each treatment to assess plasma cabozantinib PK. See “Pharmacokinetics” section for results. 
 
In Study XL184-008, subjects with advanced solid tumors (particularly renal cell carcinoma 
[RCC] and differentiated thyroid cancer [DTC]) are evaluated for any potential clinically 
significant drug-drug interaction of cabozantinib on the CYP isozyme CYP2C8. The effect of qd 
dosing of 175 mg cabozantinib and a single dose of rosiglitazone will be evaluated. In 11 
patients evaluated for AEs, the most common grade 3 or higher AEs were fatigue (9%), 
hypophosphatemia (27%), blood amylase increase (9%), and hyponatremia (9%). 
 


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17 
In a phase 1 study, CA205-001, Japanese subjects with advanced or metastatic solid tumors for 
whom the standard of care is ineffective or inappropriate, received cabozantinib at a starting dose 
of 75 mg PO qd. Two of the three subjects in the first cohort experienced DLTs of proteinuria 
and thrombocytopenia. Because of a change in study sponsor, this study was reinitiated as 
XL184-014. One additional subject was enrolled as of May 2011 at 50 mg PO qd.  
 
Study XL184-202 was a phase 1b/2 trial that evaluated the safety and tolerability of cabozantinib 
and erlotinib administered in combination in non-small-cell lung cancer (NSCLC) subjects. Of 
the 64 subjects enrolled in the phase 1 dose-escalation portion of the study, all but two had been 
previously treated with and progressed on erlotinib therapy. A cPR was observed in 5 subjects 
(8%) and 24 subjects (37%) had SD/PR ≥4 months. The most common grade 3 or higher AEs in 
the phase 1 portion included diarrhea (44%), fatigue (22%), hypokalemia (11%), decreased 
appetite (6%), dyspnea (14%), lipase increase (6%), hypomagnesemia (6%), and dehydration 
(5%). Twenty-eight subjects were enrolled in the phase 2 portion of the study, in which subjects 
who had received clinical benefit from erlotinib and subsequently experienced progressive 
disease (PD), received single-agent cabozantinib or cabozantinib with erlotinib. AEs ≥grade 3 
included dehydration (8%) and hypertension (8%). One patient, who was treated with single-
agent cabozantinib, had a cPR. 
 
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 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.  
 
Phase 3 Studies 
Study XL184-301 is a blinded, randomized control trial for subjects with unresectable, locally 
advanced or metastatic MTC, randomized 2:1 to cabozantinib or placebo. SAEs reported in 


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18 
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). 
 
Adverse Events 
The clinical studies with XL184 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 XL184 
(806 in single-agent studies and 107 in combination studies of XL184 with erlotinib, 
rosiglitazone, or TMZ ± radiation) (Investigator’s Brochure, 2011). Data from the 806 subjects 
who received single-agent XL184 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 XL184 studies. The most commonly reported 
SAEs that were assessed as related to study treatment with XL184 (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. 
 
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: 175 and 250 mg qd) (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 XL184 were 91.3 ± 33.3 hours 
(n = 23), and apparent steady-state plasma levels were reached by Day 15 (Kurzrock, 2011). 
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 XL184 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 


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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). Based on this result, cabozantinib must be taken on 
an empty stomach (fasting is required 2 hour before and 1 hours after each cabozantinib dose). 
 
 
Rationale for Targeting HGF and Angiogenesis in Endometrial Cancer 
 
Endometrial cancers are a heterogeneous group that can be separated into two distinct 
histological sub-types with differing molecular backgrounds. The more common endometriod 
cancers are characterized by aberrant PI3K/PTEN/AKT pathway activation as a consequence of 
oncogenic mutation of PI3K, PTEN loss and over-expression of upstream growth factor 
receptors. Serous cancers on the other hand, harbour mutations in p53 and p16 with consequent 
cell-cycle dysregulation. A subset of these also demonstrates up-regulation of PI3K signaling 
through gene amplification and oncogenic mutation. Also noteworthy is abnormal regulation of 
growth factor (HER2, EGFR) and MAPK signalling, the latter via KRAS mutation, specifically 
in endometroid cancers [8].  
 
It is increasingly evident that focused inhibition of single oncogenic pathways is of limited utility 
in genetically complex tumours where molecularly driven escape and resistance mechanisms 
emerge under the selection pressure of isolated pathway inhibition. Consequently, targeting 
multiple arms of a network (either through combination therapies or multi-targeted agents) has 
become the recent focus of drug development [24] . In addition, the recognition of the 
importance of cellular and physical features of the tumoral microenvironment in cancer 
progression has identified further targets for a multi-pronged approach to tumour targeting [25]. 
 
The prognostic importance of microvascular density (MVD) in predicting for advanced disease 
stage and inferior patient outcome in endometrial cancer lends credence to targeting angiogenic 
pathways in this disease [26, 27]. It is a particularly appealing therapeutic strategy as it involves 
simultaneous inhibition of mitogenic pathways in malignant epithelial cells and of paracrine 
support from the stromal compartment [28]. Since multiple molecular pathways have been 
implicated in the promotion of angiogenesis the findings of Wagatsuma correlating high MVD 
with diffuse membranous c-MET expression are interesting  and suggest a potential relevance of 


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hepatocyte growth factor (HGF) – MET molecular cross-talk in promoting tumoral angiogenesis 
in endometrial cancer [29]. Preclinical work in a variety of in vivo tumour models supports a 
potentiation of antiangiogenic strategies through contemporaneous inhibition of MET and VEGF 
RTK pathways [19, 30, 31]. 
c-MET is a RTK for which the only known ligand is HGF. Ligand binding promotes receptor 
activation and downstream signalling through MAPK and PI3K, influencing a number of 
processes integral to malignant progression including growth, motility, invasion and 
angiogenesis [32]. Over-expression of the MET receptor has been reported in a variety of 
cancers, and leads to increased paracrine and autocrine signalling through increased sensitivity to 
stroma produced HGF [33]. Similar findings have been demonstrated in endometrial cancer (in 
endometroid and serous subtypes) where increased tumour expression of MET and stromal 
reactivity for HGF correlated with more aggressive tumour biology and inferior patient outcome 
[29, 34]. 
 
Unfortunately, clinical benefit across tumour types from isolated VEGF-pathway targeting 
strategies has been modest at best and transient in duration[35] . In situations where treatment 
results in an initial response followed by progression it is likely that acquired mechanisms of 
resistance related to alternative molecular pathways promoting angiogenesis and tumour 
progression are the cause. Multiple molecular mediators have been implicated in this regard 
including FGF (fibroblast growth factor), ephrins, angiopoietins and HGF. Preclinical work also 
suggests that these mechanisms may also be relevant to the increased metastatic potential noted 
with VEGF-targeting [36]. It has been suggested that either through targeting of multiple 
pathways or initiating inhibition of compensatory pathways at the emergence of resistance may 
result in greater clinical efficacy [37, 38].  
 
The recently reported Phase II trial of single agent bevacizumab in endometrial cancer is one 
such example. Although activity level was encouraging with a response rate of 13% and a 40% 
6-month PFS, these responses were transient. Benefit was noted in all histological subgroups. 
Interestingly, although tumour VEGF-A levels did not predict for response, circulating levels of 
the same cytokine seemed to correlate with poor outcome on trial. What remains unclear is 
whether the lack of discrepancy is related to the use of archival tumour or a true lack of 
correlation [39]. 
 
Current data implies that dual targeting of VEGFR2 and MET signaling, as can be achieved with 
the multi-targeted tyrosine kinase inhibitor cabozatinib, is likely to result in significant clinical 
efficacy in endometrial cancer where high levels of angiogenesis and aberrant proliferation 
pathways are relevant. 
 
Targeting angiogenic pathways has emerged as an attractive therapeutic strategy in endometrial 
cancer given the prognostic relevance of micro-vascular density (and hence heightened 
angiogenic activity) in this disease [26, 27, 40]. The results of the recently reported endometrial 
bevacizumab trial are in accordance with this hypothesis. In women previously receiving 
cytotoxic treatment for advanced disease, the VEGF monoclonal antibody had a response rate of 
13.5%, with 40% women remaining progression-free for at least 6 months [39]. Still, benefit 
from VEGF targeting strategies is generally transient due to alternate angiogenic pathways and 


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21 
stromal elaboration of soluble factors [28, 38]. In this regard, two independent studies have 
suggested relevance of hepatocyte growth factor (HGF) signaling and angiogenesis in 
endometrial cancer, demonstrating increased expression of HGF’s cognate receptor c-MET, in 
around 60% of endometroid and serous cancers. Further, upregulated c-MET/HGF correlated 
with aggressive tumour biology and inferior patient survival [29, 34]. From a mechanistic 
standpoint, preclinical experimental work demonstrates efficacy of HGF-MET targeting through 
inhibition of both mitogenic and angiogenic tumoral pathways [41].  
 
