Conditions: Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer AJCC v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
This phase II trial studies how well cabozantinib-s-malate and erlotinib hydrochloride works in treating patients with previously treated metastatic non-small cell lung cancer. Cabozantinib-s-malate and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Giving cabozantinib-s-malate together with erlotinib hydrochloride may be an effective treatment for non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate for efficacy by response rate (RR) when patients with advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation who have progressed following EGFR tyrosine kinase inhibitor (TKI) therapy are treated with XL184 (cabozantinib \[cabozantinib-s-malate\]) and erlotinib (erlotinib hydrochloride).

SECONDARY OBJECTIVES:

I. Determine progression free survival (PFS) for combination XL184 (cabozantinib) and erlotinib in EGFR mutation positive patients following progression on erlotinib.

II. Assess overall survival. III. Evaluate change in tumor growth rate on XL184 (cabozantinib) and erlotinib.

IV. Evaluate type, severity, duration and outcome of toxicities. V. Correlate outcome with tumor biomarkers such as met proto-oncogene (MET) amplification, T790M mutation, and serum markers of the vascular endothelial growth factor (VEGF) and MET pathways in a preliminary manner.

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) daily and erlotinib hydrochloride 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 12 weeks for 1 year and then annually thereafter.

Arms:
arm 1: Patients receive cabozantinib-s-malate PO daily and erlotinib hydrochloride 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: Erlotinib Hydrochloride intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #: 9303 
Consortium Protocol # PhII-125 
Version Date: January 24, 2014 
 
i 
 
SUMMARY OF CHANGES 
 
Date: 
 
January 24, 2014 
Document: 
NCI Protocol #9303, PhII-125: “Phase II Trial of XL184 (Cabozantinib) 
Plus Erlotinib in Patients with Advanced EGFR-Mutant Non-Small Cell 
Lung Cancer (NSCLC) who have Progressed on Epidermal Growth Factor 
Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy.” 
Note: 
The following is a Summary of Changes between the 11.5.13 and 1.24.14 
versions of protocol 
# 
Section 
Comments 
1. 
Face page 
and 
Protocol 
Version 
Changed protocol version to January 24, 2014.  Dates in the headers were also 
changed to 1.24.14v. 
2. 
Table of 
Contents 
Updated page numbers in the Table of Contents. 
3. 
7 
References to the “Adverse Event Expedited Reporting System (AdEERS)” have 
been changed to “CTEP Adverse Event Reporting System (CTEP-AERS)” 
throughout the protocol. 
4. 
7.1 
Per the Request for Rapid Amendment distributed on 1/7/14, inserted revised 
CAEPR (Version 2.1, August 26, 2013) for XL184: 
 
• Added New Risk:   
• Also Reported on XL184 Trials But With the Relationship to XL184 
Still Undetermined:  Alkaline phosphatase increased; Allergic rhinitis; 
Ataxia; Blurred vision; CPK increased; Cataract; Cheilitis; Colitis; 
Disseminated intravascular coagulation; Edema face; Endocrine 
disorders - Other (autoimmune thyroiditis); Endocrine disorders - Other 
(thyroiditis); Esophageal ulcer; Eye disorders - Other (corneal 
epithelium defect); Febrile neutropenia; Gastrointestinal disorders - 
Other (glossitis); Gastrointestinal disorders - Other 
(pneumoperitoneum); GGT increased; Gastric ulcer; General disorders 
and administration site conditions - Other (implant site inflammation); 
Hematuria; Hemolytic uremic syndrome; Hepatobiliary disorders - 
Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic 
cirrhosis); Hyperthyroidism; Hypoalbuminemia; Injury, poisoning and 
procedural complications - Other (post procedural hemorrhage); Injury, 
poisoning and procedural complications - Other (tendon injury); 
Investigations - Other (eosinophil count increased); Investigations - 
Other (glucose urine present);  Investigations – Other (urine ketone 


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# 
Section 
Comments 
body present); Left ventricular systolic dysfunction; Lymphocyte count 
decreased; Malaise; Metabolism and nutrition disorders - Other 
(hypoproteinemia); Musculoskeletal and connective tissue disorder - 
Other (muscle hemorrhage); Musculoskeletal and connective tissue 
disorder - Other (rhabdomyolysis); Neck pain; Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (lip and/or 
oral cavity cancer); Nervous system disorders - Other (hemiparesis); 
Osteoporosis; Pleural effusion; Portal vein thrombosis; Psychiatric 
disorders - Other (mental status changes); Rectal pain; Renal and 
urinary disorders - Other (hemorrhage urinary tract); Respiratory, 
thoracic and mediastinal disorders - Other (rales); Skin ulceration; 
Stroke; Urinary tract obstruction; Vascular disorders - Other (bleeding 
varicose vein); Wrist fracture 
 
• Increase in Risk Attribution: 
• Changed to Likely from Less Likely:  Aspartate aminotransferase 
increased; Dysgeusia; Hypertension; Voice alteration; Vomiting; 
Weight loss 
• Changed to Less Likely from Rare But Serious:  Thromboembolic event 
• Changed to Less Likely from Reported But Undetermined:  Anemia; 
Arthralgia; Back pain; Cough; Edema limbs; Hypokalemia; Insomnia; 
Musculoskeletal and connective tissues disorder – Other (muscle 
spasms)      
 
 
 
 
• Decrease in Risk Attribution:   
• Changed to Reported But Undetermined from Less Likely:  
Investigations - Other (blood lactate dehydrogenase increased); 
Neutrophil count decreased; Proteinuria; Serum amylase increased; 
White blood cell decreased 
 
• Provided Further Clarification: 
• Investigations – other (pancytopenia) is now reported as Blood and 
lymphatic system disorders - Other (pancytopenia) 
 
• Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) 
reporting requirements:   
• Added:  Abdominal pain; Dry mouth; Dry skin; Dyspepsia; 
Hypothyroidism; Lipase increased; Oral pain; Platelet count decreased; 
Rash maculo-papular; Skin and subcutaneous tissue disorders - Other 


NCI Protocol #: 9303 
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Version Date: January 24, 2014 
 
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# 
Section 
Comments 
(hair color changes) 
 
• Deleted Risk:  
• 
Deleted from Reported But Undetermined: Atrial flutter; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(glossodynia); Investigations - Other (electrocardiogram ST segment 
depression); Presyncope; Renal and urinary disorders - Other (Nephrotic 
syndrome) 
 
 


NCI Protocol #: 9303 
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Version Date: January 24, 2014 
 
1 
 
NCI Protocol #: 
9303 
 
Local Protocol #: 
PhII-125 
 
TITLE:   
Phase II Trial of XL184 (Cabozantinib) Plus Erlotinib in Patients with 
Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) who 
have Progressed on Epidermal Growth Factor Receptor (EGFR) Tyrosine 
Kinase Inhibitor (TKI) Therapy  
 
Coordinating Center: 
California Cancer Consortium Data Coordinating Center 
 
City of Hope National Medical Center 
 
1500 E. Duarte Road, Duarte, California 91010 
 
Phone:  626-256-HOPE(4673), extension 65928 
 
Fax:      626-256-8654 
 
 
 
 
 
 
 
 
Email:  cccp@coh.org  
 
*Principal Investigator: 
Karen Reckamp, MD 
 
City of Hope 
 
1500 E. Duarte Road. 
 
Duarte, CA 91010 
 
Telephone: 626-256-4673 
 
Fax: 626-930-5461 
 
Email:  kreckamp@coh.org  
 
Co-Investigators: 
Barbara Gitlitz, MD 
 
USC/Norris Comprehensive Cancer Center  
 
1441 Eastlake Avenue 
 
Los Angeles, CA 90033-0804 
 
Phone: 323-865-3959 
 
Fax: (323) 865-0061 
 
Email: gitlitz@usc.edu  
 
 
David R. Gandara, MD 
University of California Davis Cancer 
4501 X Street, Sacramento CA 95817 
Telephone:  916-734-3771 
Fax:  916-734-7946 
 
Email: david.gandara@ucdmc.ucdavis.edu  
 
 
Mark A. Socinski, MD 
 
UPMC Cancer Pavilion 
 
5150 Centre Avenue, Fifth Floor 
 
Pittsburgh, PA  15232 
 
Telephone: 412-623-4083 
 
E-mail: socinskima@upmc.edu    


NCI Protocol #: 9303 
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Version Date: January 24, 2014 
 
2 
 
 
Chandra P. Belani, MD 
 
Penn State Hershey Cancer Institute 
 
500 University Drive, H072 
 
Hershey, PA  17033 
 
Telephone: 717-531-1078 
 
Fax: 717-531-0002 
 
Email: cbelani@psu.edu  
 
 
Suresh Gadgeel, MD 
 
Karmanos Cancer Institute/Wayne State University 
 
4100 John R, 4HWCRC 
 
Detroit, MI 48201  
 
Telephone : 313-576-8753 
 
Fax :  313-576-8699 
 
Email : gadgeels@karmanos.org  
 
City of Hope affiliates: 
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: skhoehler@cohmg.com   
 
Statistician: 
Paul Frankel, Ph.D. 
City of Hope National Medical Center 
1500 E. Duarte Rd, Duarte, CA 91010-3000 
Phone: 626-359-8111 x65265 
Fax: 626-471-7106 
E-mail: pfrankel@coh.org 
 
Participating Centers: 
City of Hope National Medical Center, Duarte CA (COH) 
 
 
and affiliates 
 
USC/Norris Comprehensive Cancer Center, Los Angeles (USC) 
 
University of California, Davis Cancer Center, Sacramento (UCD) 
 
 
and affiliates 
 
University of Pittsburgh, Pittsburgh, PA (UOP) 
 
Hershey Penn State Institute (PSU) 
 
Karmanos / Wayne State University (WSU) 
 
 
 
 


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3 
 
NCI Supplied Agent(s):  
 XL184 (cabozantinib) (NSC 761968; IND 116059) 
 
Erlotinib (NSC 718781; IND # 63383) 
 
IND Sponsor:   
National Cancer Institute   
 
Protocol Type / Version # / Version Date: October 22, 2012 – Original Protocol 
 
 
 
January 3, 2013 – Consensus Review 
 
 
 
February 25, 2013 – Follow Up Review 
 
 
 
June 17, 2013 – Amendment 
 
 
 
October 15, 2013 – Amendment (disapproved) 
 
 
 
November 5, 2013 - Amendment 
 
 
 
 
January 24, 2014 _ Request for Rapid Amendment 
 
 


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4 
SCHEMA 
 
 
 
 
This is a phase II trial to evaluate XL184 (cabozantinib) plus erlotinib in patients with advanced 
NSCLC harboring an EGFR mutation who have progressed following EGFR TKI therapy. 
Patients may have received prior chemotherapy, and must have progression on erlotinib 
(retreatment with erlotinib is allowed). Patients will receive cabozantinib at 40 mg p.o. daily plus 
erlotinib at 150 mg p.o. daily.  All subjects will be monitored for clinical and biological 
responses and toxicity.  The cycle length is 28 days.  The duration of treatment will continue 
until subjects develop progressive disease or unacceptable toxicity. The primary endpoint is to 
determine the response rate of XL184 (cabozantinib) and erlotinib in patients with an EGFR 
mutation who have progressed on erlotinib. 
 
Archival tissue specimens and serial blood draws will be prospectively collected from all 
patients. Patients who have an additional biopsy following initial EGFR TKI therapy or after 
progression on study will have archival tissue collected to identify factors contributing to EGFR 
resistance (i.e., EGFR T790M mutations, MET amplification). Analysis of ligands, growth 
factors and soluble receptors will be conducted in serial blood draws from all consenting 
patients, with an emphasis on baseline levels and changes in VEGF and HGF levels, as well as 
other ligands that may mediate resistance. 
XL184 
(cabozantinib) + 
erlotinib 
EGFR mutation 
positive NSCLC  
• Following 
progression on 
EGFR TKI 
therapy 
  
• Tumor tissue 
available 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objective ....................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
EGFR Mutation-Positive NSCLC............................................................................7 
2.2 
XL184 (Cabozantinib) .............................................................................................8 
2.3 
Erlotinib (OSI-774) ................................................................................................16 
2.4 
Rationale ................................................................................................................19 
2.5 
Correlative Studies Background ............................................................................19 
3. 
PATIENT SELECTION ....................................................................................................19 
3.1 
Eligibility Criteria ..................................................................................................19 
3.2 
Exclusion Criteria ..................................................................................................21 
3.3 
Inclusion of Women and Minorities ......................................................................25 
4. 
REGISTRATION PROCEDURES ...................................................................................26 
4.1 
General Guidelines .................................................................................................26 
4.2 
Registration Process ...............................................................................................26 
5. 
TREATMENT PLAN ........................................................................................................27 
5.1 
Agent Administration .............................................................................................27 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................30 
5.3 
Duration of Therapy ...............................................................................................33 
5.4 
Duration of Follow Up ...........................................................................................34 
5.5 
Criteria for Removal from Study ...........................................................................34 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................34 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................51 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............51 
7.2 
Adverse Event Characteristics ...............................................................................60 
7.3 
Expedited Adverse Event Reporting ......................................................................61 
7.4 
Routine Adverse Event Reporting .........................................................................63 
7.5 
Secondary Malignancy ...........................................................................................63 
7.6 
Second Malignancy ................................................................................................63 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................63 
8.1 
CTEP IND Agent(s) ...............................................................................................64 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................69 


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9.1 
Biomarker Studies ..................................................................................................69 
10. 
STUDY CALENDAR .......................................................................................................72 
11. 
MEASUREMENT OF EFFECT........................................................................................75 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................75 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................81 
12.1 
Data Reporting .......................................................................................................81 
12.2 
CTEP Multicenter Guidelines ................................................................................82 
12.3 
Collaborative Agreements Language .....................................................................82 
13. 
STATISTICAL CONSIDERATIONS...............................................................................84 
13.1 
Study Design/Endpoints.........................................................................................84 
13.2 
Sample Size/Accrual Rate ......................................................................................84 
13.3 
Analysis of Secondary Endpoints ..........................................................................84 
13.4 
For phase 2 protocols only: Reporting and Exclusions .........................................85 
14. 
CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS .................................86 
15. REFERENCES ........................................................................................................................88 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................90 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ....................................................91 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................93 
APPENDIX D 
PATIENT’S MEDICATION DIARY .......................................................96 
APPENDIX E 
 CCCP Registration Procedures for Phase II Trials ...................................97 
APPENDIX F 
CCCP Specimen Submission Form ...........................................................98 
APPENDIX G 
Correlative Studies .....................................................................................99 
APPENDIX H 
Guidelines for Tissue Biopsies ................................................................101 
 
 
 


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7 
1. OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate for efficacy by response rate (RR) when patients with advanced  non-small cell lung 
cancer (NSCLC) harboring an EGFR mutation who have progressed following EGFR TKI 
therapy are treated with XL184 (cabozantinib) and erlotinib. 
 
1.2 
Secondary Objectives 
 
1.2.1 Determine PFS for combination XL184 (cabozantinib) and erlotinib in EGFR 
mutation positive patients following progression on erlotinib.  
1.2.2 Assess overall survival. 
1.2.3 Evaluate change in tumor growth rate on XL184 (cabozantinib) and erlotinib. 
1.2.4 Evaluate type, severity, duration and outcome of toxicities. 
1.2.5 Correlate outcome with tumor biomarkers such as MET amplification, T790M 
mutation, and serum markers of the VEGF and MET pathways in a preliminary 
manner.  
 
2. BACKGROUND 
 
2.1 
EGFR Mutation-Positive NSCLC 
The search for improved therapies in NSCLC has led to the investigation of agents that target 
novel pathways involved in tumor proliferation, invasion, and survival. EGFR signaling activates 
a pathway that promotes tumor proliferation, migration, stromal invasion, neovascularization, 
and resistance to apoptosis (Shawver, Slamon et al. 2002).  A subgroup of patients with NSCLC 
that have specific mutations in the EGFR gene that correlate with clinical responsiveness to 
tyrosine kinase inhibitor therapy (Lynch, Bell et al. 2004; Paez, Janne et al. 2004). These 
mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor, and 
improved progression-free survival (PFS) when used as first-line therapy in advanced NSCLC 
(Mok, Wu et al. 2009; Mitsudomi, Morita et al. 2010). Research evaluating which NSCLC 
patients respond to these agents reveals that the majority of responders have activating mutations 
in the EGFR gene, approximately 90% of which are deletions in exon 19 or L858R point 
mutations in exon 21.  
 
