A Phase 2 Study of XL184 (Cabozantinib) in Treating Patients With Relapsed Osteosarcomas and Ewing Sarcomas
Phase: PHASE2
Conditions: Metastatic Ewing Sarcoma, Metastatic Osteosarcoma, Recurrent Ewing Sarcoma, Recurrent Osteosarcoma, Stage III Osteosarcoma AJCC v7, Stage IV Osteosarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7, Unresectable Ewing Sarcoma, Unresectable Osteosarcoma
Sponsor: National Cancer Institute (NCI)

i 
 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment # to: 
 
NCI Protocol #: 9620 
Local Protocol #: CABONE 
 
NCI Version Date: 04/04/2019 
Protocol Date: 04/04/2019 
 
Please provide a list of changes from the previous CTEP approved version of the protocol. The 
list shall identify by page and section each change made to a protocol document with hyperlinks 
to the section in the protocol document.  All changes shall be described in a point-by-point 
format (i.e., Page 3, section 1.2, replace ‘xyz’ and insert ‘abc’). When appropriate, a brief 
justification for the change should be included. 
 
As requested by your request for Amendment, protocol has been updated. 
 
# 
Section 
Comments 
1. 
Protocol 
1) New Protocol Amendment/Version Date Included on the Title/Cover Page per Operations 
Office Policy: 
 
Protocol Cover Page: Page Number(s):  5 
Version Date: 04/04/2019 
2. 
Section 7.1 
2) Revision of the Protocol CAEPR: 
 
Protocol Section(s) for Insertion of Revised CAEPR (Version 2.4, December 17, 2018): 
7.1 
Page Number(s): 54 
 
• The SPEER grades have been updated. 
• The section below utilizes CTCAE 5.0 language unless otherwise noted. 
 
• 
Added New Risk: 
• 
Also Reported on XL184 Trials But With Insufficient Evidence for 
Attribution: Anal mucositis; Atrioventricular block complete; Budd-Chiari 
syndrome; Cardiac disorders - Other (hypokinetic cardiomyopathy); Chest 
wall pain; Death NOS; Dysphasia; Ejection fraction decreased; 
Gastroesophageal reflux disease; Gastrointestinal pain; General disorders and 
administration site conditions - Other (general physical health deterioration); 
Gingival pain; Hepatobiliary disorders - Other (hepatic thrombus); 
Hepatobiliary disorders - Other (hepatorenal syndrome); Hoarseness; 
Hypothermia; Pain of skin; Pelvic pain; Periodontal disease; Scrotal pain; 
Sinus bradycardia; Sinus tachycardia; Skin hypopigmentation; Sudden death 
NOS; Thyroid stimulating hormone increased; Toothache; Vaginal 
inflammation; Vaginal perforation 
 

ii 
# 
Section 
Comments 
• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on XL184 Trials But With 
Insufficient Evidence for Attribution: Generalized muscle weakness; 
Hematuria; Hypophosphatemia 
• 
Changed to Rare but Serious from Also Reported on XL184 Trials But With 
Insufficient Evidence for Attribution: Intracranial hemorrhage; Ischemia 
cerebrovascular; Stroke; Transient ischemic attacks 
 
• 
Decrease in Risk Attribution: 
• 
Changed to Less Likely from Likely: Voice alteration  
• 
Changed to Also Reported on XL184 Trials But With Insufficient Evidence 
for Attribution from Less Likely: Acute kidney injury  
 
• 
Provided Further Clarification: 
• 
Footnote #8 has been updated to “Respiratory hemorrhage includes 
Bronchopulmonary hemorrhage, Epistaxis, Hemoptysis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural 
hemorrhage under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC” from “Respiratory hemorrhage includes 
Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage 
under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC.” 
• 
Musculoskeletal and connective tissue disorder - Other (muscle spasm) 
(CTCAE 4.0 language) is now reported as Muscle cramp.  
• 
Skin and subcutaneous tissue disorders - Other (hair color changes) (CTCAE 
4.0 language) is now reported as Hair color changes. 
• 
Acute coronary syndrome is now reported as part of Chest pain - cardiac. 
• 
Endocrine disorders - Other (hypopituitarism) (CTCAE 4.0 language) is now 
reported as Hypopituitarism. 
• 
Gastrointestinal disorders - Other (gastroenteritis) is now reported as part of 
Infection.  
• 
Gastrointestinal disorders - Other (anal fissure) (CTCAE 4.0 language) is 
now reported as Anal fissure. 
• 
Investigations - Other (blood lactate dehydrogenase increased) (CTCAE 4.0 
language) is now reported as Blood lactate dehydrogenase increased. 
• 
Investigations - Other (eosinophil count increased) (CTCAE 4.0 language) is 
now reported as Eosinophilia under the BLOOD AND LYMPHATIC 
SYSTEM DISORDERS SOC.  
• 
Investigations - Other (glucose urine present) (CTCAE 4.0 language) is now 
reported as Glucosuria under the RENAL AND URINARY DISORDERS 
SOC. 
• 
Musculoskeletal and connective tissue disorder - Other (osteonecrosis) 
(CTCAE 4.0 language) is now reported as Osteonecrosis.  
• 
Musculoskeletal and connective tissue disorder - Other (rhabdomyolysis) 
(CTCAE 4.0 language) is now reported as Rhabdomyolysis.  
• 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(tumor hemorrhage) (CTCAE 4.0 language) is now reported as Tumor 
hemorrhage. 

iii 
# 
Section 
Comments 
• 
Nervous system disorders - Other (cerebral hematoma) is now reported as 
part of Hematoma under the VASCULAR DISORDERS SOC.  
• 
Nervous system disorders - Other (spinal cord compression) (CTCAE 4.0 
language) is now reported as Spinal cord compression. 
• 
Renal and urinary disorders - Other (azotemia) is now part of Acute kidney 
injury.  
• 
Respiratory, thoracic and mediastinal disorders - Other (oropharyngeal pain) 
(CTCAE 4.0 language) is now reported as Oropharyngeal pain. 
• 
Skin and subcutaneous tissue disorders - Other (splinter hemorrhage) is now 
reported as Nail changes.  
 
 
PLEASE NOTE:  The specific detailed changes listed here compare the new revised 
CAEPR Version 2.4, and associated risk information for the ICD, to the most recent 
CAEPR Version 2.3.   If your trial contains an older CAEPR version (i.e., does NOT 
currently contain CAEPR Version 2.3), you MUST include a description of any 
additional changes resulting from migration from the older CAEPR version. 
 
 
 

 
1 
NCI Protocol #: 
9620 
 
Local Protocol #: 
CABONE. 
 
TITLE:  A Phase 2 Study of XL184 (Cabozantinib) in treating patients with relapsed 
Osteosarcomas and Ewing Sarcomas 
 
 
 
Coordinating Center: 
 
 
Institut Bergonié (Bordeaux, France)  
 
*Principal Investigator: 
 
Italiano Antoine, MD, PhD  
Institut Bergonie, Department of Medical Oncology  
229 cours de l’Argonne  
33000 Bordeaux, France 
+ 33 5 56 33 33 33 
+ 33 5 56 33 04 85  
a.italiano@bordeaux.unicancer.fr  
 
Co-Investigators: 
 
Maud Toulmonde MD 
Institut Bergonie, Department of Medical Oncology  
229 cours de l’Argonne  
33000 Bordeaux, France 
Tel : + 33 5 56 33 33 33 
Fax: + 33 5 56 33 33 85  
m.toulmonde@bordeaux.unicancer.fr 
 
Others Centers : 
Jean-Yves Blay, MD, PhD, Isabelle Ray-Coquard, MD, Perrine Marec-Berard, MD ;Christophe 
Bergeron, MD; Olivia Bally, MD and Medhi Brahmi, MD 
Centre Léon Bérard, Department of Medical Oncology 
28, rue Laennec  
69373 Lyon Cedex 08, France 
Tel: +33 4 78 78 28 28 
Fax: + 33 4 78 78 29 29   
jean-yves.blay@lyon.unicancer.fr ; isabelle.ray-coquard@lyon.unicancer.fr ;  perrine.marec-
berard@lyon.unicancer.fr; christophe.bergeron@lyon.unicancer.fr, 
olivia.bally@lyon.unicancer.fr, medhi.brahmi@lyon.unicancer.fr                                           
 
Olivier Mir, MD, Julien Domont, MD, Axel Le Cesne, MD ; Olivier Mir, MD ; Elsa 
Nathalie,Gaspar, MD , and Laurence Brugieres, MD  
Institut Gustave Roussy, Department of Medecine     
39 rue Camille Desmoulins 
94800 Villejuif, France  

NCI Protocol #: 9620 
Version Date: 04/04/2019 
 
2 
Tel: +33 1 42 11 43 16 
Fax: + 33 1 42 11 52 19 
julien.domont@gustaveroussy.fr ; axel.lecesne@gustaveroussy.fr ; Olivier.mir@gustaveroussy.fr 
; nathalie.gaspar@gustave.roussy.fr ; Laurence.brugieres@gustaveroussy.fr ;  
 
Nicolas Penel, MD, Antoine Adenis, MD, PhD, Fredrick Laestadius, MD, PhD, Anne-Sophie 
Defachelles-Thomassin, MD, Cyril Lervat, MD, Diane Pannier, MD and Thomas Ryckewaert, 
MD 
Centre Oscar Lambret, Department of General Oncology                                                            
3, rue Frédéric Combemale 
BP 307 - 59020 LILLE Cedex, France 
Tél. : +33 3 20 29 59 20   
Fax: +33 3 20 29 59 63 
n-penel@o-lambret.fr; a-adenis@o-lambret.fr; f-laestadius@o-lambret.fr; c-lervat@o-lambret.fr, 
as-defachelles@o-lambret.fr ; d-pannier@o-lambret.fr; t-ryckewaert@o-lambret.fr  
 
Sophie Piperno-Neumann, MD; Valérie Laurence, MD, Sarah Cohen-Gogo, MD; Aurore 
Surun, MD; François Doz, MD; Jean Michon, MD; Irène Jimenez, MD; Isabelle Aerts, MD; 
Daniel Orbach, MD; Dominique Levy, MD and Gudrun Schleiermacher, MD   
Institut Curie, Department of Medecine                                                                                        
25 rue d’ULM 
75005 Paris, France  
Tél : +33 1 44 32 46 80 
Fax : +33 1 44 32 46 71  
sophie.piperno-neumann@curie.net ; valerie.laurence@curie.net; Sarah.cohen-gogo@curie.fr, 
aurore.surun@curie.fr, francois.doz@curie.fr, jean.michon@curie.fr, irene.jimenez@curie.fr, 
isabelle.aerts@curie.fr, daniel.orbach@curie.fr, dominique.levy@curie.fr, 
gudrun.schleiermacher@curie.fr 
 
Chevreau Christine, MD, Alberto Gomez Rocca, MD, Cécile Gandy, MD, Ewa Cottura, MD, 
Sarah Zahi, MD and; Valentin, MD 
Institut Claudius Regaud, IUCT-Oncopole - Department of Medecine 
1 Avenue Irène Joliot-Curie 
31052 Toulouse Cedex 09, France 
Tél : +33  
Fax : +33 
Chevreau.christine@iuct-oncopole.fr, gomez.carlos@iuct-oncopole.fr, gandy.cecile@iuct-
oncopole.fr, cottura.ewa@iuct-oncopole.fr, zahi.sarah@iuct-oncopole.fr  
 
Emmanuelle Bompas, MD, Frederic Rolland, MD; Damien Vansteene, MD, Mathilde Cabart, 
MD and Carole Gourmelon, MD 
Institut de Cancérologie de l’Ouest – Site René Gauducheau 
Boulevard Jacques Monod 
44805 Nantes St-Herblain, France 
Tél : +33 2 40 67 99 39 
Fax : +33 2 

NCI Protocol #: 9620 
Version Date: 04/04/2019 
 
3 
emmanuelle.bompas@ico.unicancer.fr, frederic.rolland@ico.unicancer.fr; 
damien.vansteene@ico.unicancer.fr ; Mathilde.cabart@ico.unicancer.fr, 
carole.gourmelon@ico.unicancer.fr  
 
Nicolas Isambert, MD, Sylvie Zanetta, MD and Anne-Laure Simonet Lamm 
Centre Georges François Leclerc 
1 rue du Professeur Marion – BP 77980 
21079 Dijon, France 
Tél : +33 3 80 73 75 06 
Fax : +33 3 80 73 77 74 
nisambert@cgfl.fr ; szanetta@cgfl.fr; allaam@cgfl.fr  
 
Florence Duffaud, MD, PhD ; Sébastien Salas, MD, Arnauld Verschuur, MD ; Jean-Claude 
Gentet 
Hôpital La Timone 
254 rue Saint Pierre 
13385 Marseille Cedex 5, France 
Tél : +33 4 91 38 74 14 
Fax : +33 4 91 38 76 58 
Florence.duffaud@ap-hm.fr, sebastien.salas@ap-hm.fr, arnauld.verschuur@ap-hm.fr, jean-
claude.gentet@ap-hm.fr 
 
Antoine Thyss, MD, PhD, Esma Saâda, MD and Lauris Gastaud, MD  
Centre Antoine Lacassagne 
33 avenue de Valombrose 
06189 Nice Cedex 02, France 
Tél : +33 4 92 03 14 97 
Fax : +33 4 92 03 10 47 
antoine.thyss@nice.unicancer.fr; esma.saada@nice.unicancer.fr; 
lauris.gastaud@nice.unicancer.fr  
 
Natacha Entz-Werle, MD PhD and Jean-Emmanuel Kurtz, MD PhD 
CHRU Strasbourg Hautepierre 
Avenue Molière 
67098 Strasbourg Cedex, France 
Tél : +33 3 88 12 80 97 
Fax : +33 3 88 12 80 92 
Natacha.entz-werle@chru-strasbourg.fr; jean-emmanuel.kurtz@chru-strasbourg.fr  
 
 
 

NCI Protocol #: 9620 
Version Date: 04/04/2019 
 
4 
Statistician:                                                 
    Study Coordinator: 
Carine Bellera, PhD                                       
   Antoine ITALIANO, MD, PhD 
Institut Bergonié                                             
   Institut Bergonié, Department of Medical                
Oncology 
229 cours de l’Argonne                                  
   229 cours de l’Argonne 
33000 Bordeaux, France                                
   33000 Bordeaux, France 
Tel: + 33 5 56 33 04 95                                           Tel: + 33 5 56 33 33 33 
Fax: + 33 5 56 33 04 85  
   Fax: + 33 5 56 33 33 85 
c.bellera@bordeaux.unicancer.fr                             a.italiano@bordeaux.unicancer.fr                                       
 
Responsible Clinical Research Assistant: 
 
Responsible Data Manager: 
Sabrina SELLAN-ALBERT, MSc 
Marina PULIDO, MSc 
Institut Bergonié 
Institut Bergonié 
229 cours de l’Argonne 
229 cours de l’Argonne 
33000 Bordeaux, France 
33000 Bordeaux, France 
Tel: +  33 5 56 33 78 05 
Tel : + 33 5 56 33 19 29 
Fax: + 33 5 56 33 04 85 
Fax: + 33 5 56 33 04 85 
s.albert@bordeaux.unicancer.fr   
m.pulido@bordeaux.unicancer.fr   
 
 
Exelixis Supplied Agent:  XL184 (cabozantinib) (NSC 761968) 
 
 
Below, please describe the IND Status of this study by choosing IND #/Sponsor OR Exemption 
from IND requirements, making sure to delete the inapplicable field(s). 
 