Study Hypothesis 
 
 
This is a single arm phase II study to evaluate the hypothesis that the multi-targeted inhibitor 
cabozantinib (with activity against MET, VEGFR2, TIE2, RET, AXL and KIT) will demonstrate 
significant activity across various histologies of endometrial cancer (with a dual primary 
endpoint of improved response rate and 12-week progression-free-survival (PFS)). Efficacy of 
this approach is likely to be related to the simultaneous targeting of epithelial cell growth factor 
signaling and angiogenic support from stromal compartments. Exploratory correlative studies are 
incorporated to evaluate the predictive potential of archival mutational profiles (including c-met 
amplification status). 
 
 
Correlative Studies Background 
 
Rationale for HGF/MET pathway biomarkers 
 
Oncogenic MET signaling is a consequence of various molecular mechanisms including gene 
amplification, mutation, over-expression, and autocrine activation, with the hierarchal relevance 
dictated by the tumour context. In addition, downstream HGF-MET signaling is complex and 
involves several networks that are already aberrantly regulated in human cancers including (but 
not limited to) PI3K/Akt and RAS-RAF-MEK-ERK. Therefore, molecular markers indicative of 
(1) the type of pathway aberration, (2) the mutational context of a patient’s tumour or (3) the 
activation status of downstream signaling mediators, may indicate dependence on MET pathway, 
potentially acting as biomarkers of response to cabozantinib/XL-184.  
 
Overview of correlative studies 
 
Correlative studies evaluating tumour biology relevant to endometrial cancer will focus on 
baseline amplification status of MET tumour mutational profiling using a custom panel to assess 
a large panel of cancer-associated mutations as well as baseline status of met amplification.  
 
3. PATIENT SELECTION 
 
 
Eligibility Criteria  
3.1.1 Patients must have histologically or cytologically confirmed metastatic endometrial 
cancer. Eligible histologies for the experimental cohort are: endometroid or serous 
Eligible histologies for the exploratory cohort are: carcinosarcoma, clear cell, mixed, 
adenosquamous and any other rare sub-type of endometrial cancer 
 


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3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥10 mm with CT scan, MRI, or calipers 
by clinical exam and ≥ 15 mm in short axis for nodal lesions. See Section 11 for the 
evaluation of measurable disease. Patients must have radiographic evidence of disease 
progression following the most recent line of treatment.  
 
3.1.3 Prior therapy:  Eligible subjects must have had 1 line of systemic cytotoxic treatment. 
This may be adjuvant therapy with documented progression within 12 months of 
completion, or 1 line of cytotoxic therapy for metastatic disease.  
NOTE: Eligible patients are allowed up to 2 lines of systemic cytotoxic treatment, of 
which only 1 line is allowed for metastatic disease. The acceptance of progression within 
12 months of adjuvant is part inclusion to not require patient to re-challenge with chemo 
if they progressed soon after adjuvant therapy. Prior hormonal therapy for 
metastatic/recurrent disease is also allowed. Prior targeted therapy not directed against 
cMET or VEGF pathways is allowed.   
 
3.1.4 Age >18 years on day of consent. As no dosing or adverse event data are currently 
available on the use of XL-184 in patients <18 years of age, children are excluded from 
this study but will be eligible for future pediatric trials.   
 
3.1.5 ECOG performance status <2 (Karnofsky >60%, see Appendix A). 
 
3.1.6 Life expectancy of greater than 3 months. 
 
3.1.7 Patients must have normal organ and marrow function ≤ 7 days before the first dose of 
study treatment as defined below: 
 
− 
absolute neutrophil count  
>1.5 x 109/L 
− 
platelets  
 
 
 
 
 
> 100 x 109/L 
− 
total bilirubin  
 
 
 
≤1.5 × ULN 
− 
AST(SGOT)/ALT(SGPT) 
<3.0 X institutional upper limit of normal 
− 
creatinine  
 
 
 
 
≤ 1.5 × ULN 
 
 
 
      OR 
− 
creatinine clearance  
 
> 50 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
− 
hemoglobin   
 
 
 
≥ 90g/L 
− 
serum albumin  
 
 
 
≥ 28g/L                                                              
− 
lipase    
 
 
 
 
 
< 2.0 × ULN; no radiologic/clinical evidence 
pancreatitis 
− 
urine protein / creatinine ratio (UPCR) ≤1 
− 
serum phosphorus, calcium, magnesium and potassium ≥ LLN 
 
3.1.8 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 


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23 
ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopausal 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, antiestrogens, ovarian suppression 
or any other reversible reason. 
 
3.1.9 The effects of XL184 on the developing human fetus are unknown. For this reason and 
because tyrosine kinase inhibitors agents are known to be teratogenic, women of child-
bearing potential must agree to use adequate contraception (see below) prior to study 
entry and for the duration of study participation. Should a woman become pregnant or 
suspect she is pregnant while she is participating in this study, she should inform her 
treating physician immediately.  
 
Sexually active subjects must agree to use medically accepted barrier methods of 
contraception (e.g., male or female condom) during the course of the study and for 
4 months after the last dose of study drug(s), even if oral contraceptives are also used. All 
subjects of reproductive potential must agree to use both a barrier method and a second 
method of birth control during the course of the study and for 4 months after the last dose 
of study drug(s). 
 
3.1.10 Patients must consent to analysis on archival tissue; if archival sample is not available, a 
sufficient tumour biopsy can be performed a minimum of 28 days prior to start of 
treatment if felt to be clinically reasonable. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy (including investigational cytotoxic chemotherapy), 
biologic agents (e.g., cytokines or antibodies) or radiotherapy within 4 weeks (6 weeks 
for nitrosoureas or mitomycin C) before the first dose of study treatment or those who 
have not recovered from adverse events due to agents administered more than 4 weeks 
earlier. 
 
3.2.2 Prior treatment with cabozantinib. 
 
3.2.3 The subject has received radiation therapy: 
• to bone metastasis within 14 days before the first dose of study treatment  
• to any other site(s) within 28 days before the first dose of study treatment. 
 
3.2.4 The subject has received radionuclide treatment within 6 weeks of the first dose of study 
treatment. 
 
3.2.5 The subject has received prior treatment with a small molecule kinase inhibitor or a 
hormonal therapy (including investigational kinase inhibitors or hormones) within 14 


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24 
days or five half-lives of the compound or active metabolites, whichever is longer, before 
the first dose of study treatment. 
 
3.2.6 The subject has received any other type of investigational agent within 28 days before the 
first dose of study treatment. 
 
3.2.7 The subject has not recovered to baseline or CTCAE ≤ Grade 1 from related toxicity to 
all prior therapies except alopecia and other non-clinically significant AEs. 
 
3.2.8 Any other prior malignancy from which the patient has been disease free for less than 3 
years, with the exception of adequately treated and cured basal or squamous cell skin 
cancer, superficial bladder cancer, carcinoma in situ of any site or any other cancer.  
 
3.2.9 Patients with known brain metastases should be excluded from this clinical trial. 
 
3.2.10 The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial 
thromboplastin time (PTT) test ≥1.3 × the laboratory ULN ≤ 7 days before the first dose 
of study treatment. 
 
3.2.11 Therapeutic anticoagulation with warfarin, antiplatelet agents (e.g., clopidogrel), 
thrombin, or Factor Xa inhibitors is not allowed. Therapeutic anticoagulation with low 
molecular weight heparin (LMWH) is allowed as well as prophylactic anticoagulation 
using low dose aspirin (≤81 mg/day), low-dose warfarin (≤1 mg/day), and LMWH.  
 
 
3.2.12 The subject requires chronic concomitant treatment of strong CYP3A4 inducers 
(e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort).  
 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/ ; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information. As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new medications 
need to be prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product. 
 