However, not all NSCLC patients with EGFR mutations respond to EGFR-targeted therapy, and 
for those who initially respond to therapy, secondary resistance eventually develops. A specific 
EGFR mutation, T790M in exon 20, which generally develops after drug treatment is found in  
approximately 50% of patients with acquired erlotinib resistance (Pao, Miller et al. 2005). It 
remains unclear whether T790M is the cause of clinical resistance in this entire population. More 
recently, germline and de novo T790M mutations have been described, with decreased 
responsiveness to EGFR TKI therapy (Bell, Gore et al. 2005; Tibaldi, Giovannetti et al. 2011; 
Su, Chen et al. 2012). This data adds evidence that MET and other mechanisms are highly 
involved in EGFR TKI resistance.  Focal amplification of the MET proto-oncogene promotes 
acquired EGFR TKI resistance in approximately 20% of cases (Bean, Brennan et al. 2007; 


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Engelman, Zejnullahu et al. 2007; Turke, Zejnullahu et al. 2010). In addition, overexpression of 
MET by immunohistochemistry may identify a larger group of patients that could respond to 
MET inhibition.  Other mechanisms of resistance in patients with activating EGFR mutations are 
still unknown.  Optimal therapy following progression on EGFR TKI therapy for patients with 
activating EGFR mutations after standard chemotherapy is not established (Miller, Hirsch et al. 
2010), although it has been demonstrated that sensitivity to EGFR inhibition can be regained 
(Sequist, Waltman et al. 2011).  For patients who are not on clinical trial,  erlotinib or gefitinib 
can be re-introduced, but limited data exists on its efficacy in this refractory population of 
patients (Becker, Crombag et al. 2011). 
 
2.2 
XL184 (Cabozantinib)  
 
XL184 (cabozantinib) inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor 
growth, metastasis, and angiogenesis (Investigator’s Brochure, 2011).  The primary targets of 
XL184 (cabozantinib) are MET and vascular endothelial growth factor receptor 2 (VEGFR2); 
additional targets include RET, AXL, KIT, and TIE-2.  Both MET and VEGFR2 are important 
mediators of tumor growth and tumor angiogenesis, and  in vivo pharmacodynamic activity of 
XL184 (cabozantinib) against MET and VEGFR2 has been demonstrated in both preclinical and 
clinical studies.  
 
RTKs regulate many processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair (Christensen, Burrows et al. 2005).  Dysregulation of RTKs 
by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and 
ligand have been implicated as causative factors in the development and progression of 
numerous human cancers. 
 
The RTK MET, encodes the high-affinity receptor for hepatocyte growth factor (HGF) or scatter 
factor (SF) (Christensen, Burrows et al. 2005).  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).  MET-
driven metastasis may be exacerbated by a number of factors, including tumor hypoxia caused 
by selective inhibition of the VEGF pathway. 
 
Evidence linking MET and HGF as causative or progression factors in human cancers include:  
(1) the overexpression of both receptor and ligand in neoplasms relative to surrounding tissues; 
(2) the correlation of receptor and ligand overexpression with disease severity and outcome; (3) 
genetic alteration of MET by mutation of gene amplification in multiple cancer types; (4) 
introduction of MET and HGF (or mutant MET) into cell lines, conferred the properties of 
tumorigenicity and metastatic propensity on engineered cells; (5) introduction of MET or HGF 
as transgenes into the germline of mice resulted in primary and secondary neoplasms; and (6) the 
inhibition of MET or HGF function with dominant-negative receptors, antibody antagonists 


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9 
(both Met and HGF), and biologic antagonists (e.g., NK4) have reversed cancer-associated 
phenotypes such as motility, invasion and proliferation of tumor cells, and tumor growth and 
dissemination in vivo (Christensen, Burrows et al. 2005). 
 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, demonstrate 
dysregulated MET activity (Liu, Newton et al. 2010), either by means of MET kinase 
overexpression (Comoglio, Giordano et al. 2008), activating MET gene mutations and/or 
amplification (Jeffers, Schmidt et al. 1997; Schmidt, Duh et al. 1997; Comoglio, Giordano et al. 
2008), or increased autocrine and/or paracrine secretion of the MET ligand, HGF/SF 
(Birchmeier, Birchmeier et al. 2003; Boccaccio and Comoglio 2006; Comoglio, Giordano et al. 
2008).  These alterations have been implicated in tumor progression and metastasis, and a high 
constitutive activation of MET has been correlated with poor clinical prognosis (Birchmeier, 
Birchmeier et al. 2003). 
 
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, 
proliferation, survival, and enhanced vascular permeability (Roskoski 2008).  Increased 
expression of VEGFR2, often in combination with VEGFR3, has been observed in the tumor 
vascular endothelium in most common human solid tumor types, on tumor cells in melanoma 
and hematological malignancies, and in colitis-associated colon cancer (Tugues, Koch et al. 
2011).  High VEGFR2 expression is an unfavorable prognostic biomarker in hepatocellular 
carcinoma (HCC), and correlated with triple-negative (i.e., therapy-resistant) breast cancer and 
poor survival. 
 
Nonclinical Development of XL184 (cabozantinib)   
 
In Vivo Activity 
Inhibition of the 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, Allen et al. 2009).  In RIP-Tag2 
transgenic mice, tumors treated with XL184 (cabozantinib) were smaller (P <0.05) than in mice 
treated with vehicle or an anti-VEGF antibody, but were also less invasive (P <0.05) and had no 
liver metastases (Sennino, Naylor et al. 2009).  All mice treated with XL184 (cabozantinib) (n = 
6) survived until 20 weeks, but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) 
reached that endpoint.  Tumor vascularity decreased after treatment, with reductions ranging 
from 67% at 3 mg/kg to 83% at 30 mg/kg for 7 days (You, Sennino et al. 2011).  Tumors were 
35% smaller after XL184 (cabozantinib) treatment than corresponding values for vehicle control 
mice.  MET protein expression in tumors was slightly decreased, but phosphorylated MET was 
markedly reduced after treatment for 7 days.   
 
Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered four oral 
doses of 100 mg/kg (Yakes, Chen et al. 2011).  XL184 (cabozantinib) increased tumor hypoxia 
(13-fold) and apoptosis (TUNEL; 2.5-fold) at 8 and 4 hours after the first and second doses, 
respectively, when compared to vehicle-treated tumors.  In addition, XL184 (cabozantinib) 
disrupted tumor vasculature by inducing endothelial cell death that negatively affected tumor 
viability.  XL184 (cabozantinib) treatment resulted in significant tumor growth inhibition of 


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10 
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 
(cabozantinib) inhibited tumor growth (P <0.001) in the MET-expressing rat C6 glioma cell line 
for all doses (1, 3, 10, 30, or 60 mg/kg) when compared with vehicle-treated tumors.  The 3 
mg/kg and 10 mg/kg doses resulted in significant tumor regression (62% and 85%, P <0.0001) 
when compared with predose tumor weights.  Subchronic administration of XL184 
(cabozantinib) was well tolerated in mice and rats with no signs of toxicity, as determined by 
stable and/or increasing body weights during the treatment period. 
 
ARCaP-M is a human prostate cancer model which expresses both MET and VEGF co-receptor 
NP-1 used in a human prostate tumor xenograft study in mouse bone (Zhang, Zhau 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 (cabozantinib) or vehicle daily (qd) 
for 7 weeks of treatment (Investigator’s brochure, 2011).  Tibiae from vehicle-treated animals 
exhibited both osteoblastic and osteolytic lesions, whereas tibiae from XL184 (cabozantinib) 
treated animals appeared mostly normal.  Thus, XL184 (cabozantinib) treatment blocked both 
osteoblastic and osteolytic progression of ARCaP-M xenograft tumors in bone. 
 
Nonclinical Pharmacodynamics 
In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at well 
tolerated doses of XL184 (cabozantinib) and at plasma exposures comparable to exposure 
observed in clinical trials (Investigator’s Brochure, 2010).  XL184 (cabozantinib) produced 
prolonged inhibition of receptor phosphorylation, such as sustained inhibition of MET and 
VEGFR2 for 10 hours after administration of a single dose of XL184 (cabozantinib).  This 
extended inhibition occurred in a manner that was generally predicted by plasma exposure, i.e., 
inhibition was diminished when plasma levels fell below approximately 20 μM for MET, 5 μM 
for VEGFR2, and 23 μM for TIE-2. 
 
Once daily administration of XL184 (cabozantinib) resulted in significant inhibition of MET 
phosphorylation in TT tumors, relative to tumors from vehicle control-treated mice, with 
maximal inhibition of 70% seen at 60 mg/kg (Investigator’s Brochure, 2010).  Dose-dependent 
inhibition of phosphorylation of MET and RET was observed among the 3, 10, and 30 mg/kg 
dose groups as well.   
 
MET phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184 (cabozantinib), 
2–8 hours post dose in H441 tumors (human lung papillary adenocarcinoma) that harbor 
constitutively phosphorylated MET (Yakes, Chen et al. 2011).  This effect was reversible, as 
MET phosphorylation returned to basal levels by 48 hours after treatment.   
 
Nonclinical Pharmacokinetics 
In the various xenograft models, plasma exposures were similar and plasma concentrations in the 
range of 3 to 27 μM were associated with efficacy (Investigator’s Brochure, 2010).  In rats, 


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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 
(cabozantinib) dosed as a solid was approximately 100% of XL184 (cabozantinib) dosed as a 
liquid.  In comparison, oral bioavailability was much lower in dogs (20%) and monkeys (18%) 
for the solid versus liquid dosage forms. 
 
Systemic drug exposure parameters (maximum plasma concentration [Cmax] and area under the 
time-concentration curve from 0 to t hours post-dose [AUC0-t] values) associated with single 
XL184 (cabozantinib) oral doses in rats increased less than dose-proportionally with increasing 
dose (100–900 mg/kg) (Investigator’s Brochure, 2010).  With repeat daily oral dosing in rats, 
systemic exposure (AUC0-t values) increased generally dose-proportionally following 14 and 178 
dosing days (dose ranges 1–15 mg/kg/day and 0.1–1 mg/kg/day, respectively).  The Cmax and 
AUC0-t values in rats administered 100 mg/kg were approximately 2-fold and 3-fold higher, 
respectively, than for dogs given 2000 mg/kg; therefore, the higher systemic exposure to XL184 
(cabozantinib) in rats correlated with the greater toxicity observed in this species at lower 
administered doses. 
 
Systemic drug exposure parameters (Cmax and AUC0-t values) associated with single XL184 
(cabozantinib) oral doses in dogs increased less than dose-proportionally with increasing XL184 
(cabozantinib) dose (400–2000 mg/kg), suggesting possible saturation of systemic absorption 
(Investigator’s Brochure, 2011).  With repeat daily dosing, exposure (Cmax and AUC0-24 values) 
both increased greater than dose-proportionally from 10 to 100 mg/kg and less than dose 
proportionally from 100 to 1000 mg/kg following 14 dosing days.   
 
Toxicology 
In rodents and non-rodents, histopathological changes associated with XL184 (cabozantinib) 
administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, 
kidney, and adrenal and reproductive tract tissues (Investigator’s Brochure, 2011).  
Histopathological changes present in the bone and pancreas were considered secondary to 
XL184 (cabozantinib) administration. Adverse effects following oral exposure to XL184 
(cabozantinib) were generally dose-related, clinically monitorable, and self-resolving upon 
discontinuation of dosing. In 6-month chronic toxicity studies, treatment-related changes were 
present only in kidney (rats) and reproductive tissues (dog).  In reproductive/developmental 
toxicity studies, XL184 (cabozantinib) administration resulted in decreased fertility in male and 
female rats, in embryotoxicity when given to pregnant rats, and in a visceral tissue malformation 
(small spleen) when given to pregnant rabbits. The no-observable-adverse-effect-levels 
(NOAELs) for the chronic toxicity and reproductive/developmental toxicity studies occurred at 
plasma exposures (AUC) below steady-state values measured in subjects with solid tumors 
administered 175 mg XL184 (cabozantinib) capsule form daily (Study XL184-001). 


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In definitive genotoxicity bioassays, XL184 (cabozantinib) was negative in an S. typhimurium/E. 
coli bacterial mutagenicity study, an in vitro chromosome aberration study using human 
peripheral blood lymphocytes, and an in vivo mouse bone marrow micronucleus study 
(Investigator’s Brochure, 2010).  In safety pharmacology studies, no adverse effects occurred on 
neurobehavioral or respiratory functions in XL184 (cabozantinib)-treated rats or on 
cardiovascular function in XL184 (cabozantinib)-treated dogs. 
 
Clinical Experience 
 
One thousand two hundred and eighty six patients have been studied in 12 ongoing Exelixis-
sponsored clinical trials with XL184 (cabozantinib) treatment 1) as a single agent at does ranging 
from 0.08 to 11.52 mg/kg on an intermittent dosing schedule, 2) from 25 to 265 mg (19.7-209 
mg freebase equivalent weight) on a fixed daily dosing schedule and 3) in combination with 
temozolomide (TMZ) and radiation therapy (RT), or with erlotinib (Exelixis Communication, 
2011).  The maximum tolerated dose (MTD) on once daily (qd) by mouth (PO) dosing schedule 
was determined to be 175 mg L-malate salt (or approximately 138 mg freebase equivalent 
weight). 
 
Detailed information for each of these studies, including pharmacokinetic data, can be found in 
the Investigator’s Brochure (2012).  Safety and efficacy information, from the 2012 
Investigator’s Brochure, is summarized below.  
 
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 to 11.52mg/kg (using 
powder-in-bottle [PIB] suspension on a 5 days on, 9 days off schedule), and at 175mg qd and 
265mg qd (using PIB suspension), and at 175mg qd and 250mg qd (using capsules [25 and/or 
100mg]) for two, 14-day cycles were enrolled.  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.   
 


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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%). 
 
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.  A total of 14 subjects in the dose-escalation portion of the study were 
treated across 3 dosing levels ranging from 50 mg qd to 100 mg qd. The capsule MTD was 
determined to be 75 mg administered qd. Because of a change in study sponsor, this study was 
reinitiated as XL184-014.   
 
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. 


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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 was a phase 2 randomized discontinuation trial.  Subjects were 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.  A total of 526 patients were 
enrolled in this study .  Patients experienced one or more SAEs that were assessed to be related 
to treatment with cabozantinib, including eight fatal related SAEs. 
 
Study XL184-205 is a randomized phase 2 trial for subjects with grade IV astrocytic tumors in 
first or second relapse.  Subjects received one of four regimens: 25 mg qd (Arm 1) continuously, 
75 mg qd (Arm 2) continuously, 125 mg qd for 2 weeks followed by 50 mg qd continuously 
(Arm 3), and 125 mg qd on an intermittent 3 week on/1 week off schedule (Arm 4).  A total of 
19 subjects were accrued before the study was terminated.  Three subjects were rolled over to 
maintenance Study XL184-900.  One subject experienced an SAE assessed to be related to 
treatment with cabozantinib.  
 
Study XL184-301 is a blind trial for subjects with unresectable, locally advanced or metastatic 
MTC, randomized 2:1 to cabozantinib or placebo.  SAEs reported in Study XL184-301 are: one 
grade 4 reversible posterior leukoencephalopathy syndrome (RPLS), one grade 5 cardiac arrest 
following asystolic vagal reaction after aspiration on study medication, and three SAEs of 
acquired trachea-esophageal fistula (two grade 3, one grade 5). 
 
Adverse Events 
The clinical studies with XL184 (cabozantinib) are ongoing and thus the AE data from the 
clinical database as of March 1, 2011 and May 4, 2011 do not yet include all SAEs (Exelixis 
Communication, 2011).  As of March 2011, AE data are available for 913 subjects who have 
been dosed with XL184 (cabozantinib) (806 in single-agent studies and 107 in combination 
studies of XL184 (cabozantinib) with erlotinib, rosiglitazone, or TMZ ± radiation) 
(Investigator’s Brochure, 2011).  Data from the 806 subjects who received single-agent XL184 
(cabozantinib) show that the most frequently (>20%) observed AEs regardless of causality were 
fatigue, diarrhea, nausea, decreased appetite, constipation, palmar-plantar erythrodysesthesia 
(PPE) syndrome, vomiting, dysphonia, and hypertension.  Effects that may be related to the 
inhibition of VEGF, including hypertension, thromboembolic events, GI perforation, fistula 
formation, hemorrhage, wound dehiscence, and proteinuria, have been observed in the single-
agent and combination XL184 (cabozantinib) studies.  The most commonly reported SAEs that 


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were assessed as related to study treatment with XL184 (cabozantinib) (as a single-agent or 
combination) were pulmonary embolism (PE), diarrhea, dehydration, deep vein thrombosis 
(DVT), vomiting, nausea, thrombocytopenia, fatigue, wound dehiscence, and PPE syndrome. 
 