IND #:  116059 
IND Sponsor:  DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: 
Original, Version 9.0, 04/04/2019 
 
 

NCI Protocol #: 9620 
Version Date: 04/04/2019 
 
5 
SCHEMA 
SYNOPSIS 
 
A Phase II study of XL 184 (Cabozantinib) in treating patients with relapsed Osteosarcomas and Ewing Sarcomas 
PROTOCOL CODE  
NCI Protocol 9620 
PRINCIPAL 
INVESTIGATOR  
 Italiano Antoine, MD, PhD  
 Institut Bergonie 
 Department of Medical Oncology  
 229 cours de l’Argonne  
 33000 Bordeaux, France 
 Tel : + 33 5 56 33 33 33 
 Fax : + 33 5 56 33 04 85    
 a.italiano@bordeaux.unicancer.fr 
 
STUDY OBJECTIVES  
Primary  
To evaluate the antitumor activity of cabozantinib in terms of : 
• 
Osteosarcoma: 6-month non-progression (Complete response, partial response 
and stable disease) and 6-month objective response (Complete response, partial 
response) rates (composite endpoint) as per the Response Evaluation Criteria in 
Solid Tumors, Revised RECIST v1.1. 
• 
Ewing sarcoma: 6-month objective response as per the revised RECIST v1.1. 
Secondary  
 
Ewing sarcoma only: 6-month objective response rate 
Both strata:  
 
Best overall response (as per the revised RECIST v1.1);  
 
1- and 2-year progression-free survival; 
 
1- and 2-year overall survival; 
 
Cabozantinib safety; 
 
To assess the ability of metabolic tumor response as measured by FDG-PET at 
the end of one cycle of treatment to predict PFS. 
 
Translational research: to determine and compare tumor expression of MET, 
phospho-MET and circulating levels of HGF, soluble MET (sMET), VEGF-A, 
and soluble VEGFR2 (sVEGFR2) prior to and following administration of 
cabozantinib.  
STUDY DESIGN  
Single-arm phase 2 clinical trials  with two strata:  
- 
Osteosarcoma: dual-endpoint design. 
- 
Ewing sarcoma: optimal 2-stage Simon’s design. 
STUDY POPULATION  
Patients aged 12 years or older with unresectable locally advanced or metastatic 
osteosarcoma or Ewing sarcoma  
INCLUSION CRITERIA 
1. Patients must have histologically confirmed diagnosis of osteosarcoma or Ewing 
sarcoma by central review, except if the diagnosis was already confirmed by the 
RRePS (Réseau de Référence en Pathologie des Sarcomes et des Tissus Mous et des 
Viscères) network. 
2. Relapsed disease after standard chemotherapy. 
3. Patients must have measurable disease (lesion in previously irradiated field could 
be considered as measurable if progressive at inclusion) defined as per RECIST v1.1 
with at least one lesion that can be measured in at least one dimension (longest 
diameter to be recorded) as > 10 mm with spiral CT scan. 
4. Age ≥12 years.  
5. ECOG performance status ≤1 (see Appendix A). 
6. Life expectancy of greater than 3 months. 
7. Patients must have normal organ and marrow function as defined below: 

NCI Protocol #: 9620 
Version Date: 04/04/2019 
 
6 
- leukocytes ≥3,000/mcL 
- absolute neutrophil count ≥1,500/mcL 
- lymphocyte count >1,000/mcL 
- platelets ≥100,000/mcL 
- total bilirubin ≤1.5 × ULN 
- AST(SGOT)/ALT(SGPT) ≤3.0 × institutional upper limit of normal  
- creatinin ≤1.5 × ULN OR creatinine clearance ≥50 mL/min/1.73 m2 for patients 
with creatinine levels above institutional normal (Cockcroft formula, see Appendix 
I). 
- hemoglobin ≥9 g/dL 
- serum albumin ≥2.8g/dL 
- lipase <2.0 × ULN and no radiologic or clinical evidence of pancreatitis 
- urine protein/creatinine, ratio (UPCR)  ≤1 
- serum phosphorus, calcium, magnesium, and potassium ≥ LLN  
8. Female subjects of childbearing potential must not be pregnant at screening. 
Females of childbearing potential are defined as premenopausal females capable of 
becoming pregnant (ie, females who have had any evidence of menses in the past 
12 months, with the exception of those who had prior hysterectomy). However, 
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, low body weight, ovarian suppression or other reasons. 
9. The effects of 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 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 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). 
10. Metastatic or unresectable locally advanced. 
11. Documented disease progression (as per RECIST v1.1) before study entry. For 
patients with osteosarcoma, this progression will be confirmed by central review on 
the basis of two CT scan or MRI obtained at less than 6 months in the period of 12 
months prior to inclusion.  
12. Ability to understand and the willingness to sign a written informed consent 
document. 
13. In accordance with French Regulatory Authorities: Patients with French Social 
Security in compliance with the French law relating to biomedical research (Article 
L.1121-11 of French Public Health Code). 
EXCLUSION CRITERIA 
 
 
 
 
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. 
2. Prior treatment with Cabozantinib. 
3. Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before the first dose of study treatment. Systemic treatment 
with radionuclides within 6 weeks before the first dose of study treatment. Subjects 
with clinically relevant ongoing complications from prior radiation therapy are not 

NCI Protocol #: 9620 
Version Date: 04/04/2019 
 
7 
eligible. 
4. Receipt of any type of small molecule kinase inhibitor (including investigational 
kinase inhibitor) within 14 days before the first dose of study treatment. Note: 
Subjects with prostate cancer currently receiving LHRH or GnRH agonists may be 
maintained on these agents. 
5. The subject has received any other type of investigational agent within 28 days 
before the first dose of study treatment. 
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. 
7. The subject has a primary brain tumor. 
8. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 2 weeks 
before the first dose of study treatment. Eligible subjects must be neurologically 
asymptomatic and without corticosteroid treatment at the time of the start of study 
treatment. 
9. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or 
partial thromboplastin time (PTT) test ≥1.3 × the laboratory ULN within 7 days 
before the first dose of study treatment. 
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. 
11. The subject requires chronic concomitant treatment of strong CYP3A4 inducers 
(e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort). Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/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. 
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 
13. The subject has radiographic evidence of cavitating pulmonary lesion(s). 
14. The subject has tumor in contact with, invading or encasing any major blood 
vessels. 
15. The subject has evidence of tumor invading the GI tract (esophagus, stomach, 
small or large bowel, rectum or anus), or any evidence of endotracheal or 
endobronchial tumor within 28 days before the first dose of cabozantinib.  
16. The subject has uncontrolled, significant intercurrent or recent illness including, 
but not limited to, the following conditions: 
1. Cardiovascular disorders including: 
a) 
Congestive heart failure (CHF): New York Heart Association 
(NYHA) Class III (moderate) or Class IV (severe) at the time of screening 
b) 
Concurrent uncontrolled hypertension defined as sustained BP 
> 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive 
treatment within 7 days of the first dose of study treatment 

NCI Protocol #: 9620 
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8 
c) 
Any history of congenital long QT syndrome 
d) 
Any of the following within 6 months before the first  dose of study 
treatment: 
• unstable angina pectoris 
• clinically-significant cardiac arrhythmias 
• stroke (including TIA, or other ischemic event) 
• myocardial infarction 
• thromboembolic event requiring therapeutic anticoagulation (Note: 
subjects with a venous filter (e.g. vena cava filter) are not eligible for this study) 
 
2. 
Gastrointestinal disorders particularly those associated with a high 
risk of perforation or fistula formation including: 
a) 
Any of the following within 28 days before the first dose of study 
treatment 
• intra-abdominal tumor/metastases invading GI mucosa 
• any evidence of active peptic ulcer disease, patients must be completely 
recovered 
• any evidence of inflammatory bowel disease (including ulcerative colitis 
and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis, patients must be completely recovered from these conditions 
• malabsorption syndrome 
b) 
Any of the following within 6 months before the first dose of study 
treatment: 
•  abdominal fistula 
• gastrointestinal perforation 
• bowel obstruction or gastric outlet obstruction 
• intra-abdominal abscess. Note: Complete resolution of an intra-
abdominal abscess must be confirmed prior to initiating treatment with cabozantinib 
even if the abscess occurred more than 6 months before the first dose of study 
treatment. 
 
3. 
Other disorders associated with a high risk of fistula formation 
including PEG tube placement within 3 months before the first dose of study therapy  
 
4. 
Other clinically significant disorders such as: 
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 7 days before the first dose of study treatment 
e) 
history of major surgery as follows: 
i. Major surgery within 12 weeks before the first dose of study 
treatment. Complete wound healing from major surgery must have occurred 1 month 
before the first dose of study treatment. 
ii. Minor surgery (including uncomplicated tooth extractions) within 28 
days before the first dose of study treatment with complete wound healing at least 10 
days before the first dose of study treatment. 
Subjects with clinically relevant ongoing complications from prior surgery are not 

NCI Protocol #: 9620 
Version Date: 04/04/2019 
 
9 
eligible  
17. The subject is unable to swallow tablets. 
18. 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. 
19. The subject is unable or unwilling to abide by the study protocol or cooperate 
fully with the investigator or designee. 
20. The subject has had evidence within 2 years of the start of study treatment of 
another malignancy which required  systemic treatment 
21. History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to Cabozantinib. 
22. Pregnant women are excluded from this study because 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 Cabozantinib, breastfeeding should be discontinued if 
the mother is treated with Cabozantinib.  These potential risks may also apply to 
other agents used in this study. 
23. HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with 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. 
24. Participation to a study involving a medical or therapeutic intervention in the last 
30 days. 
25. Prior participation in this study. 
STUDY POPULATION  
Translational research study   
All patients included in the trial are eligible for the translational research study. 
Only those patients that voluntarily sign the Informed Consent Form for translational 
study will participate. The refusal for participation in the translational study will not 
affect the patients’ participation in this clinical trial. 
Available paraffin-embedded tumor tissue. 
NUMBER OF PATIENTS  
Osteosarcoma:  
- 
single-arm phase 2 trial based on a dual-endpoint design  
- 
41 eligible and evaluable patients. 45 to be recruited. 
Ewing sarcoma:  
- 
single-arm phase 2 trial based on an optimal two-stage Simon’s design  
- 
41 eligible and evaluable patients. 45 to be recruited 
NUMBER OF SITES  
This is a multicenter study with 11 centres. Young patient age between 12 – 15 could 
be included in only 6 centers (Bordeaux, Lyon, Villejuif, Lille, Marseille and Paris). 
A complete list of investigators will be provided as a separate document.  
STUDY DRUG  
 
Formulation: XL 184 (Cabozantinib) – Available in 20 mg and 60 mg tablet. Tablets 
are yellow film coated. The 20 mg tablets have a round shape and the 60 mg tablets 
have an oval shape, and they are packaged as 30 tablets per bottle. 
Route of administration: Oral 
Administered dose: to take without food , and not eat for at least 2 hours before and 
1 hour after taking it: 
- 
for patients ≥16 years: 60 mg  
- 
For patients ≥12 years < 16 years: 40 mg/m² (Chuck et al., 2014) 
Treatment schedule: Daily, day 1-28 during 4 weeks (ie. 1 cycle) 

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10 
EFFICACY 
EVALUATIONS  
Patients will be evaluated for efficacy if they receive at least one complete or two 
incomplete cycles of Cabozantinib, and if they have at least one disease measurement 
recorded not less than eight weeks after treatment onset (except for in case of early 
disease progression).  
Antitumor activity will be assessed using RECIST v1.1 on a set of measurable 
lesions identified at baseline as target lesions and followed until disease progression 
by the appropriate method (computed tomography [CT] scan or magnetic resonance 
imaging [MRI]).  
Radiological and clinical (whenever appropriate) tumor assessment will be performed 
at baseline and every eight weeks until evidence of disease progression (PD). 
Whenever the criteria of response are met, the appropriate imaging tests will be 
repeated at least four weeks later in order to confirm the response.  
Efficacy will be evaluated based on 6-month non-progression and 6-month objective 
response (composite primary endpoint) for osteosarcoma and 6-month objective 
response rate (ORR - primary endpoint) for Ewing sarcoma.  
Secondary endpoints include 6-month ORR for Ewing sarcoma, as well as for both 
strata: best overall response, 1- and 2-year PFS, and 1- and 2-year OS. 
Primary endpoint efficacy analyses will be based on radiological data reviewed by an 
independent expert radiologist. 
SAFETY EVALUATIONS  
Patients will be evaluable for safety if they have received at least one dose of 
Cabozantinib. All AEs will be graded according to the CTEP CTCAE Version 4.0.  
Safety profile will be continuously followed during treatment and up to 30 days after 
the last Cabozantinib dose or until the start of a new antitumor therapy, whichever 
occurs first.  
 
 

 
11 
STUDY ASSESSMENTS 
 
SCREENING 
CYCLE 1 
CYCLES 2 à 4 
CYCLE 
N 
End of 
treatment (30-
37 days) 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
XL184 
 
X ………………………..continuous ………………………………….X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments 
X 
X ………………………………………………………………………X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Vital signsa 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Clinical laboratory testb 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Urinalysis and UPCR 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
PT/INR, PTT 
X 
X 
 
 
 
X 
 
 
 
X 
 
TFTs (TSH, free T3, free 
T4) 
X 
X 
 
 
 
X 
 
 
 
X 
 
ECGf  
X 
X 
 
 
 
X 
 
 
 
X 
X 
Toxicity 
 
X ………………………………………………………………………X 
X 
Tumor measurement 
X 
Repeated every 2 cycles (ie. 8 weeks). Documentation (radiologic) must be 
provided for patients removed from study for progressive disease 
 
Chest X-ray 
 
 
 
 
 
Xh 
 
 
 
Xh 
 
B-HCG c (if indicated) 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Blood samples 
 
Xd 
 
Xd 
Xd 
 
 
 
 
 
 
PET-FDG 
Xg 
 
 
 
D28 
 
 
 
 
 
 
Biopsy for translational 
research 
X 
 
 
 
Xe 
 
 
 
 
 
 
a: Heart rate, blood pressure, temperature 
b: CBC, differential, platelets, albumin, alkaline phosphatase, SGOT [AST], SGPT [ALT], amylase, bicarbonate, bilirubin, blood urea nitrogen, 
calcium, chloride, creatinine, γ-glutamyltransferase (GGT),  glucose, lactate dehydrogenase (LDH),  lipase, magnesium, phosphorus, 
potassium, sodium, total bilirubin, total protein 
c: Serum test 10-14 days and within 24 hours prior to the first dose of XL 184. Pregnancy test must be repeated at least once every month 
thereafter (serum or urine).  
d: on Day 1, Day 15 and Day 28 of cycle 1 
e: to be performed on Day 1 of cycle 1 predose and on Day 28 of Cycle 1 postdose on the same scanner for the two evaluation  
f: Required in triplicate at baseline. Three ECG should be obtained within 30 minutes but at least 3 minutes apart. 
g: to be done within 1 week prior do Day 1 of Cycle 1 
h:  to be performed at the end of cycle 1, 3, 5, etc… every 8 weeks between each tumor evaluation 
 