3.2.13 The subject has experienced any of the following: 
• clinically-significant gastrointestinal bleeding within 6 months before the first dose 
of study treatment 
• hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first 
dose of study treatment 
• any other signs indicative of pulmonary hemorrhage within 3 months before the first 
dose of study treatment 
 
3.2.14 The subject has tumor in contact with, invading or encasing any major blood vessels. 


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25 
 
3.2.15 The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or 
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor 
within 28 days before the first dose of cabozantinib.  
 
3.2.16 The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
 
1. Cardiovascular disorders including: 
a) Congestive heart failure (CHF): New York Heart Association (NYHA) Class III 
(moderate) or Class IV (severe) at the time of screening 
b) Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg 
systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment 
within 7 days of the first dose of study treatment 
c) Any history of congenital long QT syndrome 
d) Any of the following within 6 months before the first  dose of study treatment: 
• unstable angina pectoris 
• clinically-significant cardiac arrhythmias 
• stroke (including TIA, or other ischemic event) 
• myocardial infarction 
• thromboembolic event requiring therapeutic anticoagulation (Note: subjects 
with a venous filter (e.g. vena cava filter) are not eligible for this study) 
 
2. Gastrointestinal disorders particularly those associated with a high risk of perforation 
or fistula formation including: 
a) Any of the following within 28 days before the first dose of study treatment 
• intra-abdominal tumor/metastases invading GI mucosa 
• active peptic ulcer disease, 
• inflammatory bowel disease (including ulcerative colitis and Crohn’s 
disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis 
• malabsorption syndrome 
b) Any of the following within 6 months before the first dose of study treatment: 
•  abdominal fistula 
• gastrointestinal perforation 
• bowel obstruction or gastric outlet obstruction 
• intra-abdominal abscess. Note: Complete resolution of an intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib 
even if the abscess occurred more than 6 months before the first dose of 
study treatment. 
 
3. Other disorders associated with a high risk of fistula formation including PEG tube 
placement within 3 months before the first dose of study therapy  
 
4. Other clinically significant disorders such as: 


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a) active uncontrolled infection requiring intravenous systemic treatment within 14 
days before the first dose of study treatment 
b) serious non-healing wound/ulcer/bone fracture within 28 days before the first 
dose of study treatment 
c) history of organ transplant 
d) concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days 
before the first dose of study treatment 
e) history of major surgery as follows: 
i. 
Major surgery within 3 months of the first dose of cabozantinib if there 
were no wound healing complications or within 6 months of the first dose 
of cabozantinib if there were wound complications 
ii. 
Minor surgery  within 1 month of the first dose of cabozantinib if there 
were no wound healing complications or within 3 months of the first dose 
of cabozantinib if there were wound complications 
 
In addition, complete wound healing from prior surgery must be confirmed at 
least 28 days before the first dose of cabozantinib irrespective of the time 
from surgery 
 
3.2.17 The subject is unable to swallow tablets. 
 
3.2.18 The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 
ms ≤ 7 days before the first dose of study treatment.  
 
3.2.19 The subject is unable or unwilling to abide by the study protocol or cooperate fully with 
the investigator or designee. 
 
3.2.20 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to XL184 
 
3.2.21 Pregnant women are excluded from this study because XL184 is a tyrosine kinase 
inhibitor with the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with XL184, breastfeeding should be discontinued if the mother is treated 
with XL184. 
 
3.2.22 Known HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with XL184. In addition, these patients 
are at increased risk of lethal infections when treated with marrow-suppressive therapy. 
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 
 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial. This study is designed to 
include minorities as appropriate. However, the trial is not designed to measure 


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27 
differences in intervention effects. The population of Southern Ontario is ethnically 
diverse. The proportion of different ethnic groups in the community is provided in the 
table below. Universal access to health care will ensure that there is no discrimination on 
the basis of race or gender (Guide to Canadian Human Rights Act: www.chrc-
ccdp.ca/public/guidechra.pdf). Individual hospital registries and databases do not 
routinely collect racial data, under the direction of the Canadian Human Rights Code. 
 
The population demographics and distribution of minorities in Southern Ontario is 
included in the following table: 
 
Table: Visible minority population by Consortium Provinces  (2001 Census)  
 
British 
Columbia 
Alberta 
Ontario 
Nova Scotia 
Total 
Total population of 
province 
3,868,870 
2,941,150 
11,285,550 
897,570 
18,993,140 
Visible Minorities 
Population % 
Population % 
Population % 
Population % 
Population % 
Black 
25,465 
1% 31,390 
1% 411,095 
4% 19,670 
2% 487,620 
3% 
Asian 
768,435 
20% 268,660 
9% 1,513,825 13% 12,630 
1% 2,563,550 13% 
Latin American (Hispanic) 23,880 
1% 18,745 
1% 106,835 
1% 520 
0% 149,980 
1% 
Visible minority, not 
included elsewhere 
4,195 
0% 4,220 
0% 78,915 
1% 1,170 
0% 88,500 
0% 
Multiple visible minority 
14,465 
0% 6,910 
0% 42,375 
0% 535 
0% 64,285 
0% 
Total Visible minority 
population 
836,440 
22% 329,925 
11% 2,153,045 19% 34,525 
4% 3,353,936 18% 
Source: Statistics Canada, Census of Population.  
 
Data (2004) from our consortium has been compiled regarding the representation of minorities 
on previous clinical trials, and the distribution is as follows: 
 
Population Percentage of Minority and Gender 
of entering PMHC Trials 
 
2002 
2003 
2004 
Visible Minorities 
 
 
 
Black 
3.6 
0 
2.8 
Asian 
7.2 
9.0 
8.4 
Hispanic 
2.4 
3.0 
1.7 
Total  
13.2 
12 
12.9 
Women 
44.6 
49.3 
46.9 
   
4. REGISTRATION PROCEDURES 
 
 
General Guidelines 
 
The Study Coordinator at the Princess Margaret Hospital Consortium Central Office will enter 
eligible patients on study centrally.  All sites should call the Study Coordinator (listed on cover 


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28 
page) to verify cohort availabilities.  The required forms (Eligibility Checklist) will be provided 
upon site activation. 
 
Following registration, patients should begin protocol treatment within 72 hours.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator (cc the central 
office study coordinator).  If a patient does not receive protocol therapy following registration, 
the patient’s registration on the study may be cancelled.  The Study Coordinator should be 
notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  A participating site may order agents only after the initial IRB 
approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
 
Registration Process 
 
Prior to registering a patient, each institution must have submitted all necessary regulatory 
documentation to the PMH Phase II Consortium Central Office.  The eligibility checklist will 
only be sent once this has been received.   
 
No patient can receive protocol treatment until registration with the Central Office has taken 
place.  All eligibility criteria must be met at the time of registration.  There will be no exceptions.  
Any questions should be addressed with the Central Office prior to registration.   
 
To register a patient, the following documents are to be completed by the research nurse or data 
manager and sent / faxed to the Central Office Study Coordinator: 
• 
Signed patient consent form 
• 
Eligibility Checklist CRF signed by the investigator  
 
To complete the registration process, central office will review the checklist and once eligibility 
has been confirmed: 
• 
Assign a patient study number 
• 
Assign the patient a dose 
• 
Register the patient on the study 
• 
Fax or e-mail the confirmation worksheet with the patient study number and dose to the 
participating site 
 
To ensure immediate attention is given to the faxed checklist, each site is advised to also call the 
study coordinator listed on the front sheet. Patient registration will be accepted between the 
hours of 9am to 5pm Monday to Friday, excluding Canadian statutory holidays when the central 
office will be closed. 
 
5. TREATMENT PLAN 
 
This is a single agent, two stage non-randomized phase II clinical trial in women with recurrent 
or metastatic endometrial cancer. Patients will be accrued in two cohorts – experimental, and 


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exploratory. The study is powered to evaluate efficacy in two histological strata (of serous and 
endometroid) of endometrial cancer as outlined in statistical plan. 
 
A second exploratory cohort of patients with unusual histology endometrial cancer (including 
clear cell, carcinosarcoma, mixed) will be accrued to a maximum of 30 patients. Response 
assessment will be by RECIST and > 4/10 objective responses in a particular histology (if 
available depending on accrual) will be considered a signal of activity in that particular subtype. 
Correlative studies are proposed to further elucidate unique features of tumour biology in these 
rare sub-types.  
 
 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 7. Appropriate dose modifications are described in Section 6. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
5.1.1 XL184 
 
XL184 will be dosed continuously (once daily) on a 28 day cycle starting at 60mg daily dose. 
Skipped/missed doses will not be made up. Patients will undergo their first response evaluation 
after 3 cycles (12 weeks) of treatment (irrespective of missed/held dose).  
 