There have been 15 grade 5 AEs related to study treatment: GI hemorrhage (two subjects), PE 
(two subjects), respiratory failure (two subjects), respiratory disorder (one subject), hemoptysis 
(one subject), death due to unknown cause (two subjects), intracranial hemorrhage (one subject), 
intestinal perforation (one subject), enterocutaneous fistula (one subject), hemorrhage (presumed 
to be hemoptysis; one subject), and diverticular perforation, peritonitis (one subject) 
(Investigator’s Brochure, 2011). 
 
Pharmacokinetics 
Pharmacokinetic analysis of 74 patients in trial XL184-001 showed dose proportional increases 
in maximum plasma concentration (Cmax) and AUC both for PIB (dose range 0.08-11.52 mg/kg) 
and the capsule formulation (dose range: 125 to 175 mg) (Kurzrock, Sherman et al. 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 (cabozantinib) 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 (cabozantinib) accumulated with repeat daily 
dosing.  There was no significant difference in exposure between patients with MTC and those 
without MTC. 
 
Based on the preliminary PK data from 23 subjects in XL184-005 who completed both 
treatments, after a single oral dose of cabozantinib at 100 mg, the terminal t1/2, z of cabozantinib 
appeared to be similar for both tablet and capsule formulations, with approximately mean values 
of 110 hours (Exelixis Communication, 2012).  The median time to the maximum plasma 
concentration (tmax) was 4 hours for the tablet formulation and 5 hours for the capsule 
formulation.  High inter-subject variability for Cmax and the area under the plasma drug 
concentration time curve (AUC) values were observed for both formulations (coefficient of 
variation [CV]% Cmax: 51% for the tablet formulation, 61% for the capsule formulation; CV% 
for the AUC from time zero to the last quantifiable time point 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 


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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 hours before and 1 hour after each cabozantinib dose). 
 
Preliminary results from a clinical pharmacology study, XL184-006, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an 
approximately 80% reduction in cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers.  Co-administration of cabozantinib with strong inducers of 
the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib 
concentrations.  The chronic use of strong CYP3A4 inducers should be avoided.  Other drugs 
that induce CYP3A4 should be used with caution because these drugs have the potential to 
decrease exposure (AUC) to cabozantinib (e.g., chronic use of modafinil) should be avoided 
because of its potential to reduce cabozantinib exposure.  Selection of alternate concomitant 
medications with no or minimal CYP3A4 enzyme induction potential is recommended.  In 
addition, caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, as this could 
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. 
 
2.3 
Erlotinib (OSI-774) 
 
Erlotinib (OSI-774 Tarceva®) is an orally active, potent, selective inhibitor of the epidermal 
growth factor receptor (EGFR) tyrosine kinase (Erlotinib Investigator's Brochure, 2012). 
Erlotinib inhibits the human EGFR tyrosine kinase with a 50% inhibitory concentration (IC50) 
of 2 nM (0.786 ng/mL) in an in vitro enzyme assay and reduces EGFR autophosphorylation in 
intact tumor cells with an IC50 of 20 nM (7.86 ng/mL). Erlotinib inhibits EGF-dependent 
proliferation of cells at submicromolar concentrations and blocks cell-cycle progression in the 
G1 phase.  
 
Erlotinib appears to bind specifically to EGFR. In a study of erlotinib binding specificity, affinity 
of erlotinib for 67 cellular receptors was examined (Erlotinib Investigator's Brochure, 2012). 
Erlotinib was shown to bind with low affinity to peripheral benzodiazepine (IC50=2.5 μM [980 
ng/ml]), adenosine A1 (IC50=6.8 μM [2700 ng/ml]), and μ-opiate (IC50=7.0 μM [2800 ng/ml]) 


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receptors. Binding affinities were 1250-fold higher than the IC50 concentration needed to inhibit 
purified EGFR tyrosine kinase (2 nM [0.79 ng/ml]). When tested at concentrations up to 1 μM 
(390 ng/ml), no significant inhibition of ligand binding to 64 other neurotransmitter receptors, 
regulatory binding sites, calcium channels, opioid receptors, or neurotransmitter uptake sites 
were observed.  
 
Non-Clinical Studies  
 
In mice, daily oral administration of erlotinib for 20 days inhibited subcutaneous (SC) growth of 
the HN5 human head and neck carcinoma in a dose-dependent manner as compared to vehicle-
treated mice, with an estimated effective dose for 50% inhibition (ED50) of 9.2 mg/kg/day 
(Erlotinib Investigator's Brochure, 2012). Treatment with 11 mg/kg/day of erlotinib immediately 
halted growth or slightly decreased the size of HN5 tumors >1 cm in diameter. The tumor stasis 
profile appeared to extend beyond the treatment period such that the tumor size for erlotinib -
treated animals did not exceed pretreatment levels until at least 33 days post-treatment. Similar 
results were observed in A431 squamous cell carcinoma xenografts at a dose of 11 mg/kg/day 
erlotinib over 20 days.  
 
Erlotinib (10 mg/kg/day) has been studied in combination with cisplatin, doxorubicin, 5-
fluorouracil, paclitaxel, vinorelbine tartrate, and gemcitabine (Erlotinib Investigator's Brochure, 
2012). No antagonism of therapeutic efficacy was observed, and additive effects were observed 
with cisplatin (10 mg/kg intravenous [IV] daily × 1), doxorubicin (15 mg/kg IV daily × 1), 
paclitaxel (10 mg/kg intraperitoneal [IP] daily × 5), and gemcitabine (100 mg/kg IP three times 
daily × 4).  
 
Nonclinical toxicology studies in rats and dogs have included acute and long-term general 
toxicology, genetic toxicology, reproductive toxicology, and local tissue tolerance of erlotinib. 
Clinical signs of toxicity in rats and/or dogs following a single dose of erlotinib were dose 
dependent and included transient emesis, ataxia, papillary dilation, increased heart rate, 
decreased blood pressure, decreased activity, irregular respiration, convulsions, rapid chewing, 
salivation, and death. Following chronic administration in rats and dogs, the following toxicities 
were observed in at least one species: effects on the cornea (atrophy and ulceration); effects on 
the skin (follicular degeneration and inflammation, redness, and alopecia); atrophy of the ovary, 
lacrimal glands, and salivary glands; necrosis of the liver; papillary necrosis and tubular 
dilatation of the kidney; inflammation in the mandibular lymph nodes; hematopoiesis; delayed 
gastric emptying; and diarrhea. Increases in alanine aminotransferase, aspartate 
aminotransferase, and bilirubin were observed.  
 
Erlotinib causes maternal toxicity with associated embryo-fetal lethality and abortion in rabbits 
at doses 3 times those in humans (AUC at 150 mg daily dose). However, when administered 
during organogenesis at plasma concentrations approximately equal to humans, no increase in 
embryo-fetal lethality or abortion in rats or rabbits was observed. Female rats treated with doses 
0.3 to 0.7 times the human dose prior to mating and during the first week of gestation had an 
increase in early resorptions. No teratogenic effects were observed in rats or rabbits.  
 


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Pharmacokinetics  
 
The total clearance of erlotinib decreased with increasing dose, resulting in supraproportional 
increases in exposure (AUC) over the dose range of 1-2 mg/kg IV in rats and 0.5-7 mg/kg IV in 
dogs (Erlotinib Investigator's Brochure, 2009). In vitro, erlotinib is slowly oxidized by liver 
microsomes. The majority of the absorbed dose is extensively metabolized in rats and dogs, and 
only a small amount is excreted as unchanged drug in urine, bile, and feces. The oral 
bioavailability of an aqueous suspension is 77% in rats and ~88% in dogs. Plasma protein 
binding of erlotinib ranges from 92% to 95% in man, monkey, rat, and mouse, and is 85% in the 
dog. Corrected for protein binding of 95%, at the average plasma concentration responsible for 
50% inhibition of tumor growth (oral dose of 9.2 mg/kg/day in the murine/human tumor 
xenograft model), the unbound concentration of drug in the plasma is estimated to be 86 nM (34 
ng/mL). The estimated unbound concentration of erlotinib in plasma is consistent (4-fold higher) 
with the IC50 for the in vitro cellular phosphotyrosine reduction assay and is 43-fold higher than 
the IC50 for the in vitro (isolated enzyme) tyrosine kinase assay. Finally, Erlotinib plasma 
protein binding depends on the levels of α-1-acid glycoprotein (AAG). Thus, AAG might be a 
significant determinant of pharmacokinetic and possibly pharmacokinetic–pharmacodynamic 
relationships in patients.  
 
Erlotinib pharmacokinetics were examined in patients with advanced solid tumors who were 
treated daily for 21 days. Plasma samples were collected on Days 1, 3, and 21 for analysis. The 
following table lists the pharmacokinetic data for these patients:  
 
Mean (%CV) Erlotinib Pharmacokinetic Parameters following Daily Dosing 
Dose 
(mg) 
N 
AUC0-24 
(ng·h/ml) 
R* 
Cavg 
(ng/ml) 
Cmax 
(ng/ml) 
Day 1 
Day 3 
Day 21 
Day 3 
Day 21 
Day 1 
Day 3 
Day 21 
Day 1 
Day 3 
Day 21 
25 
3 
1580 
(40) 
2180 
(49) 
 
1.38 
(11) 
 
66 
91 
 
208 
(38) 
310 
(40) 
 
50 
6a 
5650 
(54) 
5790 
(57) 
14900 
(69) 
1.59 
(31) 
1.83 
(30) 
235 
241 
621 
508 
(34) 
716 
(55) 
682 
(59) 
100 
8b 
9210 
(92) 
9080 
(49) 
32200 
(148) 
1.75 
(35) 
3.21 
(56) 
384 
378 
1340 
765 
(69) 
1140 
(49) 
1740 
(85) 
150 
7c 
14200 
(71) 
20600 
(22) 
45800 
(99) 
1.74 
(6.7) 
2.57 
(47) 
670 
859 
1910 
1040 
(70) 
2040 
(21) 
1730 
(82) 
200 
7 
36000 
(34) 
 
74200 
(29) 
 
2.01 
(42) 
1360 
 
3200 
1420 
(47) 
 
2910 
(29) 
Abbreviations: AUC0-24, Area under the time-concentration curve from 0 to 24 hours; Cavg, daily average plasma concentration; Cmax, maximum 
serum/plasma concentration; CV, coefficient of variance; R, accumulation ratio  
*Accumulation ratio = AUCDay 3 or 21/AUCDay 1  
aOnly 3 patients day 3, 3 subjects day 21  
bOnly 2 patients day 3, 3 subjects day 21  
cOnly 6 patients day 21 
 
After oral ingestion, the Erlotinib Cmax values (Tmax) were achieved at a median of 3 hours 
(range, 2 to 12 hours). Both Cmax and AUC0-24 values were roughly proportional to the 
erlotinib dose in the range of 25 to 200 mg/d (R2 = 0.33 and 0.46, respectively, on Day 1). Inter-
subject variability was moderate at the 150-mg/d dose level, as indicated by coefficient of 
variation values of 64% for Day 1 AUC0-24 and Cmax. 


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2.4 
Rationale 
 
The discovery of the role of angiogenesis in tumorigenesis and metastasis has paved the way for 
novel antiangiogenic therapies.  The combination of EGFR TKI therapy and vascular endothelial 
growth factor (VEGF) inhibition was evaluated in the phase III BeTa trial (Herbst, Ansari et al. 
2011). Bevacizumab/ erlotinib did not improve overall survival versus placebo/erlotinib, but 
prolonged PFS and was associated with a higher response rate.  Additionally, the MET inhibitor 
ARQ197 improved outcomes when combined with erlotinib, which may provide a mechanism to 
overcome EGFR resistance (Sequist, von Pawel et al. 2011).  In a recent phase 2 study (XL184-
202) combining XL184 (cabozantinib) + erlotinib, PR was seen in 3 patients with prior erlotinib 
therapy and prolonged SD was demonstrated in a patient with a T790M mutation (9+ months).  
 
Evidence suggests that MET and VEGF are important in NSCLC tumorigenesis and EGFR TKI 
resistance. Therefore, we hypothesize that treatment with XL184 (cabozantinib) plus erlotinib in 
EGFR mutation-positive NSCLC following EGFR TKI therapy may allow for tumors to 
overcome this resistance or restore sensitivity to therapy.    This trial will evaluate the 
combination of XL184 (cabozantinib) with erlotinib in patients with EGFR-mutant NSCLC who 
have progressed on EGFR TKI therapy.    Potential correlative markers will be studied by 
evaluating HGF in serum, and in a subset of patients; if available, pre-treatment tissue samples 
will be analyzed for T790M mutation and MET amplification to better understand mechanisms 
for overcoming resistance in these patients.    
 
2.5 
Correlative Studies Background 
 
This study provides an opportunity to evaluate mechanisms of resistance and sensitivity to 
therapy for these patients. Archival tissue specimens and serial blood draws will be prospectively 
collected from all patients. Patients will have the opportunity to have an additional biopsy 
following initial EGFR TKI therapy, and prior to protocol therapy.  All patients will have 
archival tissue collected to identify factors contributing to EGFR resistance (i.e., EGFR T790M 
mutations, MET amplification). Analysis of ligands, growth factors and soluble receptors will be 
conducted in serial blood draws from all consenting patients, with an emphasis on baseline levels 
and changes in VEGF and HGF levels, as well as other ligands that may mediate resistance.  
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed non-small cell lung cancer 
harboring an EGFR mutation. 
NOTE: EGFR mutational status will be known and assays performed in CLIA certified 
laboratories will be accepted. 
 


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3.1.2 Patients should have tumor tissue available for retrieval. Tissue blocks or unstained slides 
from the time of original diagnosis are acceptable if repeat biopsy is not indicated. Please 
see Section 9.0 for preparation and shipping of specimens. 
 
3.1.3 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 >20 mm with conventional techniques 
or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.  See Section 11 for 
the evaluation of measurable disease. 
 
3.1.4 Patients must have received prior EGFR TKI therapy for metastatic disease and have 
documented evidence of radiologic disease progression while on EGFR TKI as treatment 
immediately prior to enrollment. (Patients may have received prior chemotherapy, and 
retreatment with erlotinib is allowed). 
 
3.1.5 Age ≥18 years on day of consent.  Because no dosing or adverse event data are currently 
available on the use of XL184 (cabozantinib) in combination with erlotinib in patients 
<18 years of age, children are excluded from this study, but will be eligible for future 
pediatric trials. 
 
3.1.6 ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A). 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes   
 
 
 
≥3,000/mcL 
− 
absolute neutrophil count  
≥1,500/mcL 
− 
platelets    
 
 
 
≥100,000/mcL 
− 
total bilirubin  
 
 
 
≤1.5 × ULN 
− 
AST(SGOT)/ALT(SGPT)≤3.0 × institutional upper limit of normal 
− 
Lipase   
 
 
 
 
 
<2.0 x ULN and no radiologic or clinical evidence of 
 
 
 
 
 
 
 
 
 
 pancreatitis 
− 
creatinine  
 
 
 
 
≤1.5 × ULN 
OR 
− 
creatinine clearance  
 
≥50 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
− 
hemoglobin   
 
 
 
≥9 g/dL 
− 
serum albumin  
 
 
 
≥2.8g/dL 
− 
urine protein/creatinine 
 
≤1 
ratio (UPCR) 
− 
serum phosphorus, calcium,  ≥ LLN  
magnesium, and potassium  
 
 


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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 
ligation, or bilateral oophorectomy) or are not postmenopausal.  Postmenopause 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 (cabozantinib) on the developing human fetus are unknown.  For 
this reason and because tyrosine kinase inhibitors agents as well as other therapeutic 
agents used in this trial are known to be teratogenic, women of child-bearing potential 
and men 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 or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 4 months after completion of XL184 (cabozantinib) administration. 
 