 
 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................5 
SYNOPSIS .......................................................................................................................................5 
1. 
OBJECTIVES ....................................................................................................................15 
1.1 
Primary Objectives.................................................................................................15 
1.2 
Secondary Objectives.............................................................................................15 
2. 
BACKGROUND ...............................................................................................................15 
2.1 
Osteosarcoma .........................................................................................................15 
2.2 
Ewing sarcoma .......................................................................................................16 
2.3 
Cabozantinib – XL 184 ..........................................................................................16 
2.4 
Rationale ................................................................................................................24 
2.5 
Correlative Studies Background ............................................................................25 
3. 
PATIENT SELECTION ....................................................................................................25 
3.1 
Eligibility Criteria ..................................................................................................25 
3.2 
Exclusion Criteria ..................................................................................................26 
4. 
REGISTRATION PROCEDURES ...................................................................................30 
4.1 
General Guidelines.................................................................................................30 
4.2 
Registration Process ...............................................................................................30 
5. 
TREATMENT PLAN ........................................................................................................32 
5.1 
Agent Administration.............................................................................................32 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................33 
5.3 
Duration of Therapy ...............................................................................................37 
5.4 
Duration of Follow Up ...........................................................................................38 
5.5 
Criteria for Removal from Study ...........................................................................38 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................38 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................53 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................54 
7.2 
Adverse Event Characteristics [Following NCI procedure] ..................................58 
7.3 
Expedited Adverse Event Reporting [Following NCI procedure] ........................58 
7.4 
Routine Adverse Event Reporting [Following NCI procedure] ............................61 
7.5 
Secondary Malignancy [Following NCI procedure] .............................................61 
7.6 
Second Malignancy [Following NCI procedure] ..................................................61 
7.7 
Safety Evaluation [Following Institut Bergonie procedure] .................................62 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................68 
8.1 
XL184 (cabozantinib) (NSC 761968) ....................................................................68 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................71 

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9.1 
Biomarker Studies ..................................................................................................71 
9.2 
Laboratory Correlative Studies ..............................................................................73 
9.3 
Imaging Studies .....................................................................................................74 
10. 
STUDY CALENDAR .......................................................................................................75 
11. 
MEASUREMENT OF EFFECT........................................................................................76 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................76 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................82 
12.1 
Data Reporting .......................................................................................................82 
12.2 
CTEP Multicenter Guidelines ................................................................................83 
12.3 
Collaborative Agreements Language .....................................................................83 
13. 
STATISTICAL CONSIDERATIONS...............................................................................85 
13.1 
Study Design/Endpoints.........................................................................................85 
13.2 
Sample Size/Accrual Rate ......................................................................................86 
13.3 
Definition of study populations .............................................................................87 
13.4 
Stratification Factors ..............................................................................................88 
13.5 
Analysis of Secondary Endpoints ..........................................................................88 
13.6 
Interim statistical analysis ......................................................................................89 
13.7 
For phase 2 protocols only: Reporting and Exclusions.........................................89 
14. 
QUALITY ASSURANCE AND TRIAL MONITORING ................................................90 
14.1 
Monitoring of the trial ............................................................................................90 
14.2 
Quality assurance ...................................................................................................91 
15. 
REGULATORY ASPECTS AND ETHICAL CONSIDERATIONS ...............................93 
15.1 
Clinical trial authorization .....................................................................................94 
15.2 
Insurance policy .....................................................................................................94 
15.3 
Informing and obtaining consent from patients .....................................................94 
15.4 
Sponsor’s responsabilities ......................................................................................95 
15.5 
Investigators’ responsabilities ................................................................................95 
15.6 
Authority to execute the trial .................................................................................96 
15.7 
Regulations governing the collection of human biological samples .....................96 
15.8 
Fédération des comités de patients pour la recherche clinique en 
cancérologie (FCPRCC) (Federations of patient committees for clinical 
research in oncology) .............................................................................................97 
15.9 
Data processing ......................................................................................................97 
16. 
CONFIDENTIALITY AND OWNERSHIP OF DATA ...................................................98 
17. 
PUBLICATION AND VALORISATION ........................................................................98 
17.1 
Scientific communication ......................................................................................98 
17.2 
Information to patients ...........................................................................................99 
REFERENCES ............................................................................................................................100 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................105 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ..................................................106 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS .................108 
APPENDIX D 
SCREENING FORM ...............................................................................111 
APPENDIX E 
INCLUSION FORM ................................................................................112 
APPENDIX F 
PATIENT MEDICATION DIARY .........................................................113 
APPENDIX G 
SERIOUS ADVERSE EVENT NOTIFICATION FORM ......................115 
APPENDIX H 
PREGNANCY NOTIFICATION FORM................................................118 
APPENDIX I 
COCKCROFT FORMULA .....................................................................119 
APPENDIX J 
DOSING TABLE FOR PATIENTS < 16 YEARS OF AGE ..................120 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To evaluate the antitumor activity of cabozantinib: 
- 
for Ewing sarcomas, in terms of 6-month objective response as per the Response 
Evaluation Criteria in Solid Tumors, Revised (RECIST v1.1) 
- 
for osteosarcoma, in terms of 6-month objective response (Complete response, partial 
response) and 6-month non-progression (Complete response, partial response and stable 
disease), as per RECIST v1.1. 
 
1.2 
Secondary Objectives 
 
Ewing sarcoma only: 
• 6-month objective response 
For each stratum (Ewing sarcoma and osteosarcoma): 
• Best overall response (as per the revised RECIST v1.1); 
• 1- and 2-year progression-free survival; 
• 1- and 2-year overall survival; 
• Cabozantinib safety; 
• To assess the ability of metabolic tumor response as measured by FDG-PET at the end of 
one cycle of treatment to predict PFS; 
• Translational research: to determine and compare tumor expression of MET, phosphor-
MET and circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble 
VEGFR2 (sVEGFR2) prior to and following administration of Cabozantinib. 
 
 
2. BACKGROUND  
 
The incidence of osteosarcoma and Ewing sarcoma are of 150 and 80 new cases/year 
respectively. The 5-overall survival rate is 60-70%. 
 
2.1 
Osteosarcoma 
 
Bone tumors make up about 3–5% of childhood cancers and less than 1% of cancers in adults. Of 
these, osteosarcoma (OSS) is the most commonly diagnosed primary malignant bone tumor. OSS 
is a primary mesenchymal malignant tumor of bone characterized by the production of osteoid or 
immature bone by the malignant cells.  
 
Despite its rarity, OSS is the most common primary malignancy of bone in children and 
adolescents, and the fifth most common malignancy among adolescents and young adults aged 
15 to 19 (Stiller et al. 2006). Indeed, OSS incidence rate has two peaks of about 4 per million per 
year, one in children and young adults ≤ 24 years, and the second after 60 (Mirabello et al., 
2009). 
 
Use of chemotherapy in the neoadjuvant/adjuvant setting has dramatically improved overall 
survival (OS) in OSS. Most active agents in OSS are anthracyclines, platinum salts, ifosfamide 

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and methotrexate given in combination in different protocols (Bramwell et al., 1997). At relapse, 
combination protocols with the same drugs are favoured when complete surgery of the 
metastases is considered achievable. However, patients (pts) not amenable to this strategy have a 
very poor prognosis and there is no standard therapy in this setting (Ferrari et al., 2003; Chou et 
al., 2005; Gelderblom et al., 2011). 
 
2.2 
Ewing sarcoma 
 
Ewing sarcoma (ES) is the second most frequent bone tumors in children and may arise also in 
soft tissues. This disease encompasses tumors formerly known as Askin's tumor, Peripheral 
Neuroectodermal Tumor (PNET) and the Ewing Sarcoma Family of Tumors (ESFT) (Hawkins et 
al., 2011). ES is most common in the second decade of life with an annual incidence of about 
225 cases in North America in children between 1 and 20 years of age (Esiashvili et al., 2008). 
Patients with Ewing sarcoma who present with localized disease have a favorable 5-year event 
free survival of around 70% due to the advent of multimodal therapy that includes 
chemotherapy, surgery and/or radiation (Grier et al., 2003 and Paulussen et al., 2008).  
 
In 25% of ES cases, there is evidence of metastatic disease at presentation (Bernstein et al., 
2006; Subbiah et al., 2009). The prognosis of patients with metastatic tumors at drops 
significantly compared to localized tumor cases (Paulussen et al. 1998). Patients with combined 
bone, bone marrow, and lung metastases have been shown to have a 4-year event free survival 
(EFS) rate of as low as 14% (Paulussen et al. 1998). Treatment regimens include chemotherapy 
in combination with radiation therapy. Intense therapies that include higher doses of 
chemotherapy, sometimes along with total body radiation and stem cell support, have not shown 
increased EFS rates (Meyers et al., 2001; Miser et al. 2007). Improving cure rates and increasing 
EFS rates have proved to be a challenge in patients presenting with metastatic disease, and 
potential molecular therapies are likely the means through which the prognosis may be 
improved. 
 
30% of patients with initial localized disease will suffer from recurrent tumors either locally, 
distally, or some combination of the two, and their prognosis remains poor (Jurgens et al., 1988). 
Upon recurrence, chances of survival have been estimated at less that 20–25% (Ahrens et al., 
1999). There is no specific treatment regimen established for recurrent cases. Therefore, there is 
a great need to develop new approaches or therapies for the treatment of this tumor that target the 
biology of the disease. 
 
2.3 
Cabozantinib – XL 184 
 
XL184 (cabozantinib) inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor 
growth, metastasis, and angiogenesis (Investigator’s Brochure, 2015).  The primary targets of 
Cabozantinib are MET (c-MET) and vascular endothelial growth factor receptor 2 (VEGFR2); 
additional targets include RET, AXL, KIT, and TIE-2.  Both c-Met and VEGFR2 are important 
mediators of tumor growth and tumor angiogenesis, and in vivo pharmacodynamic activity of 
Cabozantinib against c-Met and VEGFR2 has been demonstrated in both preclinical and clinical 
studies. 
 
RTKs regulate many processes including cell growth and survival, organ morphogenesis, 

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neovascularization, and tissue repair (Christensen 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 c-Met, encodes the high-affinity receptor for hepatocyte growth factor (HGF) or scatter 
factor (SF) (Christensen et al., 2005).  c-Met and HGF are each required for normal mammalian 
development and have been shown to be important in cell migration, morphogenic 
differentiation, and organization of three-dimensional tubular structures (e.g., renal tubular cells, 
gland formation, etc.), as well as cell growth, angiogenesis, and tumor invasiveness and 
metastasis.  Upregulation of MET is found in a wide range of malignancies including thyroid, 
prostate, ovarian, lung, and breast cancers, and is associated with more aggressive and invasive 
phenotypes of cancer cells in vitro and metastases in vivo (Investigator’s Brochure, 2015).  C-
Met-driven metastasis may be exacerbated by a number of factors, including tumor hypoxia 
caused by selective inhibition of the VEGF pathway. 
 
Evidence linking c-Met and HGF as causative or progression factors in human cancers include:  
(1) the overexpression of both receptor and ligand in neoplasms relative to surrounding tissues; 
(2) the correlation of receptor and ligand overexpression with disease severity and outcome; (3) 
genetic alteration of c-Met by mutation of gene amplification in multiple cancer types; (4) 
introduction of c-Met and HGF (or mutant c-Met) into cell lines, conferred the properties of 
tumorgenicity and metastatic propensity on engineered cells; (5) introduction of c-Met or HGF 
as transgenes into the germline of mice resulted in primary and secondary neoplasms; and (6) the 
inhibition of c-Met or HGF function with dominant-negative receptors, antibody antagonists 
(both Met and HGF), and biologic antagonists (e.g., NK4) have reversed cancer-associated 
phenotypes such as motility, invasion and proliferation of tumor cells, and tumor growth and 
dissemination in vivo (Christensen et al., 2005). 
 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, demonstrate 
dysregulated c-Met activity (Liu et al., 2010), either by means of c-Met kinase overexpression 
(Comoglio et al., 2008), activating c-Met gene mutations and/or amplification (Comoglio et al., 
2008; Jeffers et al., 1997; Schmidt et al., 1997), or increased autocrine and/or paracrine secretion 
of the c-Met ligand, HGF/SF (Birchmeier et al., 2003; Boccaccio and Comoglio, 2006).  These 
alterations have been implicated in tumor progression and metastasis, and a high constitutive 
activation of c-Met has been correlated with poor clinical prognosis (Birchmeier 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 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. 
 
 
 

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Nonclinical Development of Cabozantinib   
 
In Vivo Activity 
Inhibition of VEGF signaling pathway was previously shown to result in more invasive tumors 
in the transgenic RIP-Tag2 mouse model of pancreatic neuroendocrine cancer that spontaneously 
develops aggressive tumors (Paez-Ribes et al., 2009).  In RIP-Tag2 transgenic mice, tumors 
treated with Cabozantinib were smaller (P <0.05) than in mice treated with vehicle or an anti-
VEGF antibody, but were also less invasive (P <0.05) and had no liver metastases (Sennino et 
al., 2009). All mice treated with Cabozantinib (n = 6) survived until 20 weeks, but none treated 
with vehicle (n = 14) or anti-VEGF antibody (n = 8) reached that endpoint. Tumor vascularity 
decreased after treatment, with reductions ranging from 67% at 3 mg/kg to 83% at 30 mg/kg for 
7 days (You et al., 2011). Tumors were 35% smaller after Cabozantinib treatment than 
corresponding values for vehicle control mice.  c-Met protein expression in tumors was slightly 
decreased, but phosphorylated c-Met was markedly reduced after treatment for 7 days.   
 
Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered four oral 
doses of 100 mg/kg (Yakes et al., 2011). Cabozantinib increased tumor hypoxia (13-fold) and 
apoptosis (TUNEL; 2.5-fold) at 8 and 4 hours after the first and second doses, respectively, when 
compared to vehicle-treated tumors. In addition, Cabozantinib disrupted tumor vasculature by 
inducing endothelial cell death that negatively affected tumor viability. Cabozantinib treatment 
resulted in significant tumor growth inhibition of MDA-MB-231 tumors (P <0.001) at all doses 
(1, 3, 10, 30, or 60 mg/kg) when compared to vehicle-treated tumors.  Dose-dependent inhibition 
was observed for the 3 and 10 mg/kg doses (P <0.01), and complete inhibition was observed at 
the 30 and 60 mg/kg doses. A single 100 mg/kg dose resulted in sustained MDA-MB-231 tumor 
growth inhibition for ~8 days after which tumors began growing at a rate similar to vehicle-
treated control tumors. In addition, Cabozantinib inhibited tumor growth (P <0.001) in the MET-
expressing rat C6 glioma cell line for all doses (1, 3, 10, 30, or 60 mg/kg) when compared with 
vehicle-treated tumors. The 3 mg/kg and 10 mg/kg doses resulted in significant tumor regression 
(62% and 85%, P <0.0001) when compared with predose tumor weights.  Subchronic 
administration of Cabozantinib was well tolerated in mice and rats with no signs of toxicity, as 
determined by stable and/or increasing body weights during the treatment period. 
 
ARCaP-M is a human prostate cancer model which expresses both c-Met and VEGF co-receptor 
NP-1 used in a human prostate tumor xenograft study in mouse bone (Zhang 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 Cabozantinib or vehicle daily (qd) for 7 
weeks of treatment (Investigator’s brochure, 2015). Tibiae from vehicle-treated animals 
exhibited both osteoblastic and osteolytic lesions, whereas tibiae from Cabozantinib treated 
animals appeared mostly normal. Thus, Cabozantinib treatment blocked both osteoblastic and 
osteolytic progression of ARCaP-M xenograft tumors in bone. 
 