Dose Level 
Cabozantinib/XL184 
1 
60 mg daily 
-1 
40 mg daily 
-2 
20 mg daily 
 
XL184 must be taken on an empty stomach. Patients must fast for 2 hours before and 1 hour 
following each dose of XL184.  
 
Patients will be requested to maintain a medication diary of each dose of medication. The 
medication diary will be returned to clinic staff at the end of each course. 
 
 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of XL184 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. 
 
 
 


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30 
5.2.1 Concomitant Medications and Therapies 
 
5.2.1.1 
Anticancer Therapy 
 
If a subject requires additional systemic anticancer treatment, study treatment must be 
discontinued. Local intervention is discouraged unless medically unavoidable. Subjects receiving 
local intervention (e.g., palliative radiation) are allowed to continue to receive study treatment at 
the PMHC investigator’s discretion.  
 
5.2.1.2 
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. 
 
5.2.1.3 
Potential Drug Interactions 
 
Cytochrome P450:  Preliminary data from a clinical drug interaction study (Study XL184-008) 
show that clinically relevant steady-state concentrations of cabozantinib appear to have no 
marked effect on the AUC of co-administered rosiglitazone, a CYP2C8 substrate. Therefore, 
cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not 
anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared 
to CYP2C8 (i.e., CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate 
that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for possible induction 
of CYP1A1 at high cabozantinib concentrations (30 μM).  
 
Cabozantinib is a CYP3A4 substrate (but not a CYP2C9 or CYP2D6 substrate), based on data 
from in vitro studies using CYP-isozyme specific neutralizing antibodies.  
 
Preliminary results from a clinical pharmacology study, XL184-006, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an 
approximately 80% reduction in cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers. Co-administration of cabozantinib with strong inducers of the 
CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib concentrations. The 


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chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 
should be used with caution because these drugs have the potential to decrease exposure (AUC) 
to cabozantinib (e.g., chronic use of modafinil) should be avoided because of its potential to 
reduce cabozantinib exposure. Selection of alternate concomitant medications with no or 
minimal CYP3A4 enzyme induction potential is recommended. In addition, caution must be used 
when discontinuing treatment with a strong CYP3A4 inducer in a subject who has been 
concurrently receiving a stable dose of cabozantinib, as this could significantly increase the 
exposure to cabozantinib.  
 
Preliminary results from a clinical pharmacology study, XL184-007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 33-
39% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in 
healthy volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 
family (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations. Grapefruit / grapefruit juice and Seville 
oranges may also increase plasma concentrations of cabozantinib. Strong CYP3A4 inhibitors and 
other drugs that inhibit CYP3A4 should be used with caution because these drugs have the 
potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant 
medications with no or minimal CYP3A4 enzyme inhibition potential is recommended.  
 
Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and 
CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (e.g., 
CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known. 
Therefore, these drugs should be used with caution when given with cabozantinib.  
 
Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors 
of selected CYP450 isozyme pathways (Flockhart 2007; 
http://medicine.iupui.edu/clinpharm/ddis/). 
 
Protein Binding:  Cabozantinib is highly protein bound (approximately 99.9%) to human plasma 
proteins. Therefore, highly protein bound drugs should be used with caution with cabozantinib 
because there is a potential displacement interaction that could increase free concentrations of 
cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase 
in pharmacologic effect). Factors that influence plasma protein binding may affect individual 
tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound 
(e.g., diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. 
Because warfarin is a highly protein bound drug with a low therapeutic index, administration of 
warfarin at therapeutic doses should be avoided in subjects receiving cabozantinib due to the 
potential for a protein binding displacement interaction.  
 
Drugs Associated with QTc Prolongation:  Treatment with cabozantinib has been associated with 
a mild prolongation of the QTc interval. Caution should be used when treating subjects on 
cabozantinib with other drugs associated with QTc prolongation (see www.crediblemeds.org ). 
Additional QTc monitoring is suggested for subjects who are treated concomitantly with QTc 
prolonging drugs. 


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32 
 
Other Interactions: In a relative bioavailability study in dogs, cabozantinib exposure was not 
significantly affected by drugs that alter gastric pH. 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 now allowed. (Note: 
Cimetidine should be avoided because of its potential to interfere with CYP3A4 mediated 
metabolism of cabozantinib).  
 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P glycoprotein (P-gp), but 
it does appear to have the potential to inhibit the P-gp transport activity.  
 
Additional details related to these overall conclusions are provided in the Investigators Brochure. 
 
 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue 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,  
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator, 
• 
Necessity for treatment with other anticancer treatment prohibited by the protocol, 
• 
Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the course of the study and for 
4 months following discontinuation of study treatment, 
• 
Women who become pregnant or are breast feeding, 
• 
Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol, or 
• 
Significant noncompliance with the protocol schedule in the opinion of the investigator. 
• 
The minimum dose of study treatment will be 20 mg daily. Subjects who cannot tolerate 20 
mg daily will have study treatment discontinued. 
 
 
 
 
 
 
 
 
 
 
 


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Duration of Follow Up 
 
 
 
Follow-Up Period 
 
 
 
Every 4 weeks (after 
the end of treatment 
visit), until disease 
progression*, up to 12 
weeks 
Adverse Events to be 
followed every  4 
weeks** 
 
Every 6 months until 
death*** 
Reason Patients 
removed from study: 
Disease progression 
 
X 
X 
Unacceptable 
adverse events (grade 
3 or 4 serious 
adverse event, related 
to study drug) 
 
X 
X 
 
 
X 
All other patients 
X 
X 
X 
* Can be documented clinically or radiologically.  
** Follow for AEs until all other follow-up requirements are met.  Follow patients for any ongoing or 
new grade 3 or higher toxicities thought to be related to protocol treatment until resolution. 
***Follow patients for survival every 6 months; can be completed via telephone, in person, or 
review of medical records.  Follow up is required from date of implementation (REB/IRB 
Approval at site) of this amendment. Deceased patients will require 1 follow up to document 
death.  
 
 
 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the following criteria apply: 
• 
Death 
• 
Withdrawal of Consent, 
• 
Lost to follow-up 
• 
Termination by Regulatory Authorities 
• 
Termination by the Principal Investigator 
 
Should early termination of the study be necessary, active patients should be seen as soon as 
possible for End of Treatment (EoT) visit and the assessments for EoT should be performed as 
described in table for study follow-up visit. The Investigator will be responsible for informing 
the REB and/or other Regulatory Authorities of the early termination of the trial, as well as to 
ensure that adequate consideration is given to the protection of the patient’s interests. 
 
The reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
 


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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose Level 
Cabozantinib/XL184 
 1 
60 mg daily 
-1 
40 mg daily 
-2 
20 mg daily 
 
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.  
 
Treatment may be delayed and interrupted to allow for recovery of toxicity according to the 
guidelines below. Any other elective or planned interruptions to therapy must be discussed with 
the PI if the duration is greater than 2 weeks. Patients with cabozantinib-related toxicity at lowest 
dose level requiring further  dosing modifications may continue on study, following dose 
interruption and sufficient recovery, if felt to be benefiting from treatment and upon discussion 
with PMHC PI. 
 


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Table 6-1. General Approach to the Management of Cabozantinib-Related Non-
Hematologic Adverse Events 
CTCAE Version 5.0 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 
Interrupt cabozantinib treatment or reduce the cabozantinib 
dose. Add supportive care as indicated.   
• If cabozantinib dosing is interrupted, 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: 
 
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 


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36 
CTCAE Version 5.0 Grade  Guidelines/Intervention 
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 investigator believes that it is in the interest of the subject’s safety.  
 
Table 6-2. General Approach to the Management of Cabozantinib-Related Hematologic 
Adverse Events 
 
CTCAE Version 5.0 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 of ANC 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. 


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CTCAE Version 5.0 Grade 
Intervention 
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). 
 
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). However given 
the potential of the 5-HT3 antagonist ondansetron to prolong QTc, care should be taken to not 
exceed a daily dose of 16 mg. Caution is also recommended with the use of nabilone, which is a 
weak inhibitor of CYP3A4. 
 
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 


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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. 
 
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 
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 v5.0 
 
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 


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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.  
 
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. 
 
≥ 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 with sponsor 
approval.. 