Sexually active subjects (men and women) 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 Prior to the first patient registration, this study must have institutional review board (IRB) 
approval.  A copy of the IRB approval for each site involved must be given to the Data 
Coordinating Center at City of Hope. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 The subject has received cytotoxic chemotherapy (including investigational cytotoxic 
chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or 
nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment. 
 
3.2.2 Prior treatment with XL184 (cabozantinib) or other MET/HGF inhibitor. 
 
3.2.3 The subject has received radiation therapy: 
• to the thoracic cavity, abdomen, or pelvis within 2 weeks before the first dose of 
study treatment, or has ongoing complications, or is without complete recovery 
and healing from prior radiation therapy 


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• to bone or brain 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 prior treatment with a small molecule kinase inhibitor or a 
hormonal therapy (including investigational kinase inhibitors or hormones) within 14 
days or five half-lives of the compound or active metabolites, whichever is longer, before 
the first dose of study treatment.  Prior erlotinib is required and does not require a 14-day 
wash out. 
 
3.2.5 The subject has received any other type of investigational agent within 28 days before the 
first dose of study treatment.  
 
3.2.6 The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all 
prior therapies except alopecia and other non-clinically significant AEs. 
 
3.2.7 The subject has a primary brain tumor. 
 
3.2.8 The subject has active brain metastases or epidural disease.  Subjects with brain 
metastases previously treated with whole brain radiation or radiosurgery or subjects with 
epidural disease previously treated with radiation or surgery who are asymptomatic and 
do not require steroid treatment for at least 2 weeks before starting study treatment are 
eligible. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects 
with known brain metastases is required to confirm eligibility. 
 
3.2.9 The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial 
thromboplastin time (PTT) test ≥1.3 × the laboratory ULN within 14 days before the first 
dose of study treatment. 
 
3.2.10 The subject requires concomitant treatment, in therapeutic doses, with anticoagulants 
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or 
antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤81 mg/day), low-dose warfarin 
(≤1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted. 
 
3.2.11 Strong CYP3A4 inducers and inhibitors should be avoided.  Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended.  
 
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/table.aspx; 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. 
 


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3.2.12 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 
 
3.2.13 Patients with active bleeding or pathologic conditions that carry high risk of bleeding, 
such as known bleeding disorder or coagulopathy. 
 
3.2.14 The subject has radiographic evidence of cavitating pulmonary lesion(s). 
 
3.2.15 The subject has tumor in contact with, invading or encasing any major blood vessels. 
 
3.2.16 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.  
 
3.2.17 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: 


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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 that 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: 
 
a) active infection requiring systemic treatment within 28 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 14 
days before the first dose of study treatment 
 
e) history of major surgery as follows (See Appendix H for definitions): 
i. 
Major surgery within 8 weeks of the first dose of cabozantinib, with 
complete wound healing. (Patients with ongoing wound healing or other 
complications will be excluded)  
 
ii. 
Minor surgery within 4 weeks of the first dose of cabozantinib. Pleurx 
catheter placement within 7 days of the first dose of cabozantinib. 
 
3.2.18 The subject is unable to swallow tablets. 
 


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3.2.19 The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 
ms within 28 days before treatment.  Note: if initial QTcF is found to be > 500 ms, two 
additional EKGs separated by at least 3 minutes should be performed.  If the average of 
these three consecutive results for QTcF is ≤500 ms, the subject meets eligibility in this 
regard. 
 
3.2.20 The subject is unable or unwilling to abide by the study protocol or cooperate fully with 
the investigator or designee. 
 
3.2.21 The subject has had evidence within 2 years of the start of study treatment of another 
malignancy which required  systemic treatment 
 
3.2.22 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to XL184 (cabozantinib) or erlotinib. 
 
3.2.23 Pregnant women are excluded from this study because XL184 (cabozantinib) 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 (cabozantinib), breastfeeding should be discontinued 
if the mother is treated with XL184 (cabozantinib).  These potential risks may also apply 
to other agents used in this study. 
 
3.2.24 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with XL184 (cabozantinib).  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
 
 
Ethnic Category 
Females 
 
Males 
Total 
Hispanic or Latino 
3 
1 
4 
Not Hispanic or Latino 
17 
16 
33 
Ethnic Category: Total of all subjects 
20 
17 
37 
Racial Category 


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American Indian or Alaskan Native 
0 
0 
0 
Asian 
4 
4 
8 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific    
Islander 
0 
0 
0 
White 
15 
12 
27 
Racial Category: Total of all subjects 
20 
17 
37 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the California Cancer 
Consortium Data Coordinating Center (DCC) at the City of Hope.  All sites should call 
the DCC at (626) 256-4673 extension 65928.   
 
Following registration, patients should begin protocol treatment within 5 days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The DCC 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.  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. 
 
4.2 
Registration Process 
 
Once the signed informed consent has been obtained, all pretreatment evaluations have 
been performed, and patient’s eligibility has been confirmed by the data coordinating 
center a patient will be entered on study.   
 
To register a patient, the research nurse or data manager must complete the 
eligibility/registration form and contact the Consortium office (Data Coordinating 
Center for the California Cancer Consortium) at the City of Hope (626-256-4673, ext. 
65928), email a copy of the completed eligibility checklist, required pre-study tests 
(laboratory and pathology report), signed Informed Consent, signed Patients' Bill of 
Rights and HIPAA authorization form. (email cccp@coh.org).  See Appendix E 
(“Registration Procedures”). 
 
The research nurse or data manager at the participating site will then call the Data 


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Coordinating Center at Tel# 626-256-4673 extension 65928 to confirm receipt of all 
registration documents. To complete the registration process, the data coordinating 
center coordinator will: 
 
• 
Verify the eligibility 
• 
Register the patient on study 
• 
Assign a patient accession number 
• 
Fax or e-mail the patient study number and dose to the participating site 
• 
Call the research nurse or data manager at the participating site and verbally 
confirm registration. 
 
Following registration, patients should begin protocol treatment within 5 days to allow 
for drug shipment via Priority Mail.  Issues that would cause treatment delays should be 
discussed with the Principal Investigator.  If a patient does not receive protocol therapy 
following registration, the patient’s registration on the study may be canceled.  The Data 
Coordinating Center should be notified of cancellations as soon as possible. 
 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Patients will receive (A) XL184 
(cabozantinib) at 40-mg p.o. daily plus erlotinib at 150-mg p.o. daily in 4-week cycles as in 
Table 1.  Cabozantinib and erlotinib may be taken at the same time on an empty stomach. 
Reported adverse events and potential risks for XL184 (cabozantinib) and erlotinib are described 
in Section 7.  Appropriate dose modifications for cabozantinib and erlotinib 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. 
 
 
Table 5-1—Dosing Instructions 
XL184 
(cabozantinib) + 
erlotinib 
EGFR mutation 
positive NSCLC  
• Following 
progression on 
EGFR TKI 
therapy  
 
•  Tumor tissue 
available 


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Regimen Description 
Agent 
Premedications; 
Precautions 
Dose* 
Route 
Schedule 
Cycle 
Length 
XL184 
(cabozantinib) 
(Tablet) 
Take on an empty 
stomach without eating 
for 2 hours before and 1 
hour following each dose 
of XL184 (cabozantinib). 
 
40-mg 
oral 
Continuous 
daily 
28 days  
(4 weeks) 
 
 
 
Erlotinib (Tablet) 
Take on an empty 
stomach without eating 
for 2 hours before and 1 
hour following each dose 
of erlotinib. 
 
150-mg 
oral 
Continuous 
daily 
* Starting dose, see Tables 6-1 and 6-2 for dose modifications 
 
The patient will be requested to maintain a medication diary (see Appendix D) of each dose of 
medication. The medication diary will be returned to clinic staff at the end of each course. 
Patients will be instructed to record doses as they take them (and not to batch entries at a later 
time) and how to correct errors if they occur.  
 
5.1.1 XL184 (cabozantinib) 
 
XL184 (cabozantinib) must be taken on an empty stomach without eating 2 hours before 
through 1 hour after taking XL184 (cabozantinib). 
 
If the patient vomits after taking the tablets, the dose is replaced only if the tablets can 
actually be seen and counted.  
• Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, 
indinavir, nelfinavir, voriconazole) 
• Do not ingest foods or nutritional supplements (e.g., grapefruit, grapefruit juice, Seville 
oranges or products made with grapefruit or Seville oranges) that are known to inhibit 
cytochrome P450. 
• Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital).  
• Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum 
perforatum)) that are known to induce cytochrome P450 activity. 


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• Cabozantinib should be taken at approximately the same time each day.  If a dose is 
missed and it is less than 12 hours till the next dose, the missed dose should not be taken.  
The next dose should be taken at the normal time. 
• Cabozantinib is highly protein bound (approximately 99.9%) to human plasma proteins. 
Medications that are highly protein bound (eg, diazepam, furosemide, dicloxacillin, and 
propranolol) should be used with caution during cabozantinib treatment. 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. 
• 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 http://www.qtdrugs.org).  Additional QTc 
monitoring is suggested for subjects who are treated concomitantly with QTc prolonging 
drugs. Some 5-HT3 antagonist agents (e.g. odansetron, granisetron) can prolong the QTc 
and should be used with caution.  Alternative medications for nausea and vomiting 
should be used when possible. 
 
5.1.2 Erlotinib 
 
Erlotinib must be taken on an empty stomach.  Patients must fast for 2 hours before and 1 
hour following each dose of erlotinib. 
 
If the patient vomits after taking the tablets, the dose is replaced only if the tablets can 
actually be seen and counted.  
 
Patients should wear sun screen protection, hat, and long sleeves to avoid sun as it can 
exacerbate skin rash.  
 
There is a potential interaction between erlotinib and warfarin. Patients have experienced 
elevated international normalized ratios (INRs) and bleeding with this combination of drugs. 
Patients on warfarin and erlotinib should have more frequent INR/prothrombin time (PT) 
determinations.  
 
Proton pump inhibitor: Erlotinib's solubility decreases as the pH increases. 
Coadministration of omeprazole with erlotinib will decrease the AUC and Cmax by 46% 
and 61%, respectively.  Caution must be observed when administering erlotinib with 
omeprazole. 
 
H2-antagonist: Avoid concomitant use of erlotinib with gastric acid-reducing agents if 
possible. When ranitidine 300 mg is given with erlotinib, erlotinib AUC and Cmax 
decrease by 33% and 54%, respectively. Increasing the dose of erlotinib will not 
compensate the loss of exposure. However, if an H2-antagonist receptor is needed, take 
erlotinib at least 2 hours before or 10 hours following the H2-antagonist 


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administration. Dosing such, erlotinib loss of exposure is minimized to AUC of 15% 
and Cmax of 17%.  
 
Smoking: Advise smokers to stop smoking while taking erlotinib. Smoking induces 
CYP1A2 enzymes and alters erlotinib exposure by 64%.  
 
Food-drug interaction: Avoid grapefruit /grapefruit juice (potent CYP3A4) while taking 
erlotinib.  
 
 
5.1.3 Other Modality(ies) or Procedures 
 
N/A 
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of XL184 (cabozantinib) and erlotinib with other 
concomitantly administered drugs through the cytochrome P450 system, the case report form 
must capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  The Principal Investigator should be alerted if the patient is taking any agent known to 
affect or with the potential to affect selected CYP450 isoenzymes.   
 
5.2.1 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 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 


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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 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 


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increase cabozantinib concentrations.  Grapefruit / grapefruit juice and Seville 
oranges may also increase plasma concentrations of cabozantinib.  Strong CYP3A4 
inhibitors and inducers should be avoided, and CYP3A4 inhibitors and inducers that 
are not strong, 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/table.aspx).  
 
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 http://www.qtdrugs.org).  Additional QTc monitoring is suggested 
for subjects who are treated concomitantly with QTc prolonging drugs. Some 5-HT3 
antagonist agents (e.g. odansetron, granisetron) can prolong the QTc and should be 
used with caution.  Alternative medications for nausea and vomiting should be used 
when possible. 
 
Other Interactions: In a relative bioavailability study in dogs, cabozantinib exposure 
was not significantly affected by drugs that alter gastric pH. Nevertheless, drugs such 
as proton pump inhibitors (PPIs) and H2-antagonists produce profound suppression of 
gastric acid secretion and significant increases in gastric pH.  By elevating gastric pH, 
PPIs and H2-antagonists may decrease cabozantinib plasma exposure levels and its 
effectiveness in vivo, resulting in clinically significant drug interactions.  The use of 


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PPIs (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) 
and/or H2-antagonists (e.g., ranitidine, famotidine, and nizatidine) is discouraged 
during this study.  If antacids are not adequate, the use of H2 blockers is preferred 
over PPIs (Note: Cimetidine should be avoided because of its potential to interfere 
with CYP3A4 mediated metabolism of cabozantinib).  Antacids, H2 blockers, or PPIs 
should be taken at least 2 hours (preferably 4 hours) after taking cabozantinib but at 
least 14 hours before the next dose of cabozantinib if possible.  
 
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 for XL184 (cabozantinib). 
 
 
5.3 
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, or 
 
• 
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. 
 


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• 
The minimum dose of study treatment will be 20 mg XL184 (cabozantinib) qod and 
50 mg erlotinib qd. Subjects who cannot tolerate 20 mg XL184 (cabozantinib) qod 
and 50 mg erlotinib qd will have study treatment discontinued. 
 
5.4 
Duration of Follow Up 
 
Patients will be followed every 12 weeks for one year and then annually after removal from 
study or until death, whichever occurs first.  Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
A window of +/- 3 days is allowed for the start of cycles following cycle 1.  Patients will be 
withdrawn from study if they fail to recover to CTCAE grade 0-2 (or within one grade of starting 
value for pre-existing laboratory abnormalities) from a treatment-related toxicity within 6 weeks 
(leading to treatment delay of >6 weeks due to AEs). 
 
Table 6-1 Dose Modifications for XL184 (cabozantinib) 
Dose Level 
XL184 (cabozantinib) Dose 
0 (Starting dose) 
40mg daily 
-1 
20mg daily 
-2 
20mg every other day 
Dose reductions will occur for toxicity attributed to the offending agent.  If toxicity is 
related to both agents, both will require dose reduction. All dose reductions are 
permanent. In situations where the toxicity is attributable to the combination of agents 
requiring a dose reduction beyond dose level -2, then both agents will be discontinued 
and the patient will be removed from protocol therapy.  
 
 
 
 
 
 
 
Table 6-2 Dose Modifications for Erlotinib 
Dose Level 
Erlotinib Dose 
0 (Starting dose) 
150mg  
-1 
100mg 
-2 
50mg 
Dose reductions will occur for toxicity attributed to the offending agent.  If toxicity is 
related to both agents, both will require dose reduction. All dose reductions are 
permanent. In situations where the toxicity is attributable to the combination of agents 
requiring a dose reduction beyond dose level -2, then both agents will be discontinued 


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and the patient will be removed from protocol therapy. 
 
XL184 (cabozantinib)-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 Tables 6-3, 6-4, 6-5, 6-6, 6-7, 6-8, 6-9, and 6-10. 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 section 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.  


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Table 6-3.  General Approach to the Management of XL184 (cabozantinib)-Related Non-
Hematologic Adverse Events 
CTCAE Version 4 Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level. 
Grade 2: 
Grade 2 AEs considered related to 
cabozantinib that are subjectively 
tolerable or easily managed 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level.  
Grade 2 AEs considered related to 
cabozantinib that are intolerable to the 
subject or deemed unacceptable in the 
investigator’s judgment; or are not 
easily managed or corrected 
Dose reduce one level 
• 
If the AE dose not resolve to Grade ≤1 or baseline in 7 to 10 days 
or worsens at any time, cabozantinib dosing should then be 
interrupted.  Then upon resolution to baseline or Grade ≤ 1, the 
reduced dose should be restarted. 
• 
If the AE does resolves to resolves to Grade ≤1 or baseline 
without a dose interruption, continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered related to 
cabozantinib which occurred without 
optimal prophylaxis or which is easily 
managed by medical intervention or 
resolved quickly 
• 
Interrupt cabozantinib and add supportive care as indicated 
• 
For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or Grade ≤1 within 24 hours,  
cabozantinib may be resumed at either the same dose or with a 
dose reduction by one level 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 by one 
level 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 one level dose reduction.  
Grade 4: 
 
Grade 4 AEs considered related to 
study treatment 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose by one level with discussion with the PI. 
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.  