 
Nonclinical Pharmacodynamics 
In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at well 
tolerated doses of Cabozantinib and at plasma exposures comparable to exposure observed in 
clinical trials (Investigator’s Brochure, 2015). Cabozantinib produced prolonged inhibition of 
receptor phosphorylation, such as sustained inhibition of c-Met and VEGFR2 for 10 hours after 

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administration of a single dose of Cabozantinib. This extended inhibition occurred in a manner 
that was generally predicted by plasma exposure, i.e., inhibition was diminished when plasma 
levels fell below approximately 20 μM for c-Met, 5 μM for VEGFR2, and 23 μM for TIE-2. 
 
Once daily administration of Cabozantinib resulted in significant inhibition of c-Met 
phosphorylation in TT tumors, relative to tumors from vehicle control-treated mice, with 
maximal inhibition of 70% seen at 60 mg/kg (Investigator’s Brochure, 2015). Dose-dependent 
inhibition of phosphorylation of c-Met and RET was observed among the 3, 10, and 30 mg/kg 
dose groups as well.   
 
c-Met phosphorylation was inhibited by a single 100 mg/kg oral dose of Cabozantinib, 2–8 hours 
post dose in H441 tumors (human lung papillary adenocarcinoma) that harbor constitutively 
phosphorylated c-Met (Yakes et al., 2011). This effect was reversible, as c-Met phosphorylation 
returned to basal levels by 48 hours after treatment.   
 
Nonclinical Pharmacokinetics 
In the various xenograft models, plasma exposures were similar and plasma concentrations in the 
range of 3 to 27 μM were associated with efficacy (Investigator’s Brochure, 2015).  In rats, 
plasma concentrations in the range of 5 to 15 μM were associated with maximal anti-tumor 
activity.  Despite the apparent requirement for high peak concentrations, trough concentrations as 
low as 0.1 μM were observed at highly efficacious doses in mice.  These results were consistent 
with in vivo target modulation studies in mice which demonstrated long (4- to 10-hour) durations 
of action, and indicated that continuous high exposure was not required to maintain efficacy.   
 
Dose proportional increases in exposure occurred at oral doses of 3–100 mg/kg in mice and at 3–
30 mg/kg in rats (Investigator’s Brochure, 2015). In rats, the oral bioavailability of Cabozantinib 
dosed as a solid was approximately 100% of XL184 dosed as a liquid. In comparison, oral 
bioavailability was much lower in dogs (20%) and monkeys (18%) for the solid versus liquid 
dosage forms. 
 
Systemic drug exposure parameters (maximum plasma concentration [Cmax] and area under the 
time-concentration curve from 0 to t hours post-dose [AUC0-t] values) associated with single 
Cabozantinib oral doses in rats increased less than dose-proportionally with increasing dose 
(100–900 mg/kg) (Investigator’s Brochure, 2015). With repeat daily oral dosing in rats, systemic 
exposure (AUC0-t values) increased generally dose-proportionally following 14 and 178 dosing 
days (dose ranges 1–15 mg/kg/day and 0.1–1 mg/kg/day, respectively). The Cmax and AUC0-t 
values in rats administered 100 mg/kg were approximately 2-fold and 3-fold higher, respectively, 
than for dogs given 2000 mg/kg; therefore, the higher systemic exposure to Cabozantinib in rats 
correlated with the greater toxicity observed in this species at lower administered doses. 
 
Systemic drug exposure parameters (Cmax and AUC0-t values) associated with single 
Cabozantinib oral doses in dogs increased less than dose-proportionally with increasing XL184 
dose (400–2000 mg/kg), suggesting possible saturation of systemic absorption (Investigator’s 
Brochure, 2015). 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.   
 

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Toxicology 
In rodents and non-rodents, histopathological changes associated with Cabozantinib 
administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, 
kidney, and adrenal and reproductive tract tissues (Investigator’s Brochure, 2015). 
Histopathological changes present in the bone and pancreas were considered secondary to 
Cabozantinib administration. Adverse effects following oral exposure to Cabozantinib were 
generally dose-related, clinically monitorable, and self-resolving upon discontinuation of dosing. 
In 6-month chronic toxicity studies, treatment-related changes were present only in kidney (rats) 
and reproductive tissues (dog).  In reproductive/developmental toxicity studies, Cabozantinib 
administration resulted in decreased fertility in male and female rats, in embryotoxicity when 
given to pregnant rats, and in a visceral tissue malformation (small spleen) when given to 
pregnant rabbits. The no-observable-adverse-effect-levels (NOAELs) for the chronic toxicity and 
reproductive/developmental toxicity studies occurred at plasma exposures (AUC) below steady-
state values measured in subjects with solid tumors administered 175 mg Cabozantinib capsule 
form daily (Study XL184-001). 
 
In definitive genotoxicity bioassays, Cabozantinib was negative in an S. typhimurium/E.coli 
bacterial mutagenicity study, an in vitro chromosome aberration study using human peripheral 
blood lymphocytes, and an in vivo mouse bone marrow micronucleus study (Investigator’s 
Brochure, 2015). In safety pharmacology studies, no adverse effects occurred on neurobehavioral 
or respiratory functions in Cabozantinib -treated rats or on cardiovascular function in 
Cabozantinib -treated dogs. 
 
Clinical Experience 
 
As of May 4, 2011, 1003 patients have been studied in 12 ongoing Exelixis-sponsored clinical 
trials with Cabozantinib treatment 1) as a single agent at does ranging from 0.08 to 11.52 mg/kg 
on an intermittent dosing schedule, 2) from 25 to 265 mg (19.7-209 mg freebase equivalent 
weight) on a fixed daily dosing schedule and 3) in combination with temozolomide (TMZ) and 
radiation therapy (RT), or with erlotinib (Exelixis Communication, 2011). The maximum 
tolerated dose (MTD) on once daily (qd) by mouth (PO) dosing schedule was determined to be 
175 mg L-malate salt (or approximately 138 mg freebase equivalent weight). 
 
Detailed information for each of these studies, including pharmacokinetic data, can be found in 
the Investigator’s Brochure (2013). Safety and efficacy information, from the 2011 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 (using powder-in-bottle [PIB] 
suspension on a 5 days on, 9 days off schedule) to 265 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 enrolled in the dose expansion phase, 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.   

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In Study XL184-002, treatment of subjects with newly diagnosed glioblastoma (GB) consisted 
of cabozantinib in combination with TMZ with or without radiation therapy. Enrollment has 
been terminated and no clinical efficacy data is presented in the 2011 Investigator’s Brochure. 
All adverse events (AEs) were assessed with respect to combination treatment and not the 
individual components. Nineteen patients were evaluated for AEs, the most common grade 3 or 
higher included neutropenia (21%), thrombocytopenia (16%), leucopenia (16%), and 
hypertension (11%). Myelosuppression, including prolonged pancytopenia, is a dose-limiting 
toxicity (DLTs) associated with TMZ use. The frequency at which bone marrow toxicity was 
observed in this study is consistent with the TMZ prescribing information.   
 
Study XL184-004 is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover study to assess the effect of food on the bioavailability of cabozantinib in healthy adult 
subjects.  According to a randomization scheme, 56 subjects received single oral doses of the 
assigned treatment of Test (175 mg cabozantinib, dosed as one 100-mg capsule and three 25-mg 
capsules 30 minutes after administration of a high-fat breakfast) or Reference (175 mg 
cabozantinib, dosed as one 100-mg capsule and three 25-mg capsules under fasting conditions). 
Blood samples were collected up to 504 hours post-dose for each subject after each treatment to 
assess plasma cabozantinib pharmacokinetics. See “Pharmacokinetics” section for results. 
 
Study XL184-005 is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover comparative bioavailability study of cabozantinib tablet and capsule formulations in 
healthy volunteers.  Subjects received single oral doses of the assigned treatment of Test (100 mg 
cabozantinib, dosed as one 100-mg tablet) or Reference (100 mg cabozantinib, dosed as two 
50-mg capsules), according to a randomization scheme. Each dosing was administered under 
fasting conditions, and blood samples were collected up to 504 hours post-dose for each subject 
after each treatment to assess plasma cabozantinib PK. See “Pharmacokinetics” section for 
results. 
 
In Study XL184-008, subjects with advanced solid tumors (particularly renal cell carcinoma 
[RCC] and differentiated thyroid cancer [DTC]) are evaluated for any potential clinically 
significant drug-drug interaction of cabozantinib on the CYP isozyme CYP2C8. The effect of qd 
dosing of 175 mg cabozantinib and a single dose of rosiglitazone will be evaluated. In 11 
patients evaluated for AEs, the most common grade 3 or higher AEs were fatigue (9%), 
hypophosphatemia (27%), blood amylase increase (9%), and hyponatremia (9%). 
 
In a phase 1 study, CA205-001, Japanese subjects with advanced or metastatic solid tumors for 
whom the standard of care is ineffective or inappropriate, received cabozantinib at a starting dose 
of 75 mg PO qd. Two of the three subjects in the first cohort experienced DLTs of proteinuria 
and thrombocytopenia.  Because of a change in study sponsor, this study was reinitiated as 
XL184-014. One additional subject was enrolled as of May 2011 at 50 mg PO qd.   
 
Study XL184-202 was a phase 1b/2 trial that evaluated the safety and tolerability of cabozantinib 
and erlotinib administered in combination in non-small-cell lung cancer (NSCLC) subjects. Of 
the 64 subjects enrolled in the phase 1 dose-escalation portion of the study, all but two had been 
previously treated with and progressed on erlotinib therapy. A cPR was observed in 5 subjects 
(8%) and 24 subjects (37%) had SD/PR ≥4 months. The most common grade 3 or higher AEs in 

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the phase 1 portion included diarrhea (44%), fatigue (22%), hypokalemia (11%), decreased 
appetite (6%), dyspnea (14%), lipase increase (6%), hypomagnesemia (6%), and dehydration 
(5%). Twenty-eight subjects were enrolled in the phase 2 portion of the study, in which subjects 
who had received clinical benefit from erlotinib and subsequently experienced progressive 
disease (PD), received single-agent cabozantinib or cabozantinib with erlotinib. AEs ≥grade 3 
included dehydration (8%) and hypertension (8%). One patient, who was treated with single-
agent cabozantinib, had a cPR. 
 
Phase 2 Studies 
In a phase 2 study, XL184-201, subjects with progressive or recurrent GB in first or second 
relapse were enrolled to receive cabozantinib qd as a single agent. Group A received an initial 
dose of 175 mg (Group A), subsequent cohorts (Groups B and C) received an initial dose of 125 
mg. Forty-six subjects were enrolled in Group A, and a total of 176 subjects were enrolled in 
Groups B/C. Fifty-seven subjects experienced one or more serious adverse events (SAEs) that 
were assessed to be related to treatment, including five fatal related. 
 
Study XL184-203 is a phase 2 randomized discontinuation trial. Subjects are enrolled into one of 
nine tumor-specific cohorts: breast cancer, gastric/gastroesophageal (GEJ) cancer, hepatocellular 
carcinoma (HCC), melanoma, NSCLC, ovarian cancer, pancreatic cancer, prostate cancer, and 
small cell lung cancer (SCLC). Eligible subjects with advanced solid tumors receive open-label 
cabozantinib at starting dose of 100 mg qd for 12 weeks. Of the 531 subjects enrolled in this 
study as of May 2011, 92 experienced one or more SAEs that were assessed to be related to 
treatment with cabozantinib, including seven fatal related SAEs. 
 
Study XL184-205 is a randomized phase 2 trial for subjects with grade IV astrocytic tumors in 
first or second relapse. Subjects received one of four regimens: 25 mg qd (Arm 1) continuously, 
75 mg qd (Arm 2) continuously, 125 mg qd for 2 weeks followed by 50 mg qd continuously 
(Arm 3) and 125 mg qd on an intermittent 3 week on/1 week off schedule (Arm 4). A total of 19 
subjects were accrued before the study was terminated. Three subjects were rolled over to 
maintenance Study XL184-900. One subject experienced an SAE assessed to be related to 
treatment with cabozantinib.  
 
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 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 (806 in single-agent studies and 107 in combination studies of XL184 
with erlotinib, rosiglitazone, or TMZ ± radiation) (Investigator’s Brochure, 2015). Data from the 
806 subjects who received single-agent Cabozantinib show that the most frequently (>20%) 
observed AEs regardless of causality were fatigue, diarrhea, nausea, decreased appetite, 
constipation, palmar-plantar erythrodysesthesia (PPE) syndrome, vomiting, dysphonia, and 

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hypertension.  Effects that may be related to the inhibition of VEGF, including hypertension, 
thromboembolic events, GI perforation, fistula formation, hemorrhage, wound dehiscence, and 
proteinuria, have been observed in the single-agent and combination Cabozantinib studies. The 
most commonly reported SAEs that were assessed as related to study treatment with 
Cabozantinib (as a single-agent or combination) were pulmonary embolism (PE), diarrhea, 
dehydration, deep vein thrombosis (DVT), vomiting, nausea, thrombocytopenia, fatigue, wound 
dehiscence, and PPE syndrome. 
 
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, 2015). 
 
Pharmacokinetics 
Pharmacokinetic analysis of 74 patients in trial XL184-001 showed dose proportional increases 
in maximum plasma concentration (Cmax) and AUC both for PIB (dose range 0.08-11.52 mg/kg) 
and the capsule formulation (dose range: 125 to 175 mg) (Kurzrock, 2011). Terminal-phase half-
life (t1/2,z) values were 59.1 to 136 hours (Investigator’s Brochure, 2015).  After repeat dosing, 
t1/2,z values (mean ± standard deviation) for XL184 were 91.3 ± 33.3 hours (n = 23), and apparent 
steady-state plasma levels were reached by Day 15 (Kurzrock, 2011). Steady-state clearance for 
the 175 mg capsule dose derived from repeat dose data was 4.2 ± 1.5 L/h. Patients who received 
175 mg capsules had four- to five-fold higher steady-state exposure (AUC) compared with Day 1 
(7.68 ± 2.85 mcg∙h/mL; n = 23 vs. 41.6 ± 15.3 mcg∙h/mL; n = 23), indicating that Cabozantinib 
accumulated with repeat daily dosing. There was no significant difference in exposure between 
patients with MTC and those without MTC. 
 
Based on the preliminary PK data from 23 subjects in XL184-005 who completed both 
treatments, after a single oral dose of cabozantinib at 100 mg, the terminal t1/2, z of cabozantinib 
appeared to be similar for both tablet and capsule formulations, with approximately mean values 
of 110 hours (Exelixis Communication, 2012). The median time to the maximum plasma 
concentration (tmax) was 4 hours for the tablet formulation and 5 hours for the capsule 
formulation.  High inter-subject variability for Cmax and the area under the plasma drug 
concentration time curve (AUC) values were observed for both formulations (coefficient of 
variation [CV]% Cmax: 51% for the tablet formulation, 61% for the capsule formulation; CV% 
for the AUC from time zero to the last quantifiable timepoint or to infinity [AUC0-last or AUC0-
inf]: 40-43% for the tablet formulation, 43% for the capsule formulation). The geometric mean 
Cmax of the tablet formulation was approximately 39% higher than the value observed for the 
capsule formulation. The geometric mean AUC0-last and AUC0-inf values for the tablet formulation 
were also higher (15% and 19%, respectively) than those observed for the capsule formulation. 
However, due to the high within-formulation variability observed, no statistical difference in 
exposure between the two formulations was apparent. 
 