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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 at a reduced dose agreed to by 
the investigator and sponsor but only with sponsor approval.. 
 
 
 


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Skin Disorders 
 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin 
rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
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 include 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.  
 
 
 
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 
If tolerable, continue cabozantinib at current dose. If intolerable, 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. If treatment was interrupted (but not reduced), treatment may be 
restarted at the same dose or at one dose level lower when reaction 
decreases to Grade 1 or 0. If a treatment interruption is again required, the 
dose must be reduced when treatment resumes. Subjects should be 


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instructed to notify investigator immediately if severity worsens. If severity 
worsens at any time, or affects self-care, proceed to the management  
guidelines for Grade 3 PPE. 
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 
 
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. 
 
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. 
 
Hypertension 
 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has 
been observed in cabozantinib clinical studies. 
 
Subjects with known hypertension should be optimally managed prior to study entry.  Patients 
are to be provided with a BP machine for at home daily monitoring for the first 28 days of 
treatment; further daily monitoring is to be determined at the physician’s discretion.  Decisions 
to decrease or hold the dose of study treatment should be based on BP readings taken by a 
medical professional and confirmed with a second measurement at least 5 minutes following the 
first measurement. However a physician can alter the patient’s treatment if there is significant 
reasoning to due to their daily BP monitoring.  Clinical judgment should be used in deciding 


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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). 
 
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 anti-hypertension 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 anti-hypertension 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 


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Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
NOTE:  If SBP and DBP meet different criteria in table, manage per higher dose-modification 
criteria 
 
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 
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 mg/mg 
• No change in treatment or monitoring 
> 1 and < 3.5 mg/mg 
 
• No change in study treatment required if UPCR ≤ 2 mg/mg or 
urine protein ≤ 2 g/24 hours on 24-hour urine collection.  
• Consider confirming with a 24-hour protein excretion within 7 
days 
• Dose reduce or interrupt cabozantinib treatment if UPCR > 2 
mg/mg on repeat UPCR testing or urine protein > 2 g/24 hours 
on 24-hour urine collection. Continue cabozantinib on a 
reduced dose if UPCR decreases to < 2 mg/mg. Consider 
holding cabozantinib treatment if UPCR remains > 2 mg/mg 
despite a dose reduction until UPCR decreases to < 2 mg/mg. 
Restart cabozantinib treatment at a reduced dose after a dose 
hold unless otherwise approved by PMHC PI. 
• 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). If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 
month or is determined to be stable (< 20% change) for 1 
month, check urine protein/creatinine per protocol or as 
clinically indicated.  
≥ 3.5 mg/mg (≥ 395.9 
mg/mmol) 
• Hold cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-hour urine protein.  
• If ≥ 3.5 mg/mg on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 
mg/mg, restart cabozantinib treatment at a reduced dose and 


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Urine Protein/Creatinine 
Ratio 
Action To Be Taken 
monitoring of urine protein/creatinine should continue weekly until 
the UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg 
and < 2 mg/mg for 1 month or is determined to be stable (< 20% 
change) for 1 month, check urine protein/creatinine per protocol or 
as clinically indicated. 
Nephrotic syndrome 
• Discontinue all study treatment 
 
UPCR, urine protein/urine creatinine ratio 
 
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). 
• 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 
while on study treatment must be discontinued from cabozantinib treatment.  
 
Developing cavitation of pulmonary tumors may be indicative of response. Patients deemed high 
risk of bleeding based on tumour location should be discontinued. If the investigator feels patient 
is low risk, a discussion should take place with PMHC investigator. Therapy may continue at the 
discretion of the PMHC PI. 
 


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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.  
 
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: 
• 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. 
 
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 


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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.  
 
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. 
 
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 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
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. Reinitiation of study treatment must be 
discussed with and approved by the Sponsor on a case by case basis. 
 
Guidelines for Management of Treatment-Emergent Corrected QT (QTc) Prolongation 
 


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48 
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 
additional study treatment is to be given to the subject until after the event has resolved, the 
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:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting (via CTEP-AERS) in addition to routine 
reporting.  
 
 
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 


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49 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 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 
 
  


NCI Protocol #: 9322 
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50 
 
 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%) 
 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Musculoskeletal and connective 
tissue disorders - Other (muscle 
spasms) 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
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. 
 


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51 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating patients with 
relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases.  
 
7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
 
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); 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; 
Anal fissure; Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal disorders - Other (glossitis); 
Gastrointestinal disorders - Other (pneumoperitoneum); Hemorrhoids; Ileus; Pancreatitis; Rectal pain; Rectal ulcer 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Fever; Gait 
disturbance; General disorders and administration site conditions - Other (implant site inflammation); Malaise; 
Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (cholelithiasis); 
Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other (hepatitis toxic); Portal vein 
thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - Other (tendon 
injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Cardiac troponin 
I increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Blood lactate 
dehydrogenase increased; Investigations - Other (D-dimer); Eosinophilia; Glucosuria; Investigations - Other (urine 


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52 
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);Osteonecrosis; 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); 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); 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); 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. 
 
 
 
 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized for AE 
reporting beginning April 1, 2018. All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP web site https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• 
For expedited reporting purposes only:   
• AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the grade 
is above the grade provided in the SPEER. 


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53 
• Other AEs for the protocol that do not require expedited reporting are outlined in section 
7.3.4. 
 
• 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
Expedited Adverse Event Reporting 
 
7.2.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP-Adverse Event 
Reporting System), accessed via the CTEP Web site (https://ctep.cancer.gov). The 
reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
(https://ctep.cancer.gov). These requirements are briefly outlined in the tables below 
(Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.2.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician. Each site will submit the electronic version 
of the CTEP-AERS report to the PMH Phase II Consortium Central Office.  Once review 
by the lead group coordinator has taken place the report will be forwarded to NCI.  CTEP-
AERS provides a copy feature for other e-mail recipients.  
 
7.2.3 Expedited Reporting Guidelines  
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below. Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth 


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54 
or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
In order to ensure the timely fulfillment of both US and Canadian IND regulatory 
reporting requirements, all CTEP-AERS reports must be sent to the PMH Phase II 
Consortium Central Office within 3 working days from the date the event was known to 
the investigator. 
 
• 
In the unlikely event that an adverse event occurs that does not meet the reporting 
requirements for CTEP-AERS, but does meet the definition of a Serious Adverse 
Event, a CTEP-AERS report must still be completed and sent to the Central Office 
within 3 working days of the event being known to the investigator.  The event must 
be telephoned or e-mailed to Central Office within 1 working day.   
 
• 
The PMH Phase II Consortium Central Office will be responsible for reporting to 
Canadian regulatory authorities all Serious Adverse Events that are both unexpected 
and related to study drug.  The Central Office will notify all Investigators of all 
Serious Adverse Events that are reportable to regulatory authorities in Canada from 
this trial or from other clinical trials as reported to the Central Office by the NCI U.S. 
 
• Investigators must notify their local Research Ethics Boards (REB/IRBs), according 
to their guidelines, of all SAE reports from their centre and file the report in their 
regulatory study binder.   In addition, all reports sent out to centres by the PMH 
Phase II Consortium Central Office must be sent to local REB/IRBs, according to 
their guidelines.  Documentation from the REB/IRB of receipt of these reportable 
events must be kept on file in each institution's regulatory binder. 
 
 


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55 
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 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
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 CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“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 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 


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56 
 
 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported through CTEP-
AERS must also be reported in routine study data submissions. 
 
 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
• 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 
 
 
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.  
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
 
CTEP IND Agent: Cabozantinib (XL 184) 
 
8.1.1 Cabozantinib (XL184)  (NSC 761968) 
 
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  
 


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57 
Molecular Formula: C28H24FN3O5.C4H6O5  
 
M.W.: 635.6  
 
Mode of Action: XL184 inhibits multiple RTKs implicated in tumor growth (progression of tumors 
in bone), metastasis, and angiogenesis, and targets primarily MET and VEGFR2. Other targets are 
RET, AXL, KIT, TIE-2, and FLT-3.  
 
How Supplied:  XL184 is supplied by Exelixis and distributed by the DCTD. XL184 is available in 
20 mg and 60 mg tablets. 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. Each bottle contains 30 tablets. 
 
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 
 
Storage:  Store intact bottles at controlled room temperature, 200 to 250C. 
  
Stability:  “Stability testing of the intact bottles is on-going.  XL184 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.” 
 