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Table 6-4.  General Approach to the Management of XL184 (cabozantinib)-Related 
Hematologic Adverse Events 
CTCAE Version 4 Grade 
Intervention 
Neutropenia 
Grade 3 neutropenia with documented 
infection 
Grade 3 neutropenia ≥ 5 days 
Grade 4 neutropenia  
Interrupt cabozantinib treatment until resolution to Grade ≤1, and 
resume cabozantinib treatment at a reduced dose by one level.  
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 
by one level. 
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 by one level. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment. 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic toxicities  
other than anemia 
Permanently discontinue study treatment. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not mandated. Dose 
reductions or dose delays for anemia should be applied as clinically 
indicated. Supportive care such as red blood cell transfusions should 
be managed according to institutional guidelines. 
ANC, absolute neutrophil count; LLN, lower limit of normal 
Neutropenia: Grade 1 (LLN ≤ ANC < 1.5 × 109/L; Grade 2 (1 × 109/L ≤ ANC <1.5 x 109/L),  
Grade 3 (0.5 × 109/L ≤ ANC < 1 × 109/L), Grade 4 (ANC < 0.5 × 109/L). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
Thrombocytopenia: Grade 1 (Platelet count <LLN – 75 x 109/L); Grade 2  (Platelet count <75.0 – 50.0 x  109/L);   
Grade 3 (Platelet count ≤ 50 - 25 × 109/L); Grade 4 (Platelet count < 25 × 109/L). 
 


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Diarrhea, Nausea, Vomiting, Stomatitis, and Mucositis 
 
Diarrhea 
 
Patients should be instructed to use loperamide for the prevention of diarrhea and initiate upon 
the first loose stool (4mg at first onset, followed by 2mg every 2-4 hours until diarrhea resolves for 12 
hours).  Patients should 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, Ajani 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 and 6-3 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  and 6-3 should 
be followed.   
 
Some 5-HT3 antagonist agents (e.g. odansetron, granisetron) can prolong the QTc and should be 
used with caution.  Alternative medications for nausea and vomiting should be used when 
possible. The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor 
antagonists and dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and 
glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure.)  Caution is also 
recommended with the use of nabilone, which is a weak inhibitor of CYP3A4. 
 
Stomatitis and Mucositis 
 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated.  Appropriate correction of local factors should 
be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of 
gingivitis.  During treatment with cabozantinib, good oral hygiene and standard local treatments 
such as non-traumatic cleansing, and oral rinses (e.g., with a weak solution of salt and baking 
soda) should be maintained.  The oral cavity should be rinsed and wiped after meals, and 
dentures should be cleaned and brushed often to remove plaque. Local treatment should be 
instituted at the earliest onset of symptoms.  When stomatitis interferes with adequate nutrition 
and local therapy is not adequately effective, dose reduction or temporary withholding of 
cabozantinib should be considered. 
 


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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: 
 
Table 6-5. General Approach to the Management of XL184 (cabozantinib)-Related 
Transaminase Adverse Events 
 
 
Transaminase elevation 
CTCAE v4.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at 
least 4 weeks.. Then resume the standard protocol-defined monitoring of LFTs. 
Grade 2 
Continue cabozantinib with at least twice weekly monitoring of LFTs for 2 weeks. 
Then weekly for 4 weeks.  If LFTs continue to rise within Grade 2, interrupt 
cabozantinib treatment.   Then continue with at least weekly LFTs until resolution 
to Grade ≤ 1.  Study treatment may then be resumed at a one-dose-level reduction 
of cabozantinib. 
Grade 3  
Interrupt cabozantinib  treatment and monitor with at least twice weekly LFTs 
until Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to 
Grade ≤ 1.  Cabozantinib may then be resumed at a one-dose-level reduction.  
Grade 4 
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.  
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline   
≥ 1.5 fold increase of AST or 
ALT AND both AST and 
ALT are ≤ 5.0 x ULN 
Continue cabozantinib treatment with at least twice weekly monitoring of LFTs 
for 4 weeks and weekly for 4 weeks.  If LFTs continue to rise, interrupt study 
treatment.   Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib. 
≥ 1.5 fold increase of AST or 
ALT and at least one of 
AST or ALT is Grade 3 (i.e. 
AST or ALT > 5.0 but ≤ 
20.0 x ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.   


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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. 
 


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Table 6-6. 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 ≤2 or baseline, cabozantinib may be restarted 
at the same dose or at a reduced dose by one level provided that this 
occurs within 6 weeks. 
• 
 
Grade 4 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤2 or baseline and if resolution occurred 
within 4 days, cabozantinib may be restarted at the same dose or a 
reduced dose by one level.  If resolution took more than 4 days, the dose 
must be reduced by one level upon retreatment provided that resolution 
occurred within 6 weeks. 
• 
 
 
Table 6-7. 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 by one level if resolution occurred within 6 weeks 
Grade 4 
Permanently discontinue treatment.   
 
 
 
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 includes the use of hypoallergenic 
moisturizing creams, ointment for dry skin, sunscreen with SPF ≥30; avoidance of exposure of 
hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; and use of 
thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects 


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with skin disorders should be carefully monitored for signs of infection (e.g., abscess, cellulitis, 
or impetigo). 
 
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild 
hyperkeratosis.  Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles.  The lateral sides of the fingers or periungual zones may also be affected.  
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas.  Aggressive management of symptoms 
is recommended, including early dermatology referral. 
 
Treatment guidelines for PPE related to study treatment are presented in the table below. 
 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent.  
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  
 


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Table 6-8 Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose.  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.   
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 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 


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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. 
 
Decisions to decrease or hold the dose of study treatment must be based on BP readings taken by 
a medical professional and must be confirmed with a second measurement at least 5 minutes 
following the first measurement.  Subjects with known hypertension should be optimally 
managed prior to study entry.  Clinical judgment should be used in deciding whether new or 
worsened hypertension emerging during treatment with cabozantinib requires immediate therapy, 
or whether therapeutic intervention can be delayed in order to confirm the finding of new or 
worsened hypertension at a second visit before taking new therapeutic action.  It is recommended 
that this second visit occur within 1 week.  Blood pressure should be monitored in a constant 
position visit to visit, either sitting or supine.  Cabozantinib dosing should be interrupted in 
subjects with severe hypertension (180 mm Hg systolic or 120 mm Hg diastolic; or sustained 
≥160 mm Hg systolic or ≥110 diastolic) who cannot be controlled with medical interventions and 
discontinued in subjects with hypertensive crises or hypertensive encephalopathy (see next Table 
below). 
 


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Table 6-9. Management of Hypertension Related to XL184 (cabozantinib) 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 140 mm Hg (systolic) and < 160 mm Hg 
OR 
> 90 mm Hg (diastolic) and < 110 mm Hg 
 
 
• Increase antihypertension therapy  (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
• Maintain dose of cabozantinib 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, or if the subject is symptomatic, the dose of 
cabozantinib should be reduced by one dose level. 
≥ 160 mm Hg (systolic) and < 180 mm Hg 
OR 
≥ 110 mm Hg (diastolic) and < 120 mm Hg 
• Reduce cabozantinib by one dose level. 
• Increase antihypertension therapy  (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
• Monitor subject closely for hypotension. 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, dose of cabozantinib should be reduced further 
by one dose level. 
≥ 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 
by one dose level. 
Hypertensive crisis or hypertensive 
encephalopathy 
Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE:  If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
 
 
 
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 


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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. 
 
Table 6-10. Management of Treatment Emergent Proteinuria 
 Urine Protein/Creatinine Ratio 
Action To Be Taken 
≤ 1 
• 
No change in treatment or monitoring 
> 1 and < 3.5 
 
• 
No change in study treatment required  
• 
Consider confirming with a 24-hour protein excretion within 7 
days 
• 
Repeat UPCR within 7 days and once every week. If UPCR is < 
1 on two consecutive readings, then UPCR monitoring can revert 
to protocol specific time points. (The second reading is a 
confirmatory reading and can be done within 1 week of the first 
reading.). 
≥ 3.5 
 
• 
Hold cabozantinib immediately and confirm with 24 hour urine 
protein excretion.  
• 
Evaluate for nephrotic syndrome. If present, discontinue 
cabozantinib treatment permanently, and monitor subject for 
resolution of nephrotic syndrome.  
• 
If proteinuria of ≥ 3.5 g/24 hours is confirmed without diagnosis 
of nephrotic syndrome, continue to hold cabozantinib and 
monitor UPCR weekly. If UPCR decreases to < 1.5, restart 
cabozantinib at a reduced dose by one dose level.  Continue 
monitoring UPCR once every week until two consecutive 
readings are < 1, then revert to UPCR monitoring frequency 
specified in the protocol. 
UPCR, urine protein/urine creatinine ratio 
 
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 


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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. 
 
Based on the described predisposing risk factors for hemoptysis, many studies with 
antiangiogenic drugs exclude subjects with NSCLC and squamous cell differentiation. Although 
enrollment of subjects with NSCLC with squamous cell differentiation has been allowed on 
cabozantinib studies, cabozantinib studies exclude NSCLC subjects with any of the following: 
tumors abutting, encasing, or invading a major blood vessel; cavitating lesions; history of 
clinically significant hemoptysis; or recent radiation therapy to the thoracic cavity including 
brachytherapy unless radiation therapy targets bone metastasis. 
 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥0.5 teaspoon (2.5mL) of red blood).  Treatment with cabozantinib 
should be interrupted if less severe forms of clinically significant hemorrhage occur and may be 
restarted after the cause of hemorrhage has been identified and the risk of bleeding has subsided 
at a dose agreed to by the sponsor and the investigator.  Therapy of bleeding events should 
include supportive care and standard medical interventions.  
 
Furthermore, subjects who develop tumors abutting, encasing, or invading a major blood vessel 
or who develop cavitation of their pulmonary tumors while on study treatment must be 
discontinued from cabozantinib treatment. 
 
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.  


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• 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 
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 
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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 
 
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 


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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. 
 
Erlotinib-Related Adverse Event Management 
 
Table 6-11. General Approach to the Management of Erlotinib-Related Adverse Events 
Toxicity 
Grade 
Dose Modification1 
Guideline for management 
Keratitis 
1 
None 
No intervention 
2 (≤ 14 days) 
None 
Preservative-free artificial tears, 
ointments, and/or other therapies as 
clinically indicated with follow-up 
examination within 2 weeks. 
2 (≥ 14 days) 
Hold until recovery to ≤ grade 
1, and then reduce 1 dose level 
≥3 
Hold until recovery to ≤ grade 
1, and then reduce 1 dose level 
Diarrhea 
1 
None 
Loperamide (4mg at first onset, 
followed by 2mg every 2-4 hours 
until diarrhea resolves for 12 hours)2 
2 
• None if tolerable 
• If intolerable, hold until 
recovery to ≤ grade 1, and 
then resume at the same dose 
level 
• If intolerable grade 2 recurs 
after resumption, hold until 
recovery to ≤ grade 1, and 
then reduce 1 dose level 
Loperamide (4mg at first onset, 
followed by 2mg every 2-4 hours 
until diarrhea resolves for 12 hours)2 
≥3 (despite 
optimal 
loperamide 
use) 
Hold until recovery to ≤ grade 
1, and then reduce 1 dose level1 


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Rash 
1 
None 
No intervention 
2 
• None if tolerable 
• If intolerable, hold until 
recovery to ≤ grade 1, and 
then resume at the same dose 
level 
• If intolerable grade 2 recurs 
after resumption, hold until 
recovery to ≤ grade 1, and 
then reduce 1 dose level1 
Any of the following: minocycline, 
doxycycline, topical tetracycline or 
clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral 
prednisone (short course, ≤ 1 week) 
≥3 
Hold until recovery to ≤ grade 
1, and then reduce 1 dose level 
Bilirubin 
≥3 x ULN 
Hold until recovery to ≤ grade 
2, and then reduce 1 dose level 
No intervention 
Liver 
Transaminases 
≥5 x ULN 
Hold until recovery to ≤ grade 
2, and then reduce 1 dose level 
No intervention 
Signs and symptoms of 
interstitial pneumonitis 
Any grade; Hold erlotinib 
pending diagnosis. 
Permanently discontinue if 
diagnosis is confirmed and 
considered possibly related to 
erlotinib. 
Patient should be thoroughly 
evaluated, closely monitored, and 
supported as clinically indicated. 
Other toxicity 
≥2 prolonged 
clinically 
significant 
toxicity (≥ 1 
week) 
Hold until recovery to ≤ grade 
2, and then reduce 1 dose level 
Treatment as clinically indicated 
1If the dose has previously been held for grade 2 rash or diarrhea and grade 2 symptoms recur, OR if the 
patients finds the symptoms unacceptable, hold dose until recovery to ≤ grade 1 and then reduce dose one 
level. 
2Loperamide is recommended at the first onset of loose stools. 
 
 
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 (Section 7.1) 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.   
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-


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specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm for 
further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously via CTEP-AERS.  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. 
 
7.1.1 CAEPRs for CTEP IND Agent(s) 
 
7.1.1.1 
CAEPR for XL184 (cabozantinib) 
 
Below is the CAEPR for XL184 (cabozantinib).  Frequency is provided based on 1345 patients. 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Cabozantinib (XL184 
(cabozantinib), NSC 761968) 
 
Version 2.1, August 26, 20131 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib s-malate) 
 (CTCAE 4.0 Term) 
[n= 1345] 
 
 
 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 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2   
 
 
Gastrointestinal 
hemorrhage3 
  
 
 
Gastrointestinal 
perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 


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Nausea 
 
 
 Nausea (Gr 2) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
Aspartate 
aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Lipase increased 
 
 Lipase increased (Gr 2) 
 
Platelet count 
decreased 
 
 Platelet count decreased (Gr 
2) 
Weight loss 
 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Musculoskeletal and 
connective tissue 
disorder -  Other 
(muscle spasms) 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  


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Reversible posterior 
leukoencephalopathy 
syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
Respiratory fistula6 
  
 
Respiratory 
hemorrhage7 
 
  
 
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(oropharyngeal pain) 
 
  
Voice alteration 
 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
 
Pruritus 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
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 2) 
 
Thromboembolic 
event8 
 
  
 
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, Enterovesical 
fistula, Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, 
Oral cavity fistula, Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the 
GASTROINTESTINAL DISORDERS SOC. 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 


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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. 
6Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, 
Pharyngeal fistula, Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC. 
7Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under 
the RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC.  
8Thromboembolic event includes pulmonary embolism which may be life-threatening. 
 
Also reported on XL184 (Cabozantinib s-malate) trials but with the relationship to XL184 
(Cabozantinib s-malate) still undetermined: 
 
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; Cardiac arrest; Chest pain - cardiac; 
Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Myocarditis; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); 
Endocrine disorders - Other (hypopituitarism); Endocrine disorders - Other (thyroiditis); 
Hyperthyroidism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal ulcer; Cheilitis; Colitis; 
Duodenal ulcer; Dysphagia; Esophageal ulcer; Esophagitis; Flatulence; Gastric ulcer; 
Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other (glossitis); 
Gastrointestinal disorders - Other (pneumoperitoneum); Hemorrhoids; Ileus; Pancreatitis; Rectal 
pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; 
Edema face; Fever; Gait disturbance; General disorders and administration site conditions - 
Other (implant site inflammation); Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatobiliary disorders - Other 
(cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - 
Other (hepatitis toxic); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Autoimmune disorder 


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INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and 
procedural complications - Other (post procedural hemorrhage); Injury, poisoning and 
procedural complications - Other (tendon injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK 
increased; Cardiac troponin I increased; Creatinine increased; Electrocardiogram QT corrected 
interval prolonged; GGT increased; Investigations - Other (blood lactate dehydrogenase 
increased); Investigations - Other (eosinophil count increased); Investigations - Other (glucose 
urine present); Investigations - Other (urine ketone body present); Lymphocyte count decreased; 
Neutrophil count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypoalbuminemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive); Metabolism and 
nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (muscle hemorrhage); 
Musculoskeletal and connective tissue disorder - Other (rhabdomyolysis); Myalgia; Neck pain; 
Osteoporosis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) -Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (lip 
and/or oral cavity cancer); Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
- Other (tumor hemorrhage) 
NERVOUS SYSTEM DISORDERS - Ataxia; Dysarthria; Dysesthesia; Encephalopathy; 
Intracranial hemorrhage; Ischemia cerebrovascular; Memory impairment; Nervous system 
disorders - Other (hemiparesis); Nervous system disorders - Other (spinal cord compression); 
Nervous system disorders - Other (vocal cord paralysis); Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Seizure; Somnolence; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Psychiatric disorders - Other 
(mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; Renal 
and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Aspiration; Atelectasis; Hypoxia; Laryngeal edema; Pharyngeal mucositis; Pleural effusion; 
Pneumonitis; Pneumothorax; Respiratory failure; Respiratory, thoracic and mediastinal disorders 
- Other (nasal septum perforation); Respiratory, thoracic and mediastinal disorders - Other 
(pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (psoriasis); Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Vascular disorders - Other (bleeding 
varicose vein) 
 
Note: XL184 (Cabozantinib s-malate) 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. 
 