Based on the preliminary PK data from 46 subjects who completed both treatments on trial 
XL184-004, a high-fat meal did not appear to alter the terminal t1/2, z of cabozantinib [mean t1/2, z 
: 131 hours (fed) vs 128 hours (fasted)]. The high-fat meal significantly increased the median tmax 

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to 6 hours from 4 hours (fasted). The high-fat meal also significantly increased both the 
cabozantinib Cmax and AUC values by 39% and 56%, respectively. The geometric mean ratio of 
Cmax fed/fasted was 1.39 (90% CI: 1.16-1.67), and the geometric mean ratio of AUC0-last 
fed/fasted was 1.56 (90% CI: 1.34-1.80). Based on this result, cabozantinib must be taken on an 
empty stomach (fasting is required 2 hours before and 1 hour after each cabozantinib dose). 
 
2.4 
Rationale  
 
MET was originally identified as the protein product of the translocated promoter region (TPR)-
MET transforming oncogene, which was derived from an osteosarcoma cell line (Cooper et al., 
1984). MET play a crucial role in tumorigenesis in several cancer types. Its activation in tumors 
most frequently occurs via increased transcription and expression. MET overexpression results in 
constitutive MET enzymatic activity that stimulates additional MET transcription, resulting in a 
paracrine positive-feedback loop supporting proliferation and dissemination of cancer cells. 
Aberrant MET activation through an autocrine feedback loop has been detected in several tumors 
models (Ferracini et al., 1996; Koochekpour et al., 1997; Tuck et al., 1996) and is a common 
feature of OS (Ferracini et al., 1995; Rong et al., 1993). Several studies have demonstrated how 
the HGF/SF and MET receptors might function together in activating biological properties that 
may contribute to osteosarcoma progression (Rong et al., 1993; Coltella et al., 2003; Patane et 
al., 2006; De Maria et al., 2009; Dani et al., 2012). Indeed, wild-type or constitutively activated 
Met has been shown to drive osteoblast transformation (Patane et al., 2006). Moreover, 
introduction of dominant-negative Met inhibits the in vivo tumorigenicity of osteosarcoma cells 
(Patane et al., 2006). A role for MET in Ewing sarcoma tumorigenesis has also been identified 
recently (Fleuren et al., 2013). 
 
Interestingly, pharmacologic inhibition of Met signaling as a therapeutic strategy has been 
validated in several preclinical models of osteosarcoma and Ewing sarcomas. For instance, the 
Met inhibitors K252a (Coltella et al., 2003), PF-2341066 (Sampson et al., 2011) and 
cabozantinib (Fleuren et al., 2013) selectively inhibited the proliferation of human OS and 
Ewing sarcoma cells and xenografts.  
 
Aberrant angiogenesis is also crucial for sustained OS and ES growth and metastasis. VEGFA is 
abundantly expressed in 74.1% of osteosarcoma cases, and patients with VEGFA-positive 
osteosarcomas had significantly worse tumor-free survival rates than patients with VEGFA-
negative osteosarcomas (Yang et al., 2011). A similar prognostic impact has been observed in 
ES patients (DuBois et al., 2010). Agents targeting angiogenesis have shown promising results in 
in vitro and in vivo preclinical models of OS and ES (DuBois et al., 2010; Brave et al., 2011; 
Scharf et al., 2013; Cassinelli et al., 2013). Preliminary clinical data suggest also that targeting 
angiogenesis could represent an efficient approach in the field of advanced OS and ES. For 
instance, treatment with cediranib (Recentin, AZD2171, AstraZeneca Pharmaceuticals, 
Wilmington, Delaware, USA), an orally available small molecule which inhibits VEGFR-1, 
VEGFR-2 and VEGFR-3, has been associated with objective responses in patients with 
metastatic OS and ES enrolled in a phase I trial (Fox et al., 2008). 
 
As indicated above (section 2.3) cabozantinib is a small molecule which target both the c-Met 
and VEGFR2 signalling pathways. This drug has shown promising pre-clinical activity in in 
vitro and in vivo OS and ES models consistent with its known anti-MET and anti-angiogenic 

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activity (Smith et al., 2013). Altogether, these data support a phase 2 study of cabozantinib in the 
field of advanced OS and ES. 
 
2.5 
Correlative Studies Background 
 
See section 9.1. 
 
 
3. PATIENT SELECTION 
 
Young patient age between 12 – 15 could be included in only 6 centers (Bordeaux, Lyon, 
Villejuif, Lille, Marseille and Paris) 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically confirmed diagnosis of osteosarcoma or Ewing sarcoma 
by central review, except if the diagnosis was already confirmed by the RRePS (Réseau de 
Référence en Pathologie des Sarcomes et des Tissus Mous et des Viscères) network. 
3.1.2 Relapsed disease after standard chemotherapy. 
3.1.3 Patients must have measurable disease (lesion in previously irradiated field could be 
considered as measurable if progressive at inclusion) defined as per RECIST v1.1 with at 
least one lesion that can be measured in at least one dimension (longest diameter to be 
recorded) as > 10 mm with spiral CT scan. 
3.1.4 Age ≥12 years.  
3.1.5 ECOG performance status ≤1 (see Appendix A). 
3.1.6 Life expectancy of greater than 3 months. 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− 
absolute neutrophil count  
≥1,500/mcL 
− 
lymphocyte count  
 
 
>1,000/mcL 
− 
platelets    
 
 
 
≥100,000/mcL 
− 
total bilirubin  
 
 
 
≤1.5 × ULN 
− 
AST(SGOT)/ALT(SGPT) 
≤3.0 × institutional upper limit of normal 
− 
creatinine  
 
 
 
 
≤1.5 × ULN 
OR 
− 
creatinine clearance  
 
≥50 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal (Cockcroft formula, see 
Appendix I). 
− 
hemoglobin   
 
 
 
≥9 g/dL 
− 
serum albumin  
 
 
 
≥2.8g/dL 
− 
lipase    
 
 
 
 
 
<2.0 × ULN and no radiologic or clinical evidence of 
pancreatitis 
− 
urine protein/creatinine 
 
≤1 
ratio (UPCR) 
− 
serum phosphorus, calcium,  ≥ LLN  

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magnesium, and potassium  
 
3.1.8 Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming 
pregnant (ie, females who have had any evidence of menses in the past 12 months, with 
the exception of those who had prior hysterectomy). However, 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, low body weight, 
ovarian suppression or other reasons. 
 
3.1.9 The effects of 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 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 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 Metastatic or unresectable locally advanced. 
3.1.11 Documented disease progression (as per RECIST v1.1) before study entry. For patients 
with osteosarcoma, this progression will be confirmed by central review on the basis of 
two CT scan or MRI obtained at less than 6 months in the period of 12 months prior to 
inclusion.  
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
3.1.13 In accordance with French Regulatory Authorities: Patients with French Social Security 
in compliance with the French law relating to biomedical research (Huriet Law 88-1138 
and related decrees). 
 
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 Cabozantinib. 
 

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3.2.3 Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before the first dose of study treatment. Systemic treatment with 
radionuclides within 6 weeks before the first dose of study treatment. Subjects with 
clinically relevant ongoing complications from prior radiation therapy are not eligible. 
 
3.2.4 Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 14 days before the first dose of study treatment. Note: Subjects with 
prostate cancer currently receiving LHRH or GnRH agonists may be maintained on these 
agents. 
 
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 Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 2 weeks 
before the first dose of study treatment. Eligible subjects must be neurologically 
asymptomatic and without corticosteroid treatment at the time of the start of study 
treatment. 
 
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 7 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 The subject requires chronic concomitant treatment of strong CYP3A4 inducers 
(e.g., dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
rifapentin, 
phenobarbital, and St. John’s Wort).  
Because the lists of these agents are constantly changing, it is important to regularly 
consult 
a 
frequently-updated 
list 
such 
as 
http://medicine.iupui.edu/clinpharm/ddis/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. 
 
3.2.12 The subject has experienced any of the following: 
• clinically-significant gastrointestinal bleeding within 6 months before the first 

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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 The subject has radiographic evidence of cavitating pulmonary lesion(s). 
 
3.2.14 The subject has tumor in contact with, invading or encasing any major blood vessels. 
 
3.2.15 The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or 
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor 
within 28 days before the first dose of cabozantinib.  
 
3.2.16 The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
 
1. Cardiovascular disorders including: 
a) Congestive heart failure (CHF): New York Heart Association (NYHA) Class 
III (moderate) or Class IV (severe) at the time of screening 
b) Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg 
systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment 
within 7 days of the first dose of study treatment 
c) Any history of congenital long QT syndrome 
d) Any of the following within 6 months before the first  dose of study treatment: 
• unstable angina pectoris 
• clinically-significant cardiac arrhythmias 
• stroke (including TIA, or other ischemic event) 
• myocardial infarction 
• thromboembolic event requiring therapeutic anticoagulation (Note: 
subjects with a venous filter (e.g. vena cava filter) are not eligible for this 
study) 
 
2. Gastrointestinal disorders particularly those associated with a high risk of 
perforation or fistula formation including: 
a) Any of the following within 28 days before the first dose of study treatment 
• intra-abdominal tumor/metastases invading GI mucosa 
• any evidence of active peptic ulcer disease, patients must be completely 
recovered 
• any evidence of inflammatory bowel disease (including ulcerative colitis 
and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis 
or appendicitis, patients must be completely recovered from these 
conditions 
• malabsorption syndrome 

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b) Any of the following within 6 months before the first dose of study treatment: 
•  abdominal fistula 
• gastrointestinal perforation 
• bowel obstruction or gastric outlet obstruction 
• intra-abdominal abscess. Note: Complete resolution of an intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib 
even if the abscess occurred more than 6 months before the first dose of 
study treatment. 
 
3. Other disorders associated with a high risk of fistula formation including PEG 
tube placement within 3 months before the first dose of study therapy  
 
4. Other clinically significant disorders such as: 
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 7 
days before the first dose of study treatment 
e) history of major surgery as follows: 
i. 
Major surgery within 12 weeks before the first dose of study treatment. 
Complete wound healing from major surgery must have occurred 1 month 
before the first dose of study treatment.  
ii. 
Minor surgery (including uncomplicated tooth extractions) within 28 days 
before the first dose of study treatment with complete wound healing at 
least 10 days before the first dose of study treatment.  
Subjects with clinically relevant ongoing complications from prior surgery are 
not eligible  
 
3.2.17 The subject is unable to swallow tablets. 
 
3.2.18 The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 
500 ms 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. 
 
3.2.19 The subject is unable or unwilling to abide by the study protocol or cooperate fully with 
the investigator or designee. 
 
3.2.20 The subject has had evidence within 2 years of the start of study treatment of another 
malignancy which required  systemic treatment 
 

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3.2.21 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Cabozantinib. 
 
3.2.22 Pregnant women are excluded from this study because 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 Cabozantinib, breastfeeding should be discontinued if the mother is 
treated with Cabozantinib. These potential risks may also apply to other agents used in 
this study. 
 
3.2.23 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with 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. 
 
3.2.24 Participation to a study involving a medical or therapeutic intervention in the last 30 
days. 
3.2.25 Prior participation in this study. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the Institut Bergonie by the Study 
Coordinator.  The required forms, Screening and registration, can be found in Appendix D and 
Appendix E. 
 
Drug will only be used by French sites.  The central EU depot/distributor that Exelixis would 
like to use is Theorem Clinical Research in Germany.  The packaging and labeling would occur 
in Canada, by Bellwyk Packaging Solution, and then these supplies would be transferred to 
Germany. 
 
A total of 10 French sites will participate in this trial. Exelixis will supply Cabozantinib directly 
to the French sites through Theorem Clinical Research (TCR) based in Germany. Additional 
information on the drug distribution process, please see Section 8.1.2. 
 
 
4.2 
Registration Process 
 
4.2.1 Screening  
Upon signature of informed consent, screened patient will be entered on study centrally at the 
Institut Bergonié Coordinating Center by the Study Coordinator.  
The following documents should be faxed as soon as possible to the Bergonie Institute Data 
Center: 

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 Screening form (Appendix D): 
o Institution number 
o Name of the responsible investigator 
o Patient’s code (2 letters of name, 2 letters of first name) 
o Patient’s birth date (day/month/year) 
o Date of signed consent form 
Clinical Trial and Epidemiology Unit – Institut Bergonié 
FAX: +33 (0)5 56 33 04 85 
From Monday through Friday – From 9.00 am to 5.00 pm 
Contact: Sabrina SELLAN-ALBERT (CRA) – Tel: +33 5 56 33 78 05, Mail – s.albert@bordeaux.unicancer.fr 
and David JUZANX (Back-up CRA) – Mail: d.juzanx@bordeaux.unicancer.fr   
Each site will send to Bergonie Institute within 7 days after the signature of informed consent: 
 Pathology request form completed  
 10 unstained slides and/or preferable FFPE (Formalin-Fixed Paraffin-Embedded) block of 
specimen tumor sampling, obtained anytime during disease development 
 Initial pathology report with patient code and date of birth (including macroscopic 
description) and pathology report of molecular biology if any. 
For osteosarcoma only, each site will send to Bergonie Institute for central review before 
registration: 
• Anonymized CD of CT-scan or MRI of two radiological assessments identical obtained 
at less than 6 months interval within the 12 months prior to inclusion 
• Baseline Clinical Subject Profile with the first shipment 
• Radiological Referral Form  
To complete the registration process, the Coordinator will assign a patient screening number. 
Once results of pathological and radiological review will be available, the CRA at Institut 
Bergonie should inform site by e-mail and return results by fax. 
 
4.2.2 Inclusion  
Upon signature of informed consent, eligible patient will be entered on study centrally at the 
Institut Bergonié Coordinating Center by the Study Coordinator. 
The registration form (Appendix E) should be faxed as soon as possible to the Bergonie Institute 
Data Center with the following information: 
- Institution number 
- Name of the responsible investigator 
- Patient’s code (2 letters of name, 2 letters of first name) 
- Patient’s birth date (day/month/year) 
- Eligibility criteria 
- Date of signed consent form 
- Date foreseen for protocol treatment start 
Clinical Trial and Epidemiology Unit – Institut Bergonié 
FAX: +33 5 56 33 04 85 
From Monday through Friday – From 9.00 am to 5.00 pm 
Contact: Sabrina SELLAN-ALBERT (CRA) – Tel: +33 5 56 33 78 05, Mail – s.albert@bordeaux.unicancer.fr  
and David JUZANX (Back-up CRA) – Mail: d.juzanx@bordeaux.unicancer.fr  

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This must be done before the start of the protocol treatment which should begin within one 
week (5 days) following registration. 
To complete the registration process, the Coordinator will: 
- Assign a patient study number 
- Register the patient on the study 
- Fax or e-mail the patient study number 
The patient study number attributed at the end of the registration procedure identifies the 
patient and must be reported on all case report forms. 
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 cancelled.  The Study Coordinator should be notified of cancellations as soon as 
possible. 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7. Appropriate dose modifications are described in Section 6. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen description 
 
Agent 
 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
XL 184 
Take without  food, and patients should not 
eat for at least two hours before and one hour 
after taking it 
60 
mg 
for 
patients ≥ 16 
years 
40mg/m² for  
patients ≥ 12 
years and <16 
years (Chuck et 
al, 2014) 
PO 
Days 1-28 
4 
weeks 
(28 days) 
 
Since dose is based on BSA for patients < 16 years of age, the calculated dose should be round to 
the nearest tablet size (see Appendix J). 
 
The patient will be requested to maintain a medication diary (Appendix F) of each dose of 
medication.  The medication diary will be returned to clinic staff at the end of each course. 
 