Route of Administration: Oral. 
 
Method of Administration: Take XL184 on an empty stomach, 2 hours before and 1 hour after 
food. Do not crush or chew.  
 
Potential Drug Interactions: XL184 is a substrate of CYP3A4. Coadministration of XL184 with 
medications that are strong inhibitors/inducers of CYP3A4 should be avoided. Examples of strong 
CYP3A4 inducers are rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampentin, 
Phenobarbital, and St. John’s Wort. Strong CYP3A4 inhibitors are ketoconazole, itraconazole, 
clarithroumycin, indinavir, nefazodone, nelfinavir, and ritonavir. Use alternative medications. Avoid 
grapefruit/ grapefruit juice and Seville oranges while participating in this trial.  


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58 
 
In vitro data, XL184 is not a P-gp substrate but may inhibit the P-gp transport activity.  
 
XL184 is highly protein bound, 99.9%. Use caution when coadminister 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. 
 
Cimetidine is a moderate CYP3A4 inhibitor. Avoid using cimetidine with XL184. 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 now allowed. 
 
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. Cimetidine or omeprazole is also 
available over-the-counter (OTC). Do not use cimetidine.   
 
Availability 
XL184 (cabozantinib) is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
XL184 (cabozantinib) is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
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 


NCI Protocol #: 9322 
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59 
status and a “current” password. For questions about drug orders, transfers, returns, or 
accountability, call (240) 276-6575. Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.2.2 
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. ANCILLARY & EXPLORATORY ANALYSES 
 
Rationale for HGF/MET pathway biomarkers 
 
Oncogenic MET signaling is a consequence of various molecular mechanisms including gene 
amplification, mutation, over-expression, and autocrine activation, with the hierarchal relevance 
dictated by the tumour context. In addition, downstream HGF-MET signaling is complex and 
involves several networks that are already aberrantly regulated in human cancers including (but 
not limited to) PI3K/Akt and RAS-RAF-MEK-ERK. Therefore, molecular markers indicative of 
(1) the type of pathway aberration, (2) the mutational context of a patient’s tumour or (3) the 
activation status of downstream signaling mediators, may indicate dependence on MET pathway, 
potentially acting as biomarkers of response to cabozantinib/XL-184.  
 
Overview of correlative studies 
 
Exploratory studies in archival tumour or fresh biopsies (if possible) will evaluate baseline 
mutational profiles and met amplification status as predictive markers of cabozantinib response.   
 
Correlative studies evaluating tumour biology relevant to endometrial cancer will focus on (1) 
evaluating baseline status of MET (using standard FISH to identify MET amplification and 
sequencing to highlight activating mutations) and (2) tumour mutational profiling using a custom 
panel to assess a large panel of cancer-associated mutations.  
 
All Correlative Studies will be conducted in the Applied Molecular Profiling Laboratory at 
Princess Margaret Cancer Centre following developed SOPs for both sample acquisition and 
performing individual assays. 
 
 
Baseline Mutational Profiling of Archival Samples 
 
All enrolled patients should have archival samples available for baseline mutational profiling.  If 
archival tissue is not available, a sufficient tumour biopsy can be performed a minimum of 28 
days prior to start of treatment if clinically reasonable to do so. 
 
 
 


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60 
9.1.1 Collection of Specimen(s) 
 
Paraffin embedded archival blocks are preferred, however if blocks cannot be released 15-20 
unstained slides 4-5 microns each mounted on positively charged slides are also acceptable.  
 
Mutational profiling and c-met amplification will be performed in the archival specimens of all 
patients.   
 
9.1.2 Handling of Specimens(s) 
 
Refer to Laboratory Manual. 
 
9.1.3 Shipping of Specimen(s) 
 
All archival specimens along with copies of the de-identified Pathology Reports should be sent 
to: 
 
Correlative Studies Program 
Princess Margaret Cancer Centre 
610 University Avenue  7-420 
Toronto, Ontario M5G 2M9 
Tel: (416) 946-4501 ext 5047 
Fax: (416) 946-4431 
Email: CCRUcorrelativestudies@uhn.ca 
 
 
Peripheral Blood Collection 
 
Peripheral whole blood for SNP samples will be drawn at baseline for PK analysis.  Samples will 
be obtained by standard venipuncture using plasma EDTA (lavender) tubes and processed 
following institutional SOPs.  
 
9.2.1   Handling of Specimens(s) 
 
Refer to Laboratory Manual. 
 
 
Shipping of Specimen(s) 
 
Refer to 9.1.3. 
 
 


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61 
10. STUDY CALENDAR 
 
Baseline (pre-study) evaluations are to be conducted ≤ 7 days prior to start of protocol therapy, 
unless specified differently in the study calendar.  Scans and x-rays must be done ≤28 days prior 
to the start of therapy. In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.  
The following schedule of assessments applies to all subjects.  More frequent assessments should 
be obtained if clinically indicated.  A cycle is 28 days long.  A 14-day delay/lapse in treatment 
will result in the patient being removed from study unless specified differently; refer to section 6.  
Refer to the calendar for cycle 1 day 1 timelines.  For subsequent cycles (2+), day 1 and day 15 
assessments can be completed up to 3 days prior to day 1 or day 15 as applicable.  
 
 
Pre-Study  
C1 
C2-3 
C4+ 
 End of 
Treatment(30-
37days after last 
dose) 
+ Follow-Up10 
Survival 
Follow-Up 
(every 6 
months) 
 
 
D1 
D15 
 
D1   
D15  
D1    
Cabozantinib 5  
 
X-----------------------------------X 
 
 
Informed consent 6 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X7 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X7 
 
X 
 
X 
X 
 
Vital signs (BP, pulse, RR, temp) 9 
X 
X7 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X7 
X 
X 
X 
X 
X 
 
Clinical laboratory tests 1  
X 
X7 
X 
X 
X 
X 
X2 
 
Urinalysis and UPCR 
X 
X7 
X 
X 
X 
X 
X2 
 
PT or INR, and PTT 
X 
X7 
 
X 
 
X 
 
 
TFTs (TSH, free T3, free T4)  
X 
X7 
 
 
 
 
 
 
12-lead ECG 
X 
X7 
 
X 
 
X 
X2 
 
Pregnancy test (β-HCG)11 
X 
X7 
 
X 
 
X 
 
 
Radiological Evaluation3 
X 
Radiologic measurements are to be 
performed at the end of cycle 3 and 
subsequently every 8 weeks 
regardless of any missed doses or 
holds..3  
Must be provided 
for patients 
removed from 
study due to PD 
 
Tumor assessment 4  
X 
Tumor measurements are to be 
completed at the end of cycle 3 and 
subsequently repeated every 8 
weeks.  Documentation (radiologic) 
must be provided for patients 
removed from study for progressive 
disease. 
 
Archival / Biopsy Tumor Tissue 
X 
 
 
 
 
 
 
 
Correlative Blood 
X 
 
 
 
 
 
 
 
Concurrent medications  
X8 
X-----------------------------------X 
 
 
Adverse event evaluation 
 
X-----------------------------------------------------------X 
 
Survival Status 
 
 
X 
 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; UPCR, urine protein/urine creatinine ratio 


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62 
1 Laboratory tests should include a standard hematology panel (CBC, differential, platelets) and chemistry panel 
(albumin, alkaline phosphatase, ALT, amylase, AST, bicarbonate, blood urea nitrogen, calcium, chloride, 
creatinine, glucose, lipase, magnesium, phosphorus, potassium, sodium, total bilirubin, total protein) 
2 For “Off Study” only, not Follow-Up 
3 For patients who have been on study for two years or longer, re-staging scans to be moved to every 12 weeks, 
irrespective of any missed doses or holds. 
4 All sites of known disease must be assessed, includes radionuclide bone scans in patients with known bony disease 
5 Dose as assigned; oral administration, continuous for 28 days, at the same time once every day, on an empty 
stomach, do not eat 2 hours before and 1 hour after taking Cabozantinib 
6 Completed prior to study related tests 
7 If completed within 4 days prior to day 1 it does not need to be completed 
8 Concurrent medications recorded as of 15 days pre-registration. 
9 Blood pressure to be measured by the patient on a daily basis for the first 28days (recorded on the diary card 
appendix E); it is the physician’s discretion if further monitoring is required.  Refer to section 6 when determining 
dose modifications due to blood pressure changes. 
10 Refer to 5.4 for subsequent follow-up expectations 
11 For Women of child bearing potential 
 
 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be evaluated by cross-sectional imaging at 
baseline, at the end of cycle 3 and then every 8 weeks irrespective of missed or held doses. 
(every 3 cycles (12 weeks) for patients on study for 2 years or longer) 
 
 
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 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with XL184. 
 