 


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7.1.1.2 
CAEPR for Erlotinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Erlotinib (OSI-774, NSC 718781) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited , JulyReporting (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 via CTEP-AERS 
(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 3622 patients.  Below is the CAEPR for 
OSI-774 (erlotinib). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
 
Version 2.4, July 24, 20131 
 
 Adverse Events with Possible  
 Relationship to OSI-774 (erlotinib) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
 
(formerly known as 
ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
 
Eye disorders - Other 
(eyelash in-growth and/or 
thickening) 
 
  
 
 
Eye disorders - Other 
(corneal perforation) 
  
 
 
Keratitis 
  


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GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal 
hemorrhage2 
 
  
 
 
Gastrointestinal 
perforation3 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Skin infection4 
 
 Skin infection4 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased  
 Blood bilirubin 
increased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage   
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
Pneumonitis 
 
 Pneumonitis (Gr 3) 


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SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
 
Nail loss 
 
 Nail loss (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular 
(Gr 3) 
 
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 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. 
 
3Gastrointestinal 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. 
 
4Includes infection of the skin (folliculitis or cellulitis) as complications of rash. 
 
Also reported on OSI-774 (erlotinib) trials but with the relationship to OSI-774 (erlotinib) 
still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation 
EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); Uveitis; Watering 
eyes 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; Dysphagia; 
Esophagitis; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (pneumatosis intestinalis); 
Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs 
HEPATOBILIARY DISORDERS - Cholecystitis 
INVESTIGATIONS - Creatinine increased; INR increased (in patients taking Coumadin); 


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Lymphocyte count decreased; Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Ischemia cerebrovascular; Peripheral sensory 
neuropathy 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Pharyngolaryngeal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: OSI-774 (erlotinib) 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. 
 
Note:  OSI-774 (erlotinib)-induced diarrhea and/or vomiting has been associated with 
dehydration, hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; hyponatremia; 
hypophosphatemia, increased creatinine, and renal failure. 
 
Note:  Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been 
reported during use of OSI-774 (erlotinib) in patients with baseline hepatic impairment.   
 
 
 
 
7.2 
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 for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• For expedited reporting purposes only:   
o 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. 
o Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 


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− 
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. 
 
7.3 
Expedited Adverse Event Reporting 
 
 
For protocols with CAEPRs not including a “SPEER” category, protocol-specific exceptions to 
the CTEP-AERS reporting table can be found in the CAEPR’s “ASAEL” category instead.  This 
protocol-specific exception is limited to Grade 1 and Grade 2 ASAEL events, i.e. Grade 3 
through Grade 5 ASAEL-listed events are NOT exceptions to CTEP-AERS reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (http://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 
(http://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. 
 
7.3.2 Multi-institutional studies 
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.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
PLEASE INCLUDE CCCP@COH.ORG ON ALL CTEP-AERS REPORTS 
SUBMITTED. 
 
7.3.3 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. 
 


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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 
or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
 
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. 


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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 
 
 
7.4 
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. 
 
7.5 
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 outlined in each protocol.  
 
7.6 
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 XL 184 and Erlotinib 
administered in this study can be found in Section 7.1. 
 


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8.1 
CTEP IND Agent(s) 
 
8.1.1 XL184 (cabozantinib) (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  
 
Molecular Formula: 
C28H24FN3O5.C4H6O5  
 
M.W.: 635.6  
 
Mode of Action:  
XL184 (cabozantinib) inhibits multiple RTKs implicated in tumor growth, 
metastasis, and angiogenesis, and targets primarily MET and VEGFR2.  Other 
targets are RET, AXL, KIT, TIE-2, and FLT-3.  
 
How Supplied: 
XL184 (cabozantinib) - NSC 761968 - will be provided free of charge by Exelixis 
and distributed by the Pharmaceutical Management Branch (PMB), Cancer 
Therapy Evaluation Program (CTEP), Division of Cancer Treatment and 
Diagnosis (DCTD), National Cancer Institute (NCI). 
 
XL184 (cabozantinib) 20 mg will be supplied as tablets for oral administration.  
The XL184 (cabozantinib) tablets contain XL184 (cabozantinib), microcrystalline 
cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, 
colloidal silicon dioxide, and magnesium stearate.  The Opadry Yellow film 
coating on the tablet contains HPMC 2910 /hypromellose 6 cp, titanium dioxide, 
triacetin, and iron oxide yellow.   
 
 
XL184 (cabozantinib) will be supplied in bottles containing 30 – 20 mg tablets of 
XL184 (cabozantinib) with a child-resistant cap and tamper evident seal. Dispense 
XL184 in its original bottle; however, 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. 
 
Administration:   
Take XL184 (cabozantinib) on an empty stomach, do not eat 2 hours before through 
1 hour after. Do not crush or chew.   


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Stability:  
Stability testing of the intact bottles is on-going.  XL184 (cabozantinib) is stable up 
to 24 hours when dispensed in an open container such as a pill cup, and up to 7 days 
when dispensed in a closed container such as a pharmacy bottle other than the 
original container.  
 
Potential Drug Interactions:  
XL184 (cabozantinib) is a substrate of CYP3A4.  Co-administration of XL184 
(cabozantinib) with medications that are strong inhibitors/inducers of CYP3A4 
should be avoided. Examples of strong CYP3A4 inducers are rifampin, 
dexamethasone, phenytoin, carbamazepine, rifabutin, rifampentin, Phenobarbital, 
and St. John’s Wort. Strong CYP3A4 inhibitors are ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir.  Use alternative 
medications.  Avoid grapefruit/ grapefruit juice and Seville oranges while 
participating in this trial.  
 
In vitro data indicate that XL184 (cabozantinib) is unlikely to be a substrate for P-
glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein 
transport activity.  Additional details related to these overall conclusions can be 
found in the investigator brochure. 
 
XL184 (cabozantinib) is highly protein bound, 99.9%.  Use caution when co-
administering XL184 (cabozantinib) with medications that are highly protein-bound 
(e.g., diazepam, furosemide, dicloxacillin, and propranolol).  Avoid administration 
of warfarin with XL184 (cabozantinib) as warfarin is highly protein-bound and has a 
very narrow therapeutic index. 
 
Avoid concomitant use of XL184 (cabozantinib) with proton pump inhibitors (PPIs) 
and H2 –antagonists, if possible.  The PPIs and H2–antagonists may decrease XL184 
(cabozantinib) plasma exposure levels and its effectiveness in humans.  Examples of 
PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole; 
examples of H2 –antagonists are ranitidine, famotidine, and nizatidine.  Cimetidine is 
a moderate CYP3A4 inhibitor.  Avoid using cimetidine with XL184 (cabozantinib).  
If needed, antacids are recommended for the initial treatment of dyspepsia or 
indigestion.  If antacids are not adequate, the use of H2 blockers (other than 
cimetidine) is preferred over PPIs.  If antacids, H2 blockers, or PPIs are needed, take 
them at least 2 hours (preferably 4 hours) after taking XL184 (cabozantinib) but at 
least 14 hours before the next dose of XL184 (cabozantinib) if possible. 
 
Potential Food Effect: 
The effect of food on the bioavailability of XL184 (cabozantinib) was evaluated in 
healthy adult subjects in a Phase 1, open-label, randomized, single-dose, two-
treatment, two way crossover study (Study XL184-004).  Based on the preliminary 
PK data, a high fat meal did not appear to alter the terminal t1/2, but significantly 


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increased the median tmax to 6 hours from 4 hours (fasted).  The high fat meal also 
significantly increased both the XL184 (cabozantinib) Cmax and AUC values by 
41% and 57%, respectively.  Based on this result, XL184 (cabozantinib) should be 
taken on an empty stomach [fasting is required 2 hours before and 1 hour after each 
XL184 (cabozantinib) dose]. 
 
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.  There are many H2-
blockers and PPIs available over-the-counter (OTC) such as cimetidine or 
omeprazole. For dyspepsia or indigestion, use an antacid first, then an H2 blocker if 
not relief with an antacid.  Do not use cimetidine.  Take an antacid, an H2 blocker, 
or a PPI at least 2 hours (preferably 4 hours) after taking XL184 (cabozantinib) but 
at least 14 hours before the next dose of XL184 (cabozantinib) if possible. 
 
Drug Returns:  
            Only undispensed drug supplies (no partial bottles) should be returned to the 
PMB.  When it is necessary to return study drug (e.g., sealed bottles remaining 
when expired supplies are recalled by the PMB), investigators should return the 
study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov).   
 
Drug Transfers: 
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 Erlotinib/OSI-774 (718781) 
 
Chemical Name: 
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
quinazolinamine, monohydrochloride 
 
Other Names:  
Erlotinib hydrochloride, Tarceva™ 
 
Classification: 
Tyrosine kinase Inhibitor (EGFR) 
 
Molecular Formula: 
C22H23N3O4 HCl 
 
 
 
 
M.W.: 
 
393.4 (free base) 
429.9 (hydrochloride salt) 
 
Mode of Action: 
Direct inhibition of EGFR tyrosine kinase 
 
How Supplied:  
Erlotinib tablets are provided by Astellas Pharmaceuticals and 
distributed by the DCTD/NCI as    25 mg, 100 mg, and 150 mg 


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white film-coated immediate-release tablets packaged in high-
density polyethylene (HDPE) bottle.  Each bottle contains 30 
tablets.  
 
The tablets are round and convex without markings.  The 25 
mg tablets are 1/4 inches (6 mm); the 100 mg tablets are 11/32 
inches (9 mm); and the 150 mg tablets are 13/32 inches (10 
mm). OSI-774 excipients include lactose monohydrate, 
microcrystalline cellulose, sodium starch glycolate, sodium 
lauryl sulfate, and magnesium stearate.  
 
Storage:   
 
Store the intact HDPE bottles as per label’s instruction. 
 
Stability:  
Current data indicates erlotinib is stable for at least 3 years at 
room temperature. 
 
Route of Administration:  Oral. 
  
Method of Administration:  
 
• Tablets should be taken once daily preferably in the morning with up to 200 mL of 
water on an empty stomach 2 hours before through 1 hour after. 
 
Potential Drug Interaction: Erlotinib is highly protein bound (92% to 95% in humans) and 
metabolizes primarily via CYP3A4 enzymes.  Dose OSI-774 cautiously with agents that are 
highly protein bound or potent CYP3A4 inhibitors/inducers enzymes. 
 
CYP Iso-Enzymes Inhibitors/Inducers: 
o Potent CYP3A4 Inhibitors:  Use alternative drug.  Alternatively, reduce erlotinib 
dose in the event of drug interaction (if permitted by the protocol).  
o Potent CYP3A4 inducers:  Use alternative drug.  If an alternative treatment is 
contraindicated, consider increasing the erlotinib dose (if permitted by the protocol).   
 
o Food-drug interaction:  Avoid grapefruit /grapefruit juice (potent CYP3A4) while 
taking erlotinib. 
 
o Smoking:  Advise smokers to stop smoking while taking erlotinib.  Smoking induces 
CYP1A2 enzymes and alters erlotinib exposure by 64%. 
 
Anticoagulant:  Concomitant NSAIDs, warfarin or warfarin-derivatives may increase 
bleeding and PT /INR. Dose adjustment may be needed.  
 
Proton Pump Inhibitor:  Erlotinib’s solubility decreases as the pH increases. Co-
administration of omeprazole with erlotinib will increase the AUC and Cmax by 46% and 
61%, respectively.  


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H2-antagonist: Avoid concomitant use of erlotinib with gastric acid reducing agents if 
possible.  When ranitidine 300 mg is given with erlotinib, erlotinib AUC and Cmax  decrease 
by 33% and 54%, respectively.  Increasing the dose of erlotinib will not compensate the loss 
of exposure.  However, if an H2-antagonist receptor is needed, take OSI-774 at least 2 
hours before or 10 hours following the H2-antagonist administration.  Dosing such, 
erlotinib loss of exposure is minimized to AUC of 15% and Cmax   of 17%.   
 
Gastrointestinal perforation:  Concomitant use of anti-angiogenic agents, corticosteroids, 
NSAIDs, and/or taxane based chemotherapy, or patients with prior medical history with 
peptic ulcers or diverticular disease are at high risk of GI perforation while on erlotinib 
treatment.  Discontinue erlotinib if GI perforation manifests. 
 
Patient Care Implications: If patient vomits after taking the tablets, readminister the 
dose only if the tablets can actually be seen and counted. 
Recommend patients to use sunscreen protection, and wear hat and long sleeve shirts as 
sunlight can exacerbate skin reactions. 
 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 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 
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. 


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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. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
Archival tissue specimens will be collected per eligibility criterion 3.1.2.  Serial blood draws are 
required and will be prospectively collected from consenting patients. Patients who have an 
additional biopsy following initial EGFR TKI therapy or after progression on study will have 
tissue collected to identify factors contributing to EGFR resistance (i.e., EGFR T790M 
mutations, MET amplification). Analysis of ligands, growth factors and soluble receptors will be 
conducted in serial blood draws from all consenting patients. 
 
Tumor specimens:  
1.   For all patients, tumor positivity for EGFR will have been established prior to enrollment 
as routine management.  If a post-progression re-biopsy is available, continued EGFR 
mutation status as well as emergence of the T790M resistance mutation will be 
determined. 
2.   Each specimen will be evaluated for MET amplification. 
3.  Given sufficient tumor specimen, each sample will be evaluated in the following priority 
order for a) for EGFR IHC expression using the established H-score system, b) the 
presence of PI3K mutations (particularly exon 20) and c) tumor RNA expression levels 
of EGFR and MET amplification as determined through Response Genetics Inc. 
 
In post-progression tumor specimens* 
 
If a biopsy was conducted at the time of progression on the prior EGFR inhibitor therapy 
(presumably erlotinib), then the following will be conducted in available archival specimens: 
 
1. MET copy number abnormalities/amplification by FISH. 
 
2. IHC evaluation of HGF as a paracrine or autocrine stimulator. 
 
 
*These assays will also be performed in the original diagnostic specimen for patients who 
have a complete or near complete response to therapy 
 
Analysis of serial plasma specimens 
 
1) A principle goal for analysis of serial patient plasma will be to quantitate baseline levels 
and treatment-induced changes in the MET ligand HGF.  Additionally, through multiplex 
analysis, ErbB family ligands, including amphiregulin, epiregulin, EGFR and TGF-alpha 
will be evaluated.  
 
 
2) Patient plasma will be monitored for the presence of the T790M EGFR mutation in 
circulating cell-free tumor DNA using previously established techniques (Mack ref).  Detection 
of the original activating mutation (e.g. E19del or L858R) will also be performed.  The ratio of 


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70 
mutant DNA (EGFR E19del, L858R and T790M) to wild-type DNA detectable in plasma will be 
correlated with tumor burden over time.  In responding patients, we expect a decrease in 
detection of EGFR mutations in peripheral circulation concomitant with decreased tumor burden.  
Progression would be associated with increased levels, potentially including emergence of the 
T790M mutation. 
 
9.1.1. EGFR and MET tissue analysis 
 
9.1.1.1. Collection of Specimens 
  
Archival tumor specimens (ideally 1-2 paraffin-embedded tissue blocks containing formalin-
fixed tumor from the time of diagnosis, or subsequent to, but prior to therapy) should be 
submitted for subsequent evaluation of expression and mutation analysis in relevant 
molecular pathways. Paraffin blocks may be processed according to standard institutional 
protocols. If blocks are unavailable, 10-15 unstained slides will be accepted as an alternative.  
 