5.1.1 XL184 - Cabozantinib 
Cabozantinib must be taken on an empty stomach.  Patients must fast for 2 hours before and 1 
hour following each dose of Cabozantinib. Cabozantinib tablets should be swallowed whole with 
at least 8 ounces of water. 
The tablets should not be crushed.  Subjects should be instructed to take their cabozantinib dose 
at approximately the same time every day.  If a subject misses a dose, the dose may be taken 

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later only if it is within 12 hours of when the missed dose should have been taken.  The missed 
dose should not be made up if it is within 12 hours of the next scheduled dose.  In case of 
vomiting, patients should be instructed to don’t take a new dose. 
Grapefruit, grapefruit juice, Seville oranges and their products should be avoided by subjects 
taking cabozantinib. 
Patients will be instructed to bring all unused tablets and their medication diary (refer to 
Appendix F) to each study visit for assessment of compliance. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of Cabozantinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  The 
Principal Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential to affect selected CYP450 isoenzymes.   
 
5.2.1 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 
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 28 days before the first dose of study treatment through 30 days after the date of the 
last dose of study treatment are to be recorded in the case report forms. 
 
5.2.1.3 
Allowed therapy 
• Antiemetics and antidiarrheal medications are allowed prophylactically in accordance to 
standard clinical practice if clinically indicated;  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, American Society of Clinical Oncology [ASCO] or [European Society for 
Medical Oncology] ESMO guidelines);  
• Drugs used to control bone loss (eg, bisphosphonates and denosumab) are allowed if started 
before screening activities but may not be initiated or exchanged during the course of the 
study and require Sponsor approval; 

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• Transfusions, hormone replacement, and short term higher doses of corticosteroids should be 
utilized as indicated by standard clinical; 
• Individualized anticoagulation therapy with heparin is allowed if it can be provided safely 
and effectively under the following circumstances:  
o Low dose heparins for prophylactic use are allowed if clinically indicated and the 
benefit outweighs the risk per the investigator’s discretion;  
o Therapeutic doses of LMWH after the first dose of study treatment are allowed if 
clinically indicated (eg, for the treatment of deep venous thrombosis), and the benefit 
outweighs the risk per the investigator’s discretion. For management of 
thromboembolic complications while on study, refer to section 6.  
o Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed. This includes, but is not 
limited to, subject education regarding potential adverse drug reactions, monitoring 
laboratory parameters, dose adjustments (eg, due to kidney dysfunction);  
o For restrictions on oral anticoagulants see Section 5.2.1.4. 
• Antacids, H2-blockers, PPIs: 
Co-administration of gastric pH modifying drugs such as PPI, H2-blockers or antacids is not 
contraindicated in subjects administered cabozantinib. 
 
5.2.1.4 
Prohibited or restricted therapies 
The following therapies are prohibited while the subject is on study: 
• Any investigational agent or investigational medical device; 
• Any drug or herbal product used specifically for the treatment of osteosarcoma and/or 
Ewing sarcoma; 
• Therapeutic doses of oral anticoagulants (eg, warfarin or other coumarin-related agents, 
direct thrombin or direct FXa inhibitors, or antiplatelet agents such as clopidogrel, or 
chronic use of aspirin above low dose levels for cardioprotection per local applicable 
guidelines); 

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• Any other systemic anticancer treatment (eg, chemotherapy, immunotherapy, 
radionuclides) and local anticancer treatment such as surgery, ablation, or embolization.  
The following therapies should be avoided if possible, while the subject is on study: 
• Palliative external radiation to bone metastasis for bone pain should not be performed 
while on study. Subjects who have such an intervention may be considered not evaluable 
(and may be assigned a censoring or progression date) for certain efficacy endpoints; 
• Erythropoietic stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be 
used based on a report of increased risk of tumor recurrence and/or progression 
associated with erythropoietin (Wright 2007); 
• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg, dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
rifapentine, 
phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib 
concentrations and should be avoided. Selection of alternate concomitant medications 
with no or minimal CYP3A4 enzyme induction potential is recommended; 
• 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, because this 
could significantly increase the exposure to cabozantinib; 
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations and should be avoided. Grapefruit 
and Seville oranges may also increase plasma concentrations of cabozantinib and should 
be avoided. 
5.2.1.5 
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.  

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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.  
 
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.  
 

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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. 
 
Other Interactions: Concomitant use of gastric pH modifying agents (ie. PPIs, H2 receptor 
antagonists, and antacids) is not contraindicated in subjects administered Cabozantinib. 
 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P glycoprotein (P-gp), but 
it does appear to have the potential to inhibit the P-gp transport activity.  
 
Additional details related to these overall conclusions are provided in the Investigators Brochure 
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 (other than 
short cycle of palliative radiotherapy for bone pain), 
 
• 
Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the course of the study and 
for 4 months following discontinuation of study treatment, 
 
• 
Women who become pregnant or are breast feeding, 
 
• 
Request by regulatory agencies for termination of treatment of an individual subject 
or all subjects under the protocol, or 
 
• 
Significant noncompliance with the protocol schedule in the opinion of the 
investigator. 
 
• 
The minimum dose of study treatment will be 20 mg qd. Subjects who cannot tolerate 

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20 mg qd will have study treatment discontinued. 
 
5.4 
Duration of Follow Up 
 
Patients will be followed every 6 months 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 
 
XL184-Related Adverse Event Management 
 
Subjects will be monitored continuously for AEs throughout the study. Subjects must be 
instructed to notify their physician immediately for any and all toxicities. 
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are presented 
in the next sections. Each dose reduction of cabozantinib should be to one dose level lower that 
the current dose. Dose reductions of more than one dose level are acceptable if agreed to by the 
Investigator. All AEs should also be managed with supportive care at the earliest signs of 
toxicity considered related to the study treatment.  
If study treatment of cabozantinib is restarted after being withheld or interrupted, the subject 
should be instructed not to make up the missed doses of cabozantinib.  
The reason for treatment delay and reduced dose must be recorded on the case report form 
(CRF). 
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this is 
clinically indicated or if causality is initially uncertain. Study treatment may be resumed at the 
same dose (or a lower dose per investigator judgment) if the AE is determined not to be related 
to cabozantinib once the investigator determines that retreatment is clinically appropriate and the 
subject meets the protocol re-treatment criteria. 
Subjects receiving a daily dose of 20 mg may be restarted at the same dose if deemed safe at the 
discretion of the investigator. Subjects unable to tolerate a daily dose of 20 mg should 
discontinue study treatment. 

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Re-escalation to the previous dose, [but not higher than 60 mg/day for patients ≥ 16 years and 
pediatric dose will not exceed the adult dose (60 mg)] may be allowed at the discretion of the 
investigator but no sooner than 2 weeks beyond resolution of AEs that led to the dose reduction. 
Dose re-escalation is not allowed for a drug-related dose reduction triggered by 
myelosuppression or by Grade 4 AEs affecting major organs (eg, central nervous system, 
cardiac, hepatic, renal). 
A patient who requires a dose interruption (regardless of the reason for the interruption) lasting > 
28 days (counting from the first day when a dose was missed) must discontinue Cabozantinib.  
Dose reduction for patients ≥ 16 years* 
 
Starting dose level -0 
Reduced dose level-1 
Reduced dose level-2 
XL-184 
60 mg QD 
40 mg QD 
20 mg QD** 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
**Dose reduction below 20 mg is not allowed. 
 
Dose reduction for patients ≥ 12 years < 16* 
 
Starting dose level -0 
Reduced dose level-1 
Reduced dose level-2 
XL-184 
40 mg/m² QD 
30 mg/m² QD 
20 mg/m² QD** 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
**Dose reduction below 20 mg/m² is not allowed. 
 

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Table 6-1.  General Approach to the Management of Cabozantinib-Related Non-
Hematologic Adverse Events 
CTCAE Version 4 Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated.  Continue cabozantinib at the 
current dose level. 
Grade 2: 
Grade 2 AEs which are intolerable and 
cannot be adequately managed 
Interrupt cabozantinib treatment or dose reduction. Add supportive 
care as indicated. 
• 
If cabozantinib dosing is interruoted, then upon resolution of the 
AE to baseline or Grade ≤ 1, or with a dose reduction at the 
discretion of the investigator unless this is a recurring event at 
which time the dose should be reduced. 
Grade 3: 
 
Grade 3 AEs considered related to 
cabozantinib which occurred without 
optimal prophylaxis or which is easily 
managed by medical intervention or 
resolved quickly 
• Interrupt cabozantinib and add supportive care as indicated 
• For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or Grade ≤1 within 24 hours,  
cabozantinib may be resumed at either the same dose or with a dose 
reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
• For AEs that require supportive care, the dose should be held while 
supportive care is initiated and optimized.  Then upon resolution of 
the AE to baseline or Grade ≤1,  cabozantinib may be resumed at 
either the same dose or with a dose reduction at the discretion of the 
investigator unless this is a recurring event at which time the dose 
should be reduced 
Grade 3 AEs considered related to study 
treatment that occurred despite optimal 
prophylaxis or is not easily managed by 
medical intervention  
Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and 
resume treatment with a dose reduction 
Grade 4: 
 
Grade 4 AEs considered related to study 
treatment 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor 
but only with sponsor approval. 
Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the investigator 
believes that it is in the interest of the subject’s safety. All dose modifications should be based on the worst 
preceding toxicity. Patients are allowed two dose reductions: a dose reduction from 60 mg QD to 40 mg QD, and, 
if necessary, a dose reduction from 40 mg QD to 20 mg QD. Dose re-escalation is not allowed for a drug-related 
dose reduction triggered by myelosuppression or by Grade 4 AEs affecting major organs (eg, central nervous 
system, cardiac, hepatic, renal). 

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Table 6-2.  General Approach to the Management of Cabozantinib-Related Hematologic 
Adverse Events 
CTCAE Version 4 Grade 
Intervention 
Neutropenia 
Grade 3 neutropenia with documented 
infection 
Grade 3 neutropenia ≥ 5 days 
Grade 4 neutropenia  
Interrupt cabozantinib treatment until resolution to Grade ≤1, and 
resume cabozantinib treatment at a reduced dose.  
Thrombocytopenia 
Grade 3 thrombocytopenia with clinically 
significant 
bleeding 
or 
Grade 4 
thrombocytopenia 
Interrupt 
cabozantinib 
treatment 
until 
platelet 
count 
is  
≥100,000/mm3, and resume cabozantinib treatment at a reduced dose 
Febrile Neutropenia 
Grade 3 febrile neutropenia 
Interrupt cabozantinib treatment until recovery of ANC to Grade ≤1 
and temperature to ≤38.0°C and resume cabozantinib treatment at a 
reduced dose. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor 
but only with sponsor approval. 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic toxicities  
other than anemia 
Permanently discontinue study treatment unless determined that the 
subject is clearly deriving clinical benefit. In this case, upon recovery 
to Grade ≤1 or baseline, the subject may be re-treated at a reduced 
dose that is to be determined by the investigator and sponsor and only 
with approval by the sponsor. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not mandated. Dose 
reductions or dose delays for anemia should be applied as clinically 
indicated. Supportive care such as red blood cell transfusions should 
be managed according to institutional guidelines. 
ANC, absolute neutrophil count; LLN, lower limit of normal 
Neutropenia: 
Grade 
1 
(LLN 
≤ ANC 
< 1.5 × 109/L; 
Grade 2 
(1 
× 109/L 
≤ ANC 
<1.5 
x 
109/L),  
Grade 3 (0.5 × 109/L ≤ ANC < 1 × 109/L), Grade 4 (ANC < 0.5 × 109/L). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
Thrombocytopenia: Grade 1 (Platelet count <LLN – 75 x 109/L); Grade 2 (Platelet count <75.0 – 50.0 x 109/L);  
Grade 3 (Platelet count ≤ 50 - 25 × 109/L); Grade 4 (Platelet count < 25 × 109/L). 
All dose modifications should be based on the worst preceding toxicity. Patients are allowed two dose reductions: a dose 
reduction from 60 mg QD to 40 mg QD, and, if necessary, a dose reduction from 40 mg QD to 20 mg QD. Dose 
re-escalation is not allowed for a drug-related dose reduction triggered by myelosuppression or by Grade 4 AEs 
affecting major organs (eg, central nervous system, cardiac, hepatic, renal). 

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Diarrhea, Nausea, Vomiting,  Stomatitis, and Mucositis 
 
Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements.  Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management.  
Loperamide is recommended as standard first line therapy.  Alternatively, diphenoxylate/atropine 
can be used.  Additional agents to consider in subjects with diarrhea that is refractory to the 
above include deodorized tincture of opium and octreotide (Benson et al., 2004).  Some subjects 
may require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized 
tincture of opium to control diarrhea.  The dose modification guidance in Table 6-1 should be 
followed.  In addition, general supportive measures should be implemented including continuous 
oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high fat meals and alcohol.  
 
Nausea and Vomiting 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting.  The dose modification guidance in Table 6-1 should be 
followed.   
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists 
and dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and 
glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure.  Caution is also 
recommended with the use of nabilone, which is a weak inhibitor of CYP3A4. 
 
Ondansetron, a 5-HT3 inhibitor, is not allowed due to QTc prolongation. Other 5-HT3 antagonists 
can be used. 
 
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. 
 
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.  

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Since subjects may enter the study with elevations of AST/ALT at baseline, the following 
guideline should be used for dose modifications: 
 
 
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 
Transaminase elevation 
CTCAE v4.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at 
least 4 weeks.. Then resume the standard protocol-defined monitoring of LFTs. 
Grade 2 
Continue  cabozantinib with at least twice weekly monitoring of LFTs for 2 
weeks. Then weekly for 4 weeks.  If LFTs continue to rise within Grade 2, 
interrupt cabozantinib  treatment.   Then continue with at least weekly LFTs until 
resolution to Grade ≤ 1.  Study treatment may then be resumed at a one-dose-level 
reduction of cabozantinib 
Grade 3  
Interrupt  cabozantinib  treatment and monitor with at least twice weekly LFTs 
until Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to 
Grade ≤ 1.  Cabozantinib may then be resumed at a one-dose-level reduction.  
Grade 4 
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.   If the subject 
was  unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose of cabozantinib as determined by the investigator  and 
sponsor but only with sponsor approval. 
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline   
≥ 1.5 fold increase of AST or 
ALT AND both AST and 
ALT are ≤ 5.0 x ULN 
Continue cabozantinib treatment with at least twice weekly monitoring of LFTs 
for 4 weeks and weekly for 4 weeks.  If LFTs continue to rise, interrupt study 
treatment.   Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib 
≥ 1.5 fold increase of AST or 
ALT and at least one of 
AST or ALT is Grade 3 (i.e. 
AST or ALT > 5.0 but ≤ 
20.0 x ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.  If the subject 
was unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose as determined by the investigator and sponsor but only 
with sponsor approval.. 

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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 has not 
been associated with clinically apparent sequelae.  It is recommended that subjects with lipase 
elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of lipase 
and/or amylase (2-3 times per week). Subjects with symptomatic pancreatitis should be treated 
with standard supportive measures. 