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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63 
11.1.2 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 or as >10 mm 
with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  


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64 
 
11.1.3 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).  
 
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. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  
 


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65 
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. 
 
Tumor markers  Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [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. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT  scans are needed to determine if there is truly progression occurring at that site (if so, 
the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-
PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 


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66 
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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, including 
baseline. Patients will not go from PR to SD.  
 
11.1.4.2 
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 tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
 


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67 
Non-CR/Non-PD:  
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The 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. 
 


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68 
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 
 
11.1.5 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 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.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 12-week  PFS is defined as the percentage of patients progression free 12 
weeks from starting treatment. 
 
11.1.7 Overall Survival 
 
OS is defined as the duration of time from start of treatment to time of death. 
 
11.1.8 Response Review 
 
During trial tumour measurements will be assessed by a study radiologist. On study completion 
all responses will be assessed by an independent expert to confirm response. 
 


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69 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
 
Data Reporting 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application. Reports are due 
January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS 
can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html).  
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above. If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for entering their data into the Medidata Rave system and 
submitting copies of their source notes to the Central Office / Coordinating Centre within 3 
weeks of the end of cycle.  Please refer to Appendix G, Data Management Guidelines, for further 
details regarding data submission requirements. 
 
The Central Office / Coordinating Centre is responsible for compiling and submitting CDUS 
data to CTEP for all participants and for providing the data to the Principal Investigator for 
review.   
 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. 
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
 
The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission to 
their individual IRBs for action as required. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP. Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 


NCI Protocol #: 9322 
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70 
 
 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1.  Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2.  For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a.  NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b.  Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own Agent. 
 
c.  Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3.  Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 


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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 Collaborator’s 
confidential/ proprietary information. 
 
13. STATISTICAL CONSIDERATIONS 
 
 
Study Design/Endpoints 
 
Evaluation of the experimental cohorts of this trial is based on a modified Simon two-stage 
design with co-primary endpoints of response rate (RR) and 12-week progression-free survival 
(PFS). A maximum of 36 evaluable patients will be enrolled to each histological cohort to 
discriminate between tumor RR rates of 30% vs. 10% and 12-week PFS rates of 55% vs. 30% 
(corresponding to median PFS of 3.4 to 1.7 months). Each cohort will be reviewed on its 
individual results. If at least 8 responses (at least 22%), or at least 16 instances of 12-week PFS 
(at least 44%), were observed among the 36 evaluable patients, this regimen would be considered 
worthy of further testing in that particular histological subgroup of endometrial cancer.   
 
Stage I has a planned accrual of 18 patients per histological cohort. If no more than 2 objective 
responses (no more than 11%), and  no more than 6 instances of 12-week PFS (no more than 
33%) were  observed amongst the initial 18 patients accrued per histological cohort, study would 


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be terminated early and declared negative. Study will go to stage II if at least 3 objective 
responses or at least 7 instances of 12-week PFS are observed in stage I in either cohort. Each 
cohort will be reviewed on its individual results. If one cohort is negative the other cohort may 
still proceed to stage II.  
 
The design yields at least 86% power to detect a true objective response rate of at least 30%. It 
yields at least 90% power to detect a true 12-week PFS rate of at least 55% (median PFS of 3.4 
months). It yields at least 0.94 probability of a negative result if the true objective response rate 
is no more than 10% and the true 12-week PFS rate is no more than 30% (median PFS of 1.7 
months), with approximately 0.53 probability, at least, of early negative stopping in this case. 
These last two probabilities are calculated assuming that tumor response rate and PFS rate are 
uncorrelated. If they are positively correlated, as is likely, the probabilities will be a bit higher. 
 
Patients with rare histology endometrial cancer (including clear cell, carcinosarcoma) will be 
enrolled in an exploratory cohort in which > 4/10 objective responses in a particular histology 
would suggest significant activity. A maximum of 30 patients will be accrued to this exploratory 
cohort. 
 
Adverse events will be graded using CTCAE v 5.0. 
 
13.2 
Sample Size/Accrual Rate 
 
In the experimental cohort, stage I has a planned accrual of 18 patients per histological cohort. If 
> 2 PRs or > 6 instances of 12-week PFS, accrual will proceed to Stage II with a planned total 
accrual of 36 evaluable patients per histological cohort. Accrual to the exploratory cohort will 
proceed as long as patients are being accrued to experimental cohort to a maximum of 30 
patients.  
 
Estimated accrual is 2-3 pts per month and is expected to take 24 to 36 months. 
 
13.3 
Analysis of Secondary Endpoints 
 
Secondary endpoints to be evaluated include:  
• 
baseline molecular status of archival tumour (c-met amplification & mutation status)  
• 
pharmacodynamic responses in levels of soluble, circulating angiogenic factors 
• 
overall survival 
 
 
Correlating with clinical response 
 
13.4 
Reporting and Exclusions 
 
13.4.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time of their 
first treatment with XL184. 
 
13.4.2 Evaluation of response – All patients included in the study must be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they are ineligible. 


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Each patient will be assigned one of the following categories:  1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 8) 
unknown (not assessable, insufficient data). [Note:  By arbitrary convention, category 8 
usually designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate. Patients in response categories 4-7 should be considered to have a 
treatment failure (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. Precise 
definitions for categories 4-7 will be protocol specific.  
 
All conclusions should be based on all eligible patients. Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.). However, these subanalyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported. The 95% 
confidence intervals should also be provided.  
 
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Casanovas, O., et al., Drug resistance by evasion of antiangiogenic targeting of VEGF 
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Ellis, L.M. and D.J. Hicklin, Pathways mediating resistance to vascular endothelial 
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Aghajanian, C., et al., Phase II trial of bevacizumab in recurrent or persistent 
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Salvesen, H.B. and L.A. Akslen, Significance of tumour-associated macrophages, 
vascular endothelial growth factor and thrombospondin-1 expression for tumour 
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538-43. 
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Arena, S., et al., Genetic targeting of the kinase activity of the Met receptor in cancer 
cells. Proc Natl Acad Sci U S A, 2007. 104(27): p. 11412-7. 
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Stein, U., et al., MACC1, a newly identified key regulator of HGF-MET signaling, 
predicts colon cancer metastasis. Nat Med, 2009. 15(1): p. 59-67. 
43. 
Catenacci, D.V., et al., RON (MST1R) is a novel prognostic marker and therapeutic 
target for gastroesophageal adenocarcinoma. Cancer Biol Ther, 2011. 12(1): p. 9-46. 
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Murukesh, N., C. Dive, and G.C. Jayson, Biomarkers of angiogenesis and their role in 
the development of VEGF inhibitors. Br J Cancer, 2010. 102(1): p. 8-18. 
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Hanrahan, E.O., et al., Baseline vascular endothelial growth factor concentration as a 
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Cancer Res, 2009. 15(10): p. 3600-9. 
46. 
Nikolinakos, P.G., et al., Plasma cytokine and angiogenic factor profiling identifies 
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Bullock, A., et al., Plasma angiopoietin-2 (ANG2) as an angiogenic biomarker in renal 
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48. 
DePrimo, S., et al., Correlative tumor molecular profiling and plasma biomarker analysis 
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49. 
Hanrahan, E.O., et al., Distinct patterns of cytokine and angiogenic factor modulation 
and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-
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50. 
Venneri, M.A., et al., Identification of proangiogenic TIE2-expressing monocytes (TEMs) 
in human peripheral blood and cancer. Blood, 2007. 109(12): p. 5276-85. 
51. 
Coffelt, S.B., et al., Angiopoietin-2 regulates gene expression in TIE2-expressing 
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70(13): p. 5270-80. 
52. 
Hristov, M., et al., An optimized flow cytometry protocol for analysis of angiogenic 
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53. 
Hedley, D.W., S. Chow, and T.V. Shankey, Cytometry of intracellular signaling: from 
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54. 
Conrotto, P., et al., Sema4D induces angiogenesis through Met recruitment by Plexin B1. 
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55. 
Torti, D., et al., A preclinical algorithm of soluble surrogate biomarkers that correlate 
with therapeutic inhibition of the MET oncogene in gastric tumors. Int J Cancer, 2011. 
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56. 
Kurzrock, R., et al., Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, 
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57. 
Agulnik, M., et al., Predictive and pharmacodynamic biomarker studies in tumor and 
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the head and neck treated with erlotinib. J Clin Oncol, 2007. 25(16): p. 2184-90. 
 