9.1.1.2. Shipping of Specimens  
 
All archival paraffin block/slide specimens should be sent at ambient temperature. Specimens 
should be shipped to the following address:  
 
Philip C. Mack, PhD  
UC Davis Cancer Center  
4501 X Street, Suite 3016  
Sacramento, CA 95817  
 
Laboratory Phone: 916-734-3734  
Fax: 916-734-2361  
Email: philip.mack@ucdmc.ucdavis.edu  
 
A Specimen Submission Form (Appendix F) and a Pathology Report corresponding to the 
submitted block/slides must be submitted with each specimen. Institutions should notify the 
recipient by either phone or fax prior to shipping specimens.  
 
9.1.2  DNA and Protein analysis of plasma 
 
9.1.2.1. Collection of Specimens  
Molecular Correlative sampling will be conducted at baseline, prior to all subsequent 
treatment cycles, and when the patient comes off of the study for any reason (see study 
calendar). It is important that blood is collected at all time points and that the specimens are 
consistently processed according to protocol instructions.  
 
9.1.2.2. Handling of Specimens  
 


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One purple top blood tube (EDTA tubes), ~ 10 ml, should be collected from patients at 
baseline, prior to all subsequent treatment cycles, and when the patient comes off of the study 
for any reason. Tube should be spun in a standard laboratory centrifuge at 800 x G for 10 
minutes to separate plasma, buffy coat cells, and red blood cells (see Appendix G for blood 
handling protocol). Plasma should be carefully removed in aliquots of 1 mL each to labeled 
cryovials. Similarly, the white blood cell buffy coat should be removed and placed in labeled 
cryovials. All tubes should be frozen as rapidly as possible, and then stored in a -70° C 
freezer until shipped.  
 
9.1.2.3. Shipping of Specimens  
 
Specimens should be batched on site. At completion, all specimens for a single patient should 
be shipped frozen on dry ice by overnight carrier Monday through Wednesday only. A 
completed specimen submission form (Appendix F) for each time point should accompany 
the shipment.  
 
Shipping Information:  
Philip C. Mack, Ph.D.  
Division of Hematology/Oncology  
University of California, Davis Cancer Center  
4501 X Street, Suite 3016  
Sacramento, CA 95817  
 
The Federal Guidelines for Shipment are as follows:  
 
1. The specimen must be wrapped in an adsorbent material;  
 
2. The specimen must be placed in an AIRTIGHT container (resealable bag);  
 
3. Pack the resealable bag and specimen in a Styrofoam shipping container along with 
enough dry ice to last for 2 days;  
 
4. Pack the Styrofoam shipping container in a cardboard box;  
 
5. The cardboard box must be labeled with a Hazardous Materials label for the Dry Ice.  
 
 
 
 
 
 
 
 
 
 


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10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks 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 (Table 10-1).  More frequent 
assessments should be obtained if clinically indicated.   


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Table 10-1.  Schedule of Assessments 
 
Study Treatment Period 
Post-Treatment Period 
Within 28 days 
Prior to 1st Dose of 
Study Treatment 
Within 14 days prior to 
the first dose of  Study 
Treatment 
Day 1 of Weeks  3, 5, 7, 9,  
11,  and 13 then every 4 
weeks (± 3 days) 
30 - 37 Days after last 
dose 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical and cancer history 
X 
 
 
 
Physical examination 
 
X 
X 
X 
Height 
X 
 
 
 
Weight 
 
X 
X 
X 
Vital signs 
 
X 
X 
X 
ECOG performance status 
 
X 
X 
X 
Clinical laboratory tests1  
 
X 
X 
X 
Urinalysis and UPCR 
 
X 
X 
X 
PT/INR, PTT 
 
X 
X2 
 
TFTs (TSH, free T3, free T4)  
 
X 
X2 
 
12-lead ECG 
 
X 
X2 
X 
XL184 (Cabozantinib) administration 
 
 
X (daily)3 
 
Erlotinib administration 
 
 
X (daily) 
 
Pregnancy test (serum)4 
X4 
 
X (every 8 weeks on study)4 
X 
Radiologic evaluation 
X 
 
X (performed every 2 
cycles; see section 11.1) 
 
Tumor assessment5 
X 
 
X (performed every 2 
cycles) 
 
Tumor specimen6 
X 
 
 
X7 
Blood for correlative studies8 
 
X 
X (every 4 weeks, at start of 
cycle) 
X 
Concomitant medications  
 
 
X 
X 
Adverse events 
Continuous 
X 
 


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ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; UPCR, urine protein/urine creatinine ratio 
1Laboratory tests should include a standard hematology panel (CBC, differential, platelets) and chemistry panel (albumin, alkaline phosphatase, ALT, amylase, AST, bicarbonate, 
bilirubin, blood urea nitrogen, calcium, chloride, creatinine, γ-glutamyltransferase (GGT), glucose, lactate dehydrogenase, lipase, magnesium, phosphorus, potassium, sodium, 
total bilirubin, total protein) 
2Done at week 4 then every 8 weeks.  Additional ECGs performed as clinically indicated. 
3Every other day dosing is allowed for dose modification, see Table 6-1.   
4Women of childbearing potential, within 14 days of study entry. To be repeated every 8 weeks while on study treatment. 
5All sites of known disease must be assessed. 
6See section 9 and Appendix G for details.   
7Optional: See section 9 and Appendix G for details. Post-treatment sample obtained for clinical indications will be collected as available within 6 months of study discontinuation. 
8Blood samples are to be obtained prior to treatment on the first day of each cycle and when the patient goes off study.  See section 9 and Appendix G for details. 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response after cycle 1 (4 
weeks) and then every 2 cycles (8 weeks).  In addition to a baseline scan, confirmatory scans 
should also be obtained at least 4 weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer, Therasse et al. 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 (cabozantinib) and erlotinib. 
 
Evaluable for objective response.  Patients who have measurable disease present at 
baseline and have received at least one dose of therapy will be considered evaluable for 
response.  These patients will have their response classified according to the definitions 
stated below.   
 
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). 
 
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. 


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‘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.  
 
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 


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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.   
 
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. 
 
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 


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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.  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. 


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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. 
 
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** 


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PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
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 
 
Progression free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 
 
 


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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). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for 
submitting data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov).  Note:  All adverse events that have occurred on the study, 
including those reported through CTEP-AERS, must be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to either 
the Coordinating Center or to the Lead Organization on the study quarterly.  The date for 
submission to the Coordinating Center or to the Lead Organization will be set by them.  
CDUS does not accept data submissions from the participants on the study.  When setting 
the dates, allow time for Coordinating Center compilation, Principal Investigator review, 
and timely submission to CTEP by the quarterly deadlines (see Section 12.1.1).  For trials 
monitored by CTMS, a quarterly report of data will be provided by Theradex to the 
Coordinating Center. 
 
The Coordinating Center is responsible for compiling and submitting CDUS data to 
CTEP for all participants and for providing the data to the Principal Investigator for 
review.   
 
12.1.3 Data Collection Forms and Submission Schedule 
 
All data will be collected using COH data collection forms via an electronic data 
capture system.  Any original data collection forms will reside at the originating 
institutions in secure location. 
 
ELIGIBILITY CHECKLIST:  The data manager at the registering site will have 
completed and faxed this form at the time of registration. 
ON-STUDY FORM (FORM OS):  Completed on-study forms due within two weeks 
of registration.  
TREATMENT FORM (FORM RX):  Completed treatment forms are due within 
four weeks of completion of a cycle.  
ADVERSE EVENT COLLECTION:  Completed adverse events collection form due 
within four weeks of completion of a cycle. 
FLOW SHEETS:  Protocol specific flow sheets are to be submitted along with each 
treatment form. 


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RESPONSE/OFF-STUDY/FOLLOW-UP:  Form F/U is to be submitted each time a 
patient is evaluated for response and/or new follow-up information is obtained.  
SUPPLEMENTAL DATA FORM: The timeline for submission of the supplemental 
data form will be protocol specific, if applicable. 
 
12.2 
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. 
 
12.3 
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 


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proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Design:  Simon’s optimal two-stage design is used.   
 
Primary endpoint: Objective response defined by RECIST.  
 
13.2 
Sample Size/Accrual Rate 
 
Enrollment will be done in two stages.  In the first stage, 12 patients will be treated.  If no 
patients exhibit a RECIST objective response, enrollment will be closed, unless the tumor 
growth rate (see secondary objective) provides sufficient evidence to proceed upon 
consultation with CTEP and the PI.  Otherwise, if 1 or more patients have an objective 
response, the study will continue enrollment to the final sample size of 37 subjects.  If 4 or 
more of the 37 patients respond, the trial will be regarded as indicating adequate activity in 
tumors with EGFR-mutations, providing other factors, such as toxicity and time to 
progression, also appear favorable.  The probability of indicating activity by this criterion is 
no more than 0.10 if the underlying response rate is 5%, and it is at least 0.90 if the underlying 
response rate is 20%.  
 
13.3 
Analysis of Secondary Endpoints 
 
1. Studies on targeted agents in a refractory patient population presents unique challenges in 
design: (1) publications from 1975 [Band and Kocandrle, 1975] and as recent as June 
2011 [Tourneau, et al, abstract #2603, ASCO 2011] suggest that therapy should not 
necessarily be stopped upon documented progression if the tumor growth is still showing 
signs of reduction from pre-treatment values [Band and Kocandrle, 1975]. (2) responses 
are expected to be rare due to the largely cytostatic nature of the agents, (3) historical 
benchmarks for PFS have limited utility in small studies in a heterogeneously and heavily 
pre-treated patient population and also due to the unknown impact of changes 
implemented as part of the new RECIST 1.1 criteria [Piatek, et al, abstract #2563, ASCO 
2011] and current scanning technology and schedules; (4) the effect of patient selection 
in referral cancer centers raises questions about single arm PFS results given variability 
of tumor growth rates, and (5) the limited patient population due to mutation specific 
selection precludes using designs employed in the larger randomized Phase II lung cancer 
studies in the consortium.  These challenges highlight the need for considering novel 
approaches to evaluating this drug combination in this setting.  
 
To address these multiple concerns, we will attempt to obtain a tumor growth estimate for 
each patient’s disease on the last erlotinib-based therapy. As patients will “fail” treatment 
on prior EGFR TKI, we will be usually be able to obtain at least two scans on the prior 
treatment to estimate the tumor growth rate, which will be estimated using an exponential 
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Additional scans will be used if available, and this will provide a unique look at the 
growth kinetics of lung cancer while being treated with EGFR TKIs. Patients whose 
progression is not measurable will be excluded from this endpoint, and when progression 
is based on new sites of disease, the previous tumor growth rate will be considered in the 
evaluation.  
 
Based on tumor growth rates, we can identify patients where the tumor doubling time has 
increased by at least 30% from the observed tumor growth rate during the prior TKI 
treatment, using each patient as their own control. This information will also be 
considered, along with toxicity and tolerability in both the interim and final analysis.   
 
Patients will come off study after progression, unless, in the opinion of the treating 
physician, the tumor doubling time continues to be more than 15% longer than the 
previous growth rate, and it is considered the best option for the patient.  [Tumor 
doubling time in the presence of multiple lesions will be taken as the median tumor 
doubling time when each tumor is considered independently].   
 
2. Additional secondary endpoints will include the type, severity (by NCI CTCAE), time 
of onset, duration, and outcome of toxicities, as well as progression-free survival rates 
and correlative tumor assays. Toxicity will be graded according to the NCI CTCAE 
version 4.0. Demographic and baseline clinical information will be collected. All 
radiographic responses will be evaluated by RECIST criteria and will be presented as 
waterfall plots. Survival and time to treatment failure will be summarized with 
Kaplan-Meier plots. Subset analysis by number of prior therapies, and prior erlotinib 
sensitivity will be evaluated. 
 
3. Analysis of Correlative Endpoints: Because of the limited sample size inherent to 
phase II studies, the analysis of secondary endpoints is primarily exploratory. Standard 
descriptive methods will be used to summarize the baseline levels and the changes 
from baseline (i.e. after treatment) which will allow us to examine whether observed 
patterns are consistent with hypothesized patterns. For example, the role of various 
EGFR mutations and other correlatives (e.g. MET amplification, VEGF and HGF 
levels) will also be considered. If the combination is not found to have sufficient 
activity, these patterns may help explain the lack of activity. If sufficient activity is 
found, then patients who experience an objective response will be compared to those 
who did not in terms of these correlates. Estimates of variation will also prove useful 
for future clinical research on this regimen. Formal testing of these comparisons is not 
planned. All analysis will clearly document the exploratory nature of these studies, 
although no attempt will be made to adjust for multiple comparisons inherent in 
correlative studies. 
 
13.4 
For phase 2 protocols only: Reporting and Exclusions 
 
13.4.1 Evaluation of Toxicity 
 


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All patients will be evaluable for toxicity from the time of their first treatment with XL184 
(cabozantinib) and erlotinib. NCI Common Terminology Criteria for Adverse Events v 4.0 
(CTCAE) will be used.  Unacceptable toxicity will be defined as any treatment-related (possible 
or higher attribution) toxicity that results in a >4 week delay in treatment or any toxicity resulting 
that the patient be taken off treatment. If in first 3 cycles, there are 3 patients with unacceptable 
toxicities in the first 10 patients, 4 in the first 16, 5 in the first 20, or 20% thereafter, the study 
will hold for review with the PI, the Data Safety and Monitoring Committee and the NCI 
regarding treatment modification or study termination. 
 
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.  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 9) unknown (not assessable, insufficient data).   
 
All of the patients who met the eligibility criteria (with the exception of those who received no 
study medication) will be included in the main analysis outcomes.  All patients will be 
summarized with regard to tumor response, time to progression, and toxicity.  Patients in 
response categories 4-9 will be considered treatment failures (i.e. classified with disease 
progression for the purpose of calculating response rates and disease control rates).  Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from the analysis 
of the response rate.  
 
 
14. CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS 
 
The protocol principal investigator (PI) is responsible for monitoring the conduct and 
progress of this Phase II trial, including the ongoing review of accrual, data and 
toxicities, as well as the accumulation of reported adverse events from other trials testing 
the same drug(s).  The participating clinicians and their designees are responsible for 
timely submission of adverse event reports (see Section 7.0) and case report forms.  The 
Data Coordinating Center for the CCCP Consortium is responsible for providing the PI 
with access to the submitted case report form data in summary and detail in a timely 
fashion.   Although the PI is responsible for evaluating the cumulative reported adverse 
events and the impact that these have on the continued conduct of the trial, it is the Data 
Coordinating Center of the CCCP that distributes all submitted SAE reports to the 
appropriate individuals, including the local protocol principal investigators, at each of the 
participating institutions.   
 
The Data Coordinating Center posts a summary (accrual, toxicities, and responses) of 
each CCCP initiated trial on the CCCP website.  In this way, each PI has access to up-to-
date information on the status of his or her trial.  In consultation with the collaborating 
statistician, the PI is responsible for review of: 
 
(a) 
for Phase I trials, all dose limiting toxicities and decisions regarding dose 


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escalation, expansion, as well as decisions to terminate escalation, and  
(b) 
for Phase II trials, the toxicities and therapeutic endpoints referred to in the 
statistical plan. 
 
The Data Coordinating Committee meets monthly to review data management and data 
quality issues – completeness of data submissions as well as accuracy in terms of built-in, 
computerized logic checks.  Any issues identified and the corrective plans are presented 
to the Internal Committee and at the next CCCP teleconference meeting for review and 
approval. 
 
Oversight 
Oversight of the conduct of CCCP trials occurs at several levels: 
 
1. 
The Data Coordinating Center for the CCCP flags all trials that are approaching a 
decision in terms of toxicity (for both Phase I and Phase II trials) or responses (for 
Phase II trials).  Decisions are made by the PI with input from the statistician and 
discussion with the principal investigator of the funding mechanism (U01 
Cooperative Agreement or N01 Contract, as appropriate) or his or her designee, 
and are communicated to the participating centers by the CCCP Data Coordinating 
Center. At the monthly teleconferences, the accrual of each open protocol is 
reviewed. 
 
2. 
For CTEP sponsored Phase I trials, data are reported to the NCI-designated 
clinical trials monitoring service (CTMS) which will audit patients’ records on 
each protocol – at each CCCP institution; this audit is initiated by CTEP.  For all 
other CCCP trials, the CCCP will contract with Theradex to audit patient records 
at each CCCP institution. 
 