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Asymptomatic Lipase or Amylase Elevations 
 
Asymptomatic Lipase or Amylase  Elevations 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is recommended 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted 
at the same dose or at a reduced dose provided that this occurs within 6 
weeks. 
• 
If retreatment following Grade 3 lipase or amylase elevation is at the 
same dose and Grade 3 or Grade 4 elevations recur, then treatment must 
be interrupted again until lipase and amylase  levels have resolved to 
Grade ≤1 or baseline and retreatment must be at a reduced dose. 
Grade 4 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline and if resolution occurred 
within 4 days, cabozantinib may be restarted at the same dose or a 
reduced dose.  If resolution took more than 4 days, the dose must be 
reduced upon retreatment provided that resolution occurred within 6 
weeks. 
• 
If retreatment following Grade 4 lipase or amylase elevation is at the 
same dose and Grade 3 or 4 elevations recur, then treatment must be 
interrupted again until lipase and amylase have resolved to Grade ≤1 or 
baseline and retreatment must be at a reduced dose. 
 
Pancreatitis 
 
Pancreatitis 
Grade 2 and asymptomatic 
• 
Continue at current dose level. More frequent monitoring of lipase and 
amylase and radiographic evaluation is recommended. 
Grade 2 symptomatic and 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline , cabozantinib may be restarted 
at a reduced dose if resolution occurred within 6 weeks 
Grade 4 
Permanently discontinue treatment.  However, if the subject was unequivocally 
deriving benefit from cabozantinib therapy, treatment may resume at a reduced at 
a reduced dose agreed to by the investigator and sponsor but only with sponsor 
approval. 
 
 
 

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Skin Disorders 
 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin 
rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been 
reported in cabozantinib-treated subjects.  All subjects on study should be advised to use 
prophylactic measures for skin care.  These measures includes the use of hypoallergenic 
moisturizing creams, ointment for dry skin, sunscreen with SPF ≥30; avoidance of exposure of 
hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; and use of 
thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects 
with skin disorders should be carefully monitored for signs of infection (e.g., abscess, cellulitis, 
or impetigo). 
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild 
hyperkeratosis.  Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles.  The lateral sides of the fingers or periungual zones may also be affected.  
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas.  Aggressive management of symptoms 
is recommended, including early dermatology referral. 
Treatment guidelines for PPE related to study treatment are presented in the table below. 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent.  
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  
 

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

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

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Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic) and < 160 mm Hg 
or 
> 100 mm Hg (diastolic) and < 110 mm Hg 
 
 
• Increase antihypertension therapy (ie, 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 interrupted and/or reduced. 
≥ 160 mm Hg (systolic) and < 180 mm Hg 
or 
≥ 110 mm Hg (diastolic) and < 120 mm Hg 
• Interrupt and/or reduce cabozantinib by one dose level; 
• Increase antihypertension therapy (ie, 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 < 150 systolic or < 
100 diastolic, dose of cabozantinib should be reduced further. 
≥ 180 mm Hg (systolic) 
or 
≥ 120 mm Hg (diastolic ) 
• Interrupt treatment with cabozantinib Add new or additional 
anti-hypertensive medications and/or increase dose of existing 
medications; 
• Monitor subject closely for hypotension; 
• When SBP < 150 and DBP < 100, restart cabozantinib 
treatment at one dose level lower; 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 150 systolic or < 
100 diastolic, dose of cabozantinib should be reduced further. 
Hypertensive emergency 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 
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. 
 
 

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

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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.  
• 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. 

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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 
for signs and symptoms associated with thyroid dysfunction is recommended for subjects treated 
with cabozantinib. Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) 
should follow accepted clinical practice guidelines. 
 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of subjects.  Monitoring with standard laboratory 
tests for endocrine disorders and clinical examination prior to initiation and during treatment 
with cabozantinib is required.  Cabozantinib should be discontinued in subjects with severe or 
life-threatening endocrine dysfunction. 
 
Guidelines for Prevention of Osteonecrosis of the Jaw 
 
Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and 
bisphosphonates and denosumab in cancer patients.  Additional risk factors for ONJ have been 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
smoking, dental or orofacial surgery procedures, and cancer disease itself.  Cases of 
osteonecrosis have been reported in subjects treated with cabozantinib, the details of which are 
provided in the current version of Investigator’s Brochure.  As a preventive measure, invasive 
dental procedures should be avoided if possible in subjects who have previously been treated 
with or concomitantly receive bisphosphonates or denosumab. In cases where dental procedures 
are unavoidable, the risks and benefits of a dental procedure and the extent of the procedure as 
well as the risk of developing osteonecrosis of the jaw need to be considered when deciding on 
the duration of a temporary treatment interruption of cabozantinib.  If clinically possible, 

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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 
less than 3 minutes apart.  If the average QTcF from the three ECGs is >500 msec, study 
treatment must be withheld and the following actions should be taken: 
• Check electrolytes, especially potassium, magnesium and calcium.  Correct abnormalities 
as clinically indicated. 
• If possible, discontinue any QTc-prolonging concomitant medications. 
•  Repeat ECG triplets hourly until the average QTcF is ≤500 msec or otherwise 
determined by consultation with a cardiologist. 
The Sponsor should be notified immediately of any QTc prolongation event.  
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation has resolved.  Cardiology consultation is recommended for evaluation and subject 
management.  Symptomatic subjects must be treated according to standard clinical practice.  No 
additional study treatment is to be given to the subject until after the event has resolved, the 
subject has been thoroughly evaluated, and further treatment has been agreed to by the Sponsor.  
If any additional study treatment is given (e.g., after correction of electrolyte abnormalities and 
normalization of QTcF), it will be at a reduced dose as agreed to by the investigator and the 
Sponsor. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via AERS) in addition to routine 
reporting.   
 

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7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification.  Frequency is provided based on 3219 patients. Below is the CAEPR for 
XL184 (Cabozantinib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
7.1.1 CAEPRs for XL184 (cabozantinib) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for XL184 (Cabozantinib 
s-malate, NSC 761968) 
     Version 2.4, December 17, 20181 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal hemorrhage3   
 
 
Gastrointestinal perforation4   
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  

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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Generalized muscle weakness  
  
 
Muscle cramp 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Intracranial hemorrhage  
  
 
 
Ischemia cerebrovascular 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
 
Stroke 
  
 
 
Transient ischemic attacks 
  
RENAL AND URINARY DISORDERS 
  
 
Hematuria 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
Pneumothorax6 
  
 
 
Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
 
Voice alteration 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  

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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hair color changes 
 
 Hair color changes (Gr 1) 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome (Gr 
3) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal 
hemorrhage, 
Oral 
hemorrhage, 
Pancreatic 
hemorrhage, 
Rectal 
hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating 
patients with relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases.  
 
7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
 
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC.  
 
9Thromboembolic event includes pulmonary embolism which may be life-threatening. 
 
Adverse events reported on XL184 (Cabozantinib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that XL184 (Cabozantinib) caused the 
adverse event: 

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BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile neutropenia; Hemolytic 
uremic syndrome 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; Cardiac 
disorders - Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left ventricular 
systolic dysfunction; Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - 
Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism; Hypopituitarism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; Anal pain; 
Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal 
ulcer; Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders 
- Other (glossitis); Gastrointestinal disorders - Other (pneumoperitoneum); Gastrointestinal pain; Gingival 
pain; Hemorrhoids; Ileus; Pancreatitis; Periodontal disease; Rectal pain; Rectal ulcer; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema face; 
Fever; Gait disturbance; General disorders and administration site conditions - Other (general physical 
health deterioration); General disorders and administration site conditions - Other (implant site 
inflammation); Hypothermia; Malaise; Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death 
NOS 
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; Hepatobiliary 
disorders - Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary 
disorders - Other (hepatic thrombus); Hepatobiliary disorders - Other (hepatitis toxic); Hepatobiliary 
disorders - Other (hepatorenal syndrome); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - 
Other (tendon injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Blood lactate 
dehydrogenase increased; CPK increased; Cardiac troponin I increased; Creatinine increased; Ejection 
fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - 
Other (D-dimer); Investigations - Other (urine ketone body present); Lymphocyte count decreased; 
Neutrophil count decreased; Serum amylase increased; Thyroid stimulating hormone increased; White 
blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to 
thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Chest wall 
pain; Flank pain; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other 
(muscle hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity cancer); Tumor 
hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory impairment; Nervous system disorders - 
Other (hemiparesis); Nervous system disorders - Other (vocal cord paralysis); Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Spinal cord 
compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; 
Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Glucosuria; Renal 
and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system and breast 
disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; Vaginal inflammation; 

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Vaginal perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal edema; Oropharyngeal pain; 
Pharyngeal mucositis; Pleural effusion; Pneumonitis; Productive cough; Pulmonary hypertension; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (nasal septum perforation); 
Respiratory, thoracic and mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and 
mediastinal disorders - Other (rales); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; Pain of skin; 
Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and 
erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin hypopigmentation; Skin 
ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders 
- Other (bleeding varicose vein); Vasculitis 
 
 
Note: XL184 (Cabozantinib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2 
Adverse Event Characteristics [Following NCI procedure] 
 
• 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 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: 
− 
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 [Following NCI procedure] 
 

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7.3.1 CTEP-AERS 
Expedited AE reporting for this study must use AERS (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 AERS by the original submitter at the 
site. 
 
7.3.2 Multi-institutional studies. 
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.  AERS provides a copy feature for other e-mail recipients.  
 
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. 
 
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 

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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 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 AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 
 
 
 
 
 

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7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via AERS.  
However, they still must be reported through the routine reporting mechanism (Section 7.4): 
 
CTCAE SOC 
Adverse 
Event 
Grade Attribution 
Endocrine disorders 
Hypothyroidism 
2 
Related 
Gastrointestinal disorders 
Abdominal pain 
2 
Related 
Diarrhea 
2 
Related 
Constipation 
2 
Related 
Dry mouth 
2 
Related 
Dyspepsia 
2 
Related 
Mucositis oral 
2 
Related 
Nausea 
2 
Related 
Oral pain 
2 
Related 
Vomiting 
2 
Related 
General disorders and administration site conditions 
Fatigue 
2 
Related 
 
7.4 
Routine Adverse Event Reporting [Following NCI procedure] 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy [Following NCI procedure] 
 
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 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 [Following NCI procedure] 
 
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 

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via CDUS unless otherwise specified.  
 
7.7 
Safety Evaluation [Following Institut Bergonie procedure] 
 
7.7.1 Description of safety evaluation criteria 
The safety evaluation will comprise an evaluation of the patient’s general condition (ECOG 
Appendix A), a physical exam, regular blood tests and the recording of adverse events occurring 
throughout the study. Toxicity will be evaluated using the NCI-CTCAE scale, version 4 
available on website: http://ctep.info.nih.gov. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.   
In an emergency situation, the patient, his/her friends/family or treating physician will contact 
the investigator to report an event and/or to discuss the treatments to be implemented. 
 
7.7.2 Definition 
7.7.2.1 
Adverse event 
An adverse event is defined as any untoward medical occurrence which occurs in a patient, a 
clinical investigation subject. Adverse events include, but are not limited to: 
• 
Abnormal test findings, 
• 
Clinical symptoms and signs,  
• 
Changes in physical examination findings,  
• 
Hypersensitivity, 
• 
Drug abuse, 
• 
Drug dependency, 
• 
Any suspected transmission of an infectious agent via a medicinal product. 
 
As well as signs and symptoms resulting from: 
 
• 
Drug overdose, 
• 
Drug withdrawal, 
• 
Drug misuse, 
• 
Drug interactions, 
• 
Extravasation, 
• 
Exposure during pregnancy, 
• 
Exposure during breastfeeding, 
• 
Medication error, 
• 
Occupational exposure. 
 
7.7.2.2 
Serious adverse event 
A serious adverse event is defined as an adverse event regardless of the dose and that: 
• 
results in death (fatal) and/or, 
• 
is life-threatening and/or, 
• 
requires inpatient hospitalization or prolongation of existing hospitalization and/or, 
• 
results in persistent or significant disability/incapacity and/or, 
• 
results in congenital anomaly/birth defect and/or, 
• 
is medically significant. 
Medical and scientific judgment is exercised in determining whether an event is an important 

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medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above, 
the important medical event should be reported as serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
Any suspected transmission via a medicinal product of an infectious agent, pathogenic or non-
pathogenic, is assessed as a serious adverse event with the seriousness criterion important 
medical event. The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a patient exposed to a medicinal product. The terms “suspected 
transmission” and “transmission” are considered synonymous. 
Any abnormal laboratory’s result resulting as a grade 4 in the CTCAE version 4 will be 
considered as serious adverse event even if this event is not clinically relevant. 
Whether or not corresponding to the above-mentioned criteria, any other adverse event 
considered as serious by any IMP, any healthcare professional or any investigator should be 
handled as a serious adverse event. 
 
 Death 
Death as such is the outcome of a SAE or the seriousness criteria and should not be used as the 
SAE term itself. Instead the cause of death should be recorded as the SAE term. When available, 
the autopsy report will be provided to the Sponsor. 
 
 Life-threatening Event 
Any event in which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
 
 Hospitalization or Prolongation of Hospitalization 
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or worsens 
during the course of a patient’s participation in a clinical trial must be reported as a SAE. 
Prolongation of hospitalization is defined as any extension of an inpatient hospitalization beyond 
the stay anticipated/required for the initial admission, as determined by the Investigator or 
treating physician. 
Hospitalizations that do not meet criteria for SAE reporting are:  
- Reasons described in protocol [e.g., investigational medicinal product (IMP) 
administration, protocol-required intervention/investigations, etc]. However, events 
requiring hospitalizations or prolongation of hospitalization as a result of a complication 
of therapy administration or clinical trial procedures will be reported as SAEs. 
- Hospitalization or prolonged hospitalization for technical, practical or social reasons, in 
absence of an AE. 
- Pre-planned hospitalizations: Any pre-planned surgery or procedure must be documented 
in the source documentation. Only if the pre-planned surgery needs to be performed 
earlier due to a worsening of the condition, should this event (worsened condition) be 
reported as a SAE.  
 

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7.7.2.3 
Non serious adverse event 
A non-serious adverse event is an adverse event whose characteristics do not meet the criteria of 
a serious adverse event. 
 
7.7.2.4 
Adverse effect 
An adverse effect is any untoward and unintended responses to an experimental drug regardless 
of the dose. 
 
7.7.2.5 
Expected/Unexpected Character 
An unexpected adverse event is an event whose nature, severity/intensity or outcome does not 
correspond to the information shown within the reference document for the study. The Sponsor 
will use as the reference safety information for the evaluation of listedness/expectedness the 
most updated Investigator’s Brochure (IB) for the studied IMP. 
In practice, the term “new effect” is sometimes used as a synonymous of “unexpected adverse 
effect”. 
 
7.7.2.6 
Intensity criterion 
The CTEP Active Version of the NCI Common Terminology Criteria for Adverse Event 
(CTCAE) will be utilized for AE reporting.  
The intensity of adverse events not listed in this classification will be assessed using the 
following descriptors: 
• 
Mild (grade 1): does not affect the patient’s usual daily activities, 
• 
Moderate (grade 2): disturbs the patient’s usual daily activities, 
• 
Severe (grade 3): prevents the patient’s usual daily activities, 
• 
Very severe (grade 4): requires critical care/life-threatening, 
• 
Death (grade 5). 
 
7.7.2.7 
New information 
A new information is any new safety data that could lead to reevaluate the ratio between the 
benefits and risks of the research, or that could be sufficiently important to consider 
modifications of the research documents, the research management or, if need be, the drug 
utilization. 
 