 


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77 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• 
The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO). The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments. The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair. There 
will be only one version of the protocol, and each participating institution will use that 
document. The Protocol Chair is responsible for assuring that all participating institutions 
are using the correct version of the protocol. 
• 
The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress. All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• 
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• 
The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
• 
Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• 
 Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• 
The Coordinating Center is responsible for central patient registration. The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating 
site prior to the first patient registration from that site. 
• 
The Coordinating Center is responsible for the preparation of all submitted data for review 
by the Protocol Chair. 
• 
The Coordinating Center will maintain documentation of AE reports. There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the Coordinating 
Center who in turn report to CTEP. The Coordinating Center will submit AE reports to the 
Protocol Chair for timely review. 
• 
Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating Center 
for audit, or (2) selected patient records may be audited on-site at participating sites. If the 
NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval 
documents, NCI Drug Accountability Record forms, patient registration lists, response 
assessments scans, x-rays, etc. available for the audit. 


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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required. The procedures for registration must be stated in 
the protocol. 
 Data collection forms should be of a common format. Sample forms should be submitted 
with the protocol. The frequency and timing of data submission forms to the Coordinating 
Center should be stated. 
 Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
investigational agents directly from CTEP. Investigational agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded by the 
Coordinating Center to the CTEP PIO. 
 
 


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APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent XL184 (cabozantinib). This clinical trial is sponsored by the National 
Cancer Institute. This form is addressed to the patient, but includes important information for 
others who care for this patient.  
 
XL184 interacts with many drugs that are processed by your liver. Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study. It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study. When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet. These are 
the things that you and they need to know:  
 
XL184 interacts with (a) certain specific enzyme(s) in your liver.  
• The enzyme(s) in question is CYP3A4. This enzyme breaks down XL184, gradually 
reducing the level of the active drug in your system.   
• Other medicines may affect the activity of the enzyme. XL184 must be used very carefully 
with these medicines, or you may need to switch to alternate medications. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors of CYP3A4.” 
• Your prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/ or 
consult a medical reference to see if any medicine they want to prescribe is on a list of 
drugs to avoid.  
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list. Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.  
•   Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age. 


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81 
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking XL184 (cabozantinib). 
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XL184 (cabozantinib) interacts with a specific liver enzyme called 
CYP3A4, and must be used very carefully with other medicines that 
interact with this enzyme.  
Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers or inhibitors of CYP3A4.” 
Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/ for a list of drugs 
to avoid, or contact your study doctor.  
Your study doctor’s name is ______________ and can be 
contacted at ______________.  
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent XL184 
(cabozantinib). This clinical trial is sponsored by the NCI. XL184 
(cabozantinib) interacts with drugs that are processed by your liver. 
Because of this, it is very important to: 
Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 


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82 
APPENDIX D 
DATA MANAGEMENT GUIDELINES 
 
Case Report Form Submission Schedule 
 
Data required for the study will be collected in Case Report Forms provided by the PMH Phase 2 
Consortium Central Office.  The site will be required to complete a paper Eligibility Checklist 
case report form (CRF) at the time of patient registration.  All other data will be collected on 
electronic case report forms (eCRFs) in the Medidata Rave system.  Site staff access to Medidata 
Rave will be initiated at the time of site activation.  The form submission schedule is outlined 
below. 
 
Case Report Form 
Submission Schedule 
Eligibility Checklist 
At the time of registration 
Baseline eCRFs 
Within 3 weeks of on study date 
On Treatment (Cycle) eCRFs 
Within 3 weeks of the end of each cycle of treatment 
Off Treatment eCRFs 
Within 3 weeks of the patient coming off-study 
Short Follow-up eCRFs 
Within 3 weeks of the patient coming to clinic.   
Final eCRFs 
Within 3 weeks from the follow-up period being complete or of 
the patient's death being known to the investigator unless this 
constitutes a reportable adverse event when it should be reported 
according to CTEP-AERS guidelines 
 
Case Report Form Completion 
 
The paper Eligibility Checklist CRF must be completed using black ink.  Any errors must be 
crossed out so that the original entry is still visible, the correction clearly indicated and then 
initialed and dated by the individual making the correction. 
 
eCRFs will be completed according to the schedule noted above and all relevant supporting 
documentation such as scans, progress notes, nursing notes, blood work, pathology reports, etc., 
will be submitted to the PMHC Phase 2 Consortium Central Office for review.  All patient 
names or other identifying information will be removed prior to being sent to the Central Office 
and the documents labeled with patient initials, study number and the protocol number.   
 
eCRF completion guidelines are available for all sites. 
 
Monitoring 
 
Central data monitoring will take place throughout the trial at the Central Office.  On-site 
monitoring will be performed once a year at participating sites during which a subset of PMHC 
studies will be picked for on-site monitoring.  
 


NCI Protocol #: 9322 
Version Date: 09Feb2018 
 
83 
Data in the Medidata Rave eCRFs will be monitored on a regular basis and quality assurance 
measures will be performed.  Electronic data queries as well as paper query letters may be issued 
to the site prior to the quarterly submission of data to CDUS. 
 
Patient Registration 
 
• Refer to section 4 of the protocol 
 
Data Safety 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study to see if there are unexpected or more serious side 
effects than described in the consent. 
 
Regulatory Requirements 
 
 
• Please submit all required documents to the PMH Phase 2 Consortium Central Office. 
• Canadian Principal Investigators must submit a completed Qualified Investigator 
Undertaking. 
• All investigators must have a current NCI investigator number on file with the PMH Phase 2 
Consortium Central Office. 
• All investigators must have an up-to-date CV (signed within 2 years) on file with the PMH 
Phase 2 Consortium Central Office. 
• Laboratory certification/accreditation and normal ranges are required 
• Confirmation of all investigators having undergone training in the Protection of Human 
Research Subjects is required.  It is preferred that other staff involved in the trial also 
undergoes such training. 
• Investigators and site staff are required to complete Medidata eCRF training modules 
depending on delegated tasks  
• OPRR assurance numbers for each institution are required 
• Consent forms must be reviewed by the Central Office before submission to the local ethics 
regulatory board (REB/IRB) and must include a statement that 1) information will be sent to 
and 2) medical records will be reviewed by the PMH Phase 2 Consortium Central Office. 
• A Membership list of the local ethics board is required. 
• A copy of the initial approval letter from the ethics board must be submitted to the PMH 
Phase 2 Consortium Central Office. 
• A completed Site Participant List/Training Log is required and must be submitted to PMHC 
• Continuing approval will be obtained at least yearly until follow-up on patients is completed 


NCI Protocol #: 9322 
Version Date: 09Feb2018 
 
84 
APPENDIX E 
PATIENT’S STUDY DRUG DIARY 
XL184 (Cabozantinib) 
Today’s Date _____________Patient Initials_____________ Patient Study ID _____________ 
INSTRUCTIONS  
1. 
Complete one form for each cycle of treatment. 
2. 
You will take ____ 20 mg and ___ 60 mg XL184 tablet(s) each day (____ mg total dose), once a day, 
continuously over a 28 day period. You must fast 2 hours before and 1 hour following each dose of XL184. 
3. 
Swallow each tablet whole.  Do not crush or chew the tablets. 
4. 
Record the date and time you took the tablet.   
5. 
If you have any comments or notice any side effects, please record them in the Comments column.   
6. 
Please bring this form and your bottle of XL184 at the end of each cycle. 
7. 
In case of errors, please place a single slash mark through the error and initial it.  Please do not white out any 
error or scribble it out with ink.  Please do not write the correct information directly over the error, but on a 
separate line next to the error. 
Day 
Date 
Time of 
Dose 
XL184 Dose 
(mg) 
Blood Pressure 
Comments 
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Physician’s Office will complete this section: 
1.  Start date for this cycle  
   End date for this cycle   
   
2.  Date patient was removed from study 
 
 
 
3.  Total number of tablets taken this cycle  
 
 
 
 
The above information has been reviewed with the patient: Physician/Nurse Signature/Date ________________  
CTEP-assigned Protocol # 9322 
Local Protocol # PHL-086