3. 
An independent CCCP DSMC will review CCCP trials every 6 months. This 
DSMC will consist of 3 voting members (2 medical oncologists or hematologists 
involved in Phase I/II cancer clinical trials but not participating in CCCP studies, 
and a statistician) and a non-voting CCCP statistician.   
 
a. DSMC meetings will take place twice a year.  Additional meetings will be 
convened if necessary.  
b. This DSMC will review each CCCP trial in terms of accrual, toxicity/safety, 
and adherence to trial design, audit results, and likelihood of successful 
completion.   
c. The DSMC will report to the CCCP leadership. 
 
 
 


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15. REFERENCES 
 
Bean, J., C. Brennan, et al. (2007). "MET amplification occurs with or without T790M mutations 
in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib." Proc Natl 
Acad Sci U S A 104(52): 20932-20937. 
Becker, A., L. Crombag, et al. (2011). "Retreatment with erlotinib: Regain of TKI sensitivity 
following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI 
treatment." Eur J Cancer 47(17): 2603-2606. 
Bell, D. W., I. Gore, et al. (2005). "Inherited susceptibility to lung cancer may be associated with 
the T790M drug resistance mutation in EGFR." Nat Genet 37(12): 1315-1316. 
Benson, A. B., 3rd, J. A. Ajani, et al. (2004). "Recommended guidelines for the treatment of 
cancer treatment-induced diarrhea." J Clin Oncol 22(14): 2918-2926. 
Birchmeier, C., W. Birchmeier, et al. (2003). "Met, metastasis, motility and more." Nat Rev Mol 
Cell Biol 4(12): 915-925. 
Boccaccio, C. and P. M. Comoglio (2006). "Invasive growth: a MET-driven genetic programme 
for cancer and stem cells." Nat Rev Cancer 6(8): 637-645. 
Christensen, J. G., J. Burrows, et al. (2005). "c-Met as a target for human cancer and 
characterization of inhibitors for therapeutic intervention." Cancer Lett 225(1): 1-26. 
Comoglio, P. M., S. Giordano, et al. (2008). "Drug development of MET inhibitors: targeting 
oncogene addiction and expedience." Nat Rev Drug Discov 7(6): 504-516. 
Eisenhauer, E. A., P. Therasse, et al. (2009). "New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247. 
Engelman, J. A., K. Zejnullahu, et al. (2007). "MET amplification leads to gefitinib resistance in 
lung cancer by activating ERBB3 signaling." Science 316(5827): 1039-1043. 
Herbst, R. S., R. Ansari, et al. (2011). "Efficacy of bevacizumab plus erlotinib versus erlotinib 
alone in advanced non-small-cell lung cancer after failure of standard first-line 
chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial." Lancet 
377(9780): 1846-1854. 
Jeffers, M., L. Schmidt, et al. (1997). "Activating mutations for the met tyrosine kinase receptor 
in human cancer." Proc Natl Acad Sci U S A 94(21): 11445-11450. 
Kurzrock, R., S. I. Sherman, et al. (2011). "Activity of XL184 (Cabozantinib), an oral tyrosine 
kinase inhibitor, in patients with medullary thyroid cancer." J Clin Oncol 29(19): 2660-
2666. 
Liu, X., R. C. Newton, et al. (2010). "Developing c-MET pathway inhibitors for cancer therapy: 
progress and challenges." Trends Mol Med 16(1): 37-45. 
Lynch, T. J., D. W. Bell, et al. (2004). "Activating mutations in the epidermal growth factor 
receptor underlying responsiveness of non-small-cell lung cancer to gefitinib." N Engl J 
Med 350(21): 2129-2139. 
Miller, V. A., V. Hirsch, et al. (2010). "Phase IIB/III double-blind randomized trial of afatinib + 
best supportive care (BSC) versus placebo + BSC in patients with NSCLC failing 1-2 
lines of chemotherapy and erlotinib or gefitinib (LUX-LUNG 1)." Ann Oncol 21(S8): 
Abstract LBA1. 
Mitsudomi, T., S. Morita, et al. (2010). "Gefitinib versus cisplatin plus docetaxel in patients with 
non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor 
(WJTOG3405): an open label, randomised phase 3 trial." Lancet Oncol 11(2): 121-128. 
Mok, T. S., Y. L. Wu, et al. (2009). "Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma." N Engl J Med 361(10): 947-957. 


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Paez-Ribes, M., E. Allen, et al. (2009). "Antiangiogenic therapy elicits malignant progression of 
tumors to increased local invasion and distant metastasis." Cancer Cell 15(3): 220-231. 
Paez, J. G., P. A. Janne, et al. (2004). "EGFR mutations in lung cancer: correlation with clinical 
response to gefitinib therapy." Science 304(5676): 1497-1500. 
Pao, W., V. A. Miller, et al. (2005). "Acquired resistance of lung adenocarcinomas to gefitinib or 
erlotinib is associated with a second mutation in the EGFR kinase domain." PLoS Med 
2(3): e73. 
Roskoski, R., Jr. (2008). "VEGF receptor protein-tyrosine kinases: structure and regulation." 
Biochem Biophys Res Commun 375(3): 287-291. 
Schmidt, L., F. M. Duh, et al. (1997). "Germline and somatic mutations in the tyrosine kinase 
domain of the MET proto-oncogene in papillary renal carcinomas." Nat Genet 16(1): 68-
73. 
Sennino, B., R. M. Naylor, et al. (2009). "Reduction of tumor invasiveness and metastasis and 
prolongation of survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by 
XL184." Mol Cancer Ther 8: Abstract A13. 
Sequist, L. V., J. von Pawel, et al. (2011). "Randomized phase II study of erlotinib plus 
tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer." 
J Clin Oncol 29(24): 3307-3315. 
Sequist, L. V., B. A. Waltman, et al. (2011). "Genotypic and histological evolution of lung 
cancers acquiring resistance to EGFR inhibitors." Sci Transl Med 3(75): 75ra26. 
Shawver, L. K., D. Slamon, et al. (2002). "Smart drugs: tyrosine kinase inhibitors in cancer 
therapy." Cancer Cell 1(2): 117-123. 
Su, K. Y., H. Y. Chen, et al. (2012). "Pretreatment Epidermal Growth Factor Receptor (EGFR) 
T790M Mutation Predicts Shorter EGFR Tyrosine Kinase Inhibitor Response Duration in 
Patients With Non-Small-Cell Lung Cancer." J Clin Oncol 30(4): 433-440. 
Tibaldi, C., E. Giovannetti, et al. (2011). "Inherited germline T790M mutation and somatic 
epidermal growth factor receptor mutations in non-small cell lung cancer patients." J 
Thorac Oncol 6(2): 395-396. 
Tugues, S., S. Koch, et al. (2011). "Vascular endothelial growth factors and receptors: anti-
angiogenic therapy in the treatment of cancer." Mol Aspects Med 32(2): 88-111. 
Turke, A. B., K. Zejnullahu, et al. (2010). "Preexistence and clonal selection of MET 
amplification in EGFR mutant NSCLC." Cancer Cell 17(1): 77-88. 
Yakes, F. M., J. Chen, et al. (2011). "Cabozantinib (XL184), a novel MET and VEGFR2 
inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth." Mol 
Cancer Ther 10(12): 2298-2308. 
You, W. K., B. Sennino, et al. (2011). "VEGF and c-Met blockade amplify angiogenesis 
inhibition in pancreatic islet cancer." Cancer Res 71(14): 4758-4768. 
Zhang, S., H. E. Zhau, et al. (2010). "Vascular endothelial growth factor regulates myeloid cell 
leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in 
human prostate cancer cells." Mol Cancer 9: 9. 
 
 
 


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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. 
Inclusion of Multicenter Guidelines in the Protocol 


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• 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) and erlotinib.  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 (cabozantinib and erlotinib interact 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 (cabozantinib) and erlotinib interact with (a) certain specific enzyme(s) in your liver.  
• The enzyme(s) in question is CYP3A4.  This enzyme breaks down XL184 (cabozantinib) 
and erlotinib, gradually reducing the level of the active drug in your system.    
• Other medicines may affect the activity of the enzyme.  XL184 (cabozantinib) and erlotinib 
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 of CYP3A4.” 
• Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 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 


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day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit or Seville oranges:  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 and erlotinib). 
 
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.  Your study 
doctor’s name is  
 
 
_____________________________________  
 
and he or she can be contacted at  
 
_____________________________________ 
 
 


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INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent XL184 
(cabozantinib) and erlotinib.  This clinical trial is sponsored by the 
NCI.  XL184 (cabozantinib) and erlotnib interact 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. 
XL184 (cabozantinib)  and erlotinib interact 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/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ____________________________ 
and can be contacted at ____________________________.  


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APPENDIX D 
PATIENT’S MEDICATION DIARY 
PATIENT’S MEDICATION DIARY 
 
Today’s date _____________________        Cycle Number: __________        Agents:  XL184 (Cabozantinib) and Erlotinib 
Patient Name_____________________(initials acceptable)  
            Patient Study ID ________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take XL184 (cabozantinb) tablets by mouth every day (or every other day).  You should take the tablets on an empty 
stomach at least 2 hours before food and 1 hour after a meal.  Dose:  take ________ 20 mg tablets. 
3.     You will take Erlotinib tablets by mouth once a day.  You should take the tablets on an empty stomach at 2 hours before food and 1 
hour after a meal.  Dose:  take _____ x __________ mg tablet(s). 
4. 
Record the date, the number of tablets of each size of tablet that you took, and when you took them.   
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 bottles of XL184 (cabozantinib) and Erlotinib tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of dose  
XL184 (cabozantinib) 
# of tablets taken 
Erlotinib # of 
tablets taken 
Comments 
 mg 
 mg 
 
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Patient’s signature  _________________________________________________________________________ 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment______________     2. Date patient was removed from study_______________ 
3. Patient’s planned total daily dose ___________________________________________________________________  
3. Total number of tablets taken this month XL184 (cabozantinib)_________________  Erlotinib_________________  
4. Physician/Nurse/Data Manager’s Signature  ___________________________________________________________  
 
CTEP-assigned Protocol # 9303 
Consortium Protocol PhII-125 
Local Protocol # ___________________ 


NCI Protocol #: 9303 
Consortium Protocol # PhII-125 
Version Date: January 24, 2014 
 
97 
APPENDIX E         CCCP REGISTRATION PROCEDURES FOR PHASE II TRIALS 
 
1. 
Registrations for Phase II protocols must be made through the California Cancer 
Consortium office at the City of Hope between the hours of 8:30 a.m. to 4:30 p.m., 
Monday through Friday (except holidays). 
 
2. 
Patients must be registered within 5 days prior to initiation of protocol therapy. 
 
3. 
A patient failing to meet all protocol requirements may not be registered.  If you have any 
questions regarding eligibility, contact the City of Hope Data Coordinating Center (DCC) 
at (626) 256-HOPE (4673), extension 65928. 
 
4. 
Prestudy laboratory tests, scans and x-rays must be completed prior to registration 
according to study calendar/protocol. 
 
5. 
Patients must sign an informed consent prior to registration. 
 
6. 
Confirm that the patient meets all inclusion and exclusion eligibility criteria for a 
protocol. 
 
7. 
Complete the Eligibility Checklist.   
 
8. 
Verify that all required prestudy tests were performed. 
 
9. 
Email the completed Eligibility Checklist, signed and dated informed consent, pathology 
report, and relevant laboratory results to the City of Hope Consortium Coordinator for 
confirmation of eligibility.  The email is cccp@coh.org.  
 
10. 
Call the City of Hope Consortium Coordinator at (626) 256-HOPE (4673), extension 
65928 to confirm the email sent. If the Consortium Coordinator is not in the office, have 
them paged at (626) 423-5365. 
 
11. 
If the patient qualifies, the City of Hope Consortium Coordinator will call the registering 
institution to complete the registration/randomization procedure and assign the patient's 
study ID number.   
 
12. 
Once a patient has been registered, the Data Coordinating Center will provide a 
"Confirmation of Registration" to the center registering the patient.  
 
 
For questions regarding eligibility call City of Hope California Cancer Consortium, Data 
Coordinating Center 
(626) 256-HOPE (4673), extension 65928 
 
 
 


NCI Protocol #: 9303 
Consortium Protocol # PhII-125 
Version Date: January 24, 2014 
 
98 
APPENDIX F 
CCCP SPECIMEN SUBMISSION FORM 
 
Please contact the Data Coordinating Center at cccp@coh.org for the CCCP Specimen 
Submission Form.  The form will be emailed to the participating institution when the study has 
been activated.   


NCI Protocol #: 9303 
Consortium Protocol # PhII-125 
Version Date: January 24, 2014 
 
99 
APPENDIX G 
CORRELATIVE STUDIES 
 
Collection, processing and shipment 
 
• Cryovials (1.5 – 2 mL size) must be labeled with the protocol number (PhII-125), Consortium 
patient ID, patient’s initials, date of specimen collection, and specimen type.  
 
• Collect ~8 mL whole blood in a purple top (EDTA) tube.  
 
• Immediately invert tube (gently) 8 – 10 times. This reduces the possibility of clot formation.  
 
• Place tube on wet ice or refrigerate until centrifugation.  
 
• Within 2 hours of blood draw, centrifuge sample at 800 x G for 10 minutes.  
 
• Immediately after centrifuging, transfer plasma in 1 mL aliquots to 4 labeled cryovials.  
• Pipette slowly to avoid disturbing the buffy coat layer.  
• Leave a small amount of plasma (~ .5 cm) above the buffy coat layer.  
 
• After removing plasma, transfer buffy coat to 1 labeled cryovial.  
• The buffy layer is the off-white layer between the plasma and the red blood cells.  
• Pipette slowly in a circular motion to obtain as many buffy coat cells as possible.  
• Contamination of the buffy coat with red blood cells is expected and not a concern. There 
is no need to further purify the white blood cells with a Ficol separation.  
 
• Snap-freeze cryovials in liquid nitrogen (if available).  
 
• Store cryovials in a -70° C freezer until shipped.  
 
Shipping Instructions  
Prior to shipping, the Specimen Submission Form (please email cccp@coh.org for a copy of the 
form) should be faxed to the Statistical Center at the City of Hope AND the Mack lab (916-734-
2361).  
 
The frozen specimens (along with completed Specimen Submission Forms) should be shipped 
on dry ice by overnight courier Monday through Wednesday to:  
Philip C. Mack, Ph.D.  
Division of Hematology/Oncology  
University of California, Davis Cancer Center  
4501 X Street, Suite 3016  
Sacramento, CA 95817  
 
Contact:  
Leslie J. Snyder or Philip C. Mack  
Phone: 916/734-3734  
E-mail: Leslie.Snyder@ucdmc.ucdavis.edu  


NCI Protocol #: 9303 
Consortium Protocol # PhII-125 
Version Date: January 24, 2014 
 
100 
 
The Federal Guidelines for Shipment are as follows:  
 
6. The specimen must be wrapped in an adsorbent material;  
 
7. The specimen must be placed in an AIRTIGHT container (resealable bag);  
 
8. Pack the resealable bag and specimen in a Styrofoam shipping container along with enough 
dry ice to last for 2 days;  
 
9. Pack the Styrofoam shipping container in a cardboard box;  
 
10. The cardboard box must be labeled with a Hazardous Materials label for the Dry Ice.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: 9303 
Consortium Protocol # PhII-125 
Version Date: January 24, 2014 
 
101 
APPENDIX H 
GUIDELINES FOR TISSUE BIOPSIES 
 
 
 
Definitions 
• 
Invasive biopsies: accessing thorax, liver, or soft tissue or deep nodes within the 
abdomen 
 
• 
Minimally invasive biopsies(and thoracentesis/paracentesis): superficial nodes, 
cutaneous or superficial lesions, bone biopsies, abdominal ascites or pleural 
effusions (when collection occurs for patient management) 
 
Collection Windows 
• 
Invasive biopsies: All invasive biopsies should be completed 28 days prior to first 
dose of cabozantinib. No invasive biopsies should be performed while on 
cabozantinib treatment. Subsequent invasive biopsy procedures should not be 
performed within 21 days after last dose of cabozantinib if possible due to the half 
life of the drug. 
 
• 
Minimally invasive biopsies(and thoracentesis/paracentesis): Minimally invasive 
biopsies are allowed at any time prior to first dose and while the subject is on 
cabozantinib treatment, providing that attention is given to potential effects of 
cabozantinib on wound healing, fistula formation or perforations. No tumors 
continguous with the esophagus or trachea should be accessed while on 
cabozantinib treatment"