7.7.2.8 
Special considerations 
Certain product safety monitoring reports should be forwarded even if there is no associated 
adverse event. These reports involve circumstances that may increase the patient/consumer’s risk 
of developing adverse events.  
These circumstances include: 
• 
medication errors, 
• 
exposure during pregnancy, 
• 
exposure during breastfeeding, 
• 
overdose, 
• 
misuse, 
• 
extravasation, 
• 
occupational exposure. 
Some of these special circumstances are considered in more details below. 

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 Medications errors: a medication error is any preventable event that may cause or lead to 
inappropriate medication use or patient harm while the medication is in the control of the 
healthcare professional, patient, or consumer. Such events may be related to professional 
practice, healthcare products, procedures, and systems, including: prescribing; order 
communication; product labeling, packaging, and nomenclature; compounding; 
dispensing; distribution; administration; education; monitoring; and use. 
A medication error does not necessarily involve the administration of the product (e.g. the error 
may have been corrected prior to administration of the product). 
Potential medication errors or “near-misses,” which are individual reports of information or 
complaints about product name, labeling, or packaging similarities that do not involve a patient, 
are also reportable. 
 
 Exposure during pregnancy: exposure during pregnancy refers to pregnancies where the 
fetus (from pre-embryo to birth) may have been exposed at a given time during 
pregnancy to a medicinal product (or a blinded treatment). Even if there is no associated 
adverse event, exposure during pregnancy must always be reported. It can indeed provide 
the opportunity to obtain pregnancy outcome important information where appropriate. 
Exposure during pregnancy may occur either: 
 
- Through maternal exposure  
A female becomes, or is found to be, pregnant either: 
• While receiving a medicinal product; 
• After discontinuing a medicinal product; 
• During or following environmental exposure to a medicinal product (eg, a nurse 
reports she is pregnant and that she was exposed to chemotherapy drugs via 
inhalation or after accidentally overturning a bottle). 
or 
 
-Through paternal exposure 
A male has been exposed to a medicinal product (either due to treatment or environmental 
circumstances) prior to or around the time of conception and/or is exposed during the partner 
pregnancy. 
 
 Exposure during breastfeeding: exposure during breastfeeding occurs where an infant or 
child may have been exposed through breast milk to a medicinal product during 
breastfeeding by a female taking the product. 
All drug exposure during breastfeeding cases are reported, whether or not there is an associated 
adverse event. 
 
7.7.3 Serious adverse events and new information notification (responsibility of the 
investigator) 
The investigator will notify the Vigilance Unit without delay about any serious adverse events or 
new events occurring: 
- From the date of the informed consent is signed, 
- During the whole patient treatment period as defined by the research, 
- Until 30 days after the last dose of the IMP/studied treatments. 

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- Beyond these periods of time specifics to each IMP, only those SAEs suspected to be related to 
the IMP or the research (other treatments used, diagnostic procedures, examinations carried out 
during the research, etc) will be collected without any limitation in terms of deadline.. 
Nonetheless, the Sponsor will evaluate any safety information related to the clinical trial that is 
spontaneously reported by an Investigator beyond the time frame specified in the protocol. 
 
Type of Event 
Reporting procedure 
Deadline for reporting to the 
sponsor 
SAE 
SAE Notification form + 
written 
report 
form 
if 
necessary 
To be reported immediately to the 
sponsor 
New information 
Written report form 
To be reported immediately to the 
sponsor 
Pregnancy 
Pregnancy Notification form 
+  Written report form if 
necessary 
As soon as pregnancy is confirmed 
The investigator must complete the “Serious Adverse Event Notification Form” (Appendix G) 
immediately, in English, and assess the relationship with the study treatment. The form must 
then be dated, signed and sent by fax to the following address without delay to: 
CELLULE DE VIGILANCE (VIGILANCE UNIT) – Institut Bergonié 
Fax: +33 5 56 33 04 85 
Or contact Sabrina Sellan-Albert (CRA) +33 5 56 33 78 05  – Mail: s.albert@bordeaux.unicancer.fr 
Dr Emilie Toulza (pharmacist) +33 5 47 30 60 53 – Mail: e.toulza@bordeaux.unicancer.fr 
Head of the Vigilance Unit: Dr Barbara Lortal +33 5 56 33 78 90 – Mail: b.lortal@bordeaux.unicancer.fr  
For each event, the investigator will record: 
 - A description of the event that is as clearly as possible, using medical terminology, 
 - The date the event started and ended, 
 - The patient’s relevant medical history, 
 - The steps taken and whether or not corrective treatment was required, whether or not the 
investigational treatment was discontinued, etc. 
 - Concomitant medications / therapies, 
 - The causal link between this event and the trial treatment, disease treated or an intercurrent 
disease or treatment, or any obligation imposed by the research (a treatment-free period, 
additional examinations requested as part of the research etc.), 
 - Clinical course. If the event was not fatal, it should be monitored until recovery, until the 
patient has returned to his/her previous condition, or until any sequelae have stabilized. 
  
Whenever possible, the investigator must also attach the following with the serious adverse event 
report: 
- A copy of the hospitalization or extended hospitalization report, 
- A copy of the autopsy report, if required, 
- A copy of all the results of any additional tests performed, including relevant negative 
results, along with the normal laboratory values, 
- Any other document he or she considers useful and relevant. 
All these documents must be anonymized. Additional information may be requested (by fax, by 
telephone or during a visit) by the CRA and/or by the Vigilance Unit using a follow-up request 

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form. 
The investigator is responsible for providing appropriate medical follow-up for patients until 
resolution or stabilization of the adverse event or until the patient’s death. Sometimes this may 
mean that follow-up will extend beyond the patient’s withdrawal from the trial. 
The investigator keeps the documents about the presumed adverse effect so that the information 
previously sent can be added to if necessary. 
The investigator responds to requests for additional information from the Vigilance Unit in order 
to document the original observation. 
 
7.7.4 Reporting pregnancy cases occurred within the clinical trial 
Pregnancy and suspected pregnancy (including a positive pregnancy test regardless of age or 
disease state) of a female patient or the female partner of a male patient occurring while the 
patient is on study drug, or within 30 days from the patient’s discontinuation visit, are considered 
immediately reportable events. 
The Investigator will report the following events immediately and always within 24 hours from 
first knowledge: 
• Any occurrence of a pregnancy where any kind of exposure to the IMP is suspected, 
• Possible exposure of a pregnant woman (this could involve a partner of a male patient or 
a pregnant female who came in contact with the clinical trial IMP), 
• All reports of elevated/questionable or indeterminate beta human chorionic gonadotropins 
(β-hCGs). 
Immediately after detecting a case of suspected pregnancy in a female clinical trial patient, the 
decision on her continued participation in the clinical trial will be jointly taken by the trial 
patient, the Investigator and the Sponsor, with the patient’s best interest in mind. A decision to 
continue the pregnancy will require immediate withdrawal from the trial.  
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the 
Vigilance Unit immediately by facsimile using the Pregnancy Report form (Appendix H).In the 
case of pregnancy of the female partner of a trial patient, the Investigator will obtain her consent 
to provide the information in these situations 
The Investigator will follow the pregnancy until its outcome, and must notify the Vigilance Unit 
the outcome of the pregnancy within 24 hours of first knowledge as a follow-up to the initial 
report. 
For any event during the pregnancy which meets a seriousness criterion (including fetal or 
neonatal death or congenital anomaly) the Investigator will also follow the procedures for 
reporting SAEs (complete and send the SAE form to the Vigilance Unit by facsimile within 24 
hours of the Investigator’s knowledge of the event).  
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death at any time thereafter that the Investigator 
suspects is related to the exposure to the study drug/IMP should also be reported to the Vigilance 
Unit by facsimile within 24 hours of the Investigators’ knowledge of the event. 
 
Whenever possible, the investigator must also attach the following with the serious adverse event 
report: 
- A copy of the hospitalization or extended hospitalization report, 
- A copy of the autopsy report, if required, 
- A copy of all the results of any additional tests performed, including relevant negative results, 

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along with the normal laboratory values, 
- Any other document he or she considers useful and relevant. 
All these documents must be anonymized. 
Additional information may be requested (by fax, by telephone or during a visit) by the 
Vigilance Unit. 
 
7.7.5 Non serious adverse events 
TYPE OF EVENT 
REPORTING 
PROCEDURES 
DEADLINE FOR 
REPORTING TO THE 
SPONSOR 
Non-serious AE 
Case report/record form 
Does not need to be reported 
immediately 
Non-serious adverse events will be reported by the investigator in the patient’s CRF and will be 
followed up until complete resolution.  
If an adverse event becomes serious, it should be reported and followed-up as mentioned in the 
previous reporting procedures. 
If the investigator would like to decrease trial treatment dose or temporarily stop study 
management without respecting protocol procedures, he/she should have previously discussed 
with the coordinator. 
However, symptomatic treatment can be prescribed to manage the adverse event. 
Any definitive interruption of the procedure has to be immediately notified to the sponsor. The 
patient remains in the study and is followed-up according to the procedures described in the 
protocol. 
 
7.7.6 Vigilance Unit 
The Vigilance Unit will analyze each SAE to define: 
-  The relationship with the study treatment, 
-  The listedness/expectedness according to the most updated reference safety information of the 
studied IMP Investigator’s Brochure (IB). 
 
7.7.7 Notification and registration of unexpected serious adverse events and new information 
(responsibility of the sponsor) 
The sponsor notifies unexpected serious adverse events and new information to the Regulatory 
Authorities (in person, or through an organization which has received allowances for this task) 
according to the usual notification procedures.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
XL184 (cabozantinib) (NSC 761968) 
 

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8.1.1 XL 184 (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: 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:  Cabozantinib is supplied by Exelixis and distributed by Theorem Clinical 
Research in Germany. Cabozantinib is available in 20 mg and 60 mg tablet. The tablets are 
yellow film coated containing cabozantinib malate equivalent to 20 mg and 60 mg of 
cabozantinib. The 20 mg tablets have a round shape and the 60 mg tablets have an oval 
shape, and they are packaged as 30 tablets per bottle.  
 
Cabozantinib should be dispensed in its original container. Cabozantinib tablets are stable 
for up to 24 hours when dispensed in an open container, such as in a pill cup, and are 
stable for up to 7 days when dispensed in a closed container, such as a pharmacy 
dispensing bottle. 
 
XL184 Tablet Components and Composition 
Ingredient  
Function 
% 
w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9
Lactose Anhydrous (60M) 
Filler 
19.4
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910 / Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00
 

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Storage:  Store intact bottles at controlled room temperature, 200 to 250C. 
 
Stability:  Stability testing of the intact bottles is on-going. Cabozantinib is stable up to 24 
hours when dispensed in an open container such as a pill cup, and up to 7 days when 
dispensed in a closed container such as a pharmacy bottle other than the original container.  
 
Route of Administration: Oral. 
 
Method of Administration: Take Cabozantinib on an empty stomach, no food 2 hours 
before and 1 hour after taking Cabozantinib.  Do not crush or chew.  
 
Potential Drug Interactions: Cabozantinib is a substrate of CYP3A4. Coadministration of 
Cabozantinib with medications that are strong inhibitors/inducers of CYP3A4 should be 
avoided. Examples of strong CYP3A4 inducers are rifampin, dexamethasone, phenytoin, 
carbamazepine, rifabutin, rifampentin, Phenobarbital, and St. John’s Wort. Strong CYP3A4 
inhibitors are ketoconazole, itraconazole, clarithroumycin, indinavir, nefazodone, nelfinavir, 
and ritonavir. Use alternative medications. Avoid grapefruit/ grapefruit juice and Seville 
oranges including herbal tea while participating in this trial.  
 
Vitro data indicate that 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. 
 
Cabozantinib is highly protein bound, 99.9%. Use caution when coadministering 
Cabozantinib with medications that are highly protein-bound (e.g., diazepam, furosemide, 
dicloxacillin, and propranolol). Avoid administration of warfarin with Cabozantinib as 
warfarin is highly protein-bound and has a very narrow therapeutic index. 
 
Avoid concomitant use of Cabozantinib with proton pump inhibitors (PPIs) and H2 -
antagonists if possible. The PPIs and H2 –antagonists may decrease Cabozantinib plasma 
exposure levels and its effectiveness in humans.  Examples of PPIs are omeprazole, 
lansoprazole, rabeprazole, pantoprazole, and esomeprazole; examples of H2 –antagonists are 
ranitidine, famotidine, and nizatidine. Cimetidine is a moderate CYP3A4 inhibitor. Avoid 
using cimetidine with 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 Cabozantinib but at least 14 
hours before the next dose of Cabozantinib if possible. 
 
Potential Food Effect 
The effect of food on the bioavailability of cabozantinib was evaluated in healthy adult 
subjects in a Phase 1, open-label, randomized, single-dose, two-treatment, two way 
crossover study (Study XL184-004). Based on the PK data, a high fat meal did not appear to 
alter the terminal t1/2 but significantly increased the median tmax. The high fat meal also 
significantly increased both the cabozantinib Cmax and AUC values. Based on this result, 
cabozantinib should be taken on an empty stomach (fasting is required 2 hours before and 1 

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hour after each cabozantinib dose). 
 
Patient Care Implications:  Do not take grapefruit/ grapefruit juice or Seville oranges including 
herbal tea 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.  Co-administration of gastric pH modifying drugs such as PPI, H2-blockers or 
antacids is not contraindicate in subjects administered cabozantinib. 
. 
Availability 
 
XL184 (cabozantinib) is an investigational agent supplied to investigators by Exelixis. 
 
XL184 (cabozantinib) is provided to the NCI under a Collaborative Agreement between 
the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
8.1.2.1 
Agent Ordering 
Each participating institution will order Cabozantinib directly from Theorem Clinical Research 
(TCR) based in Germany (TheoremCSshippingorders@theoremclinical.com). A specific 
procedure will be provided by the sponsor. 
 
8.1.2.2 
Agent Accountability  
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all Cabozantinib 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 
 
Biomarkers have the potential to shape diagnostic strategies and influence therapeutic 
management. In the future, biomarkers may promote a personalized medicine approach, 
grouping patients by the molecular signatures of their tumors and of markers in the blood rather 
than by cancer type. We are concentrating our efforts in identifying predictive biomarkers, which 
provide information about the likely efficacy of Cabozantinib. To evaluate the pharmacodynamic 
and mechanistic effects of a drug on the tumor a tumor biopsy is often required. 
Preclinical studies have shown that Cabozantinib dramatically altered tumor pathology, resulting 
in decreased tumor and endothelial cell proliferation coupled with a strong inhibition of 
phosphorylation of MET. Cabozantinib has also been shown to induce changes in the levels of 
circulating biomarkers related to its mechanism of action of cabozantinib, including VEGF-A, 
soluble VEGFR2, and soluble MET.  

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Optional serial tumor samples (day 1 cycle 1 predose and day 28 postdose in cycle one) will be 
analyzed in consenting patients for: 
• Hematoxylin and eosin staining (H&E). 
• Immunohistochemistry (IHC) assessments including, but not limited to the following markers: 
MET, phospho-MET, CD31 (microvessel density), Ki67.  
The analysis will be prioritized based on the amount of material available. 
The MET and Phospho-Met antibodies (Tyr1349, Cell Signaling, Danvers, MA antibody 
(AF276, R&D Systems, Minneapolis, MN) will be used to assess MET and phosphor-MET 
protein expression on tumor samples. The assay will be evaluated on a semi-quantitative scale in 
which the percentage of tumor cells staining will be recorded at the following levels: 0 
(unstained), 1+ (weak staining), 2+ (moderate staining), and 3+ (strong staining). A negative 
isotype control will be run on every sample and a positive staining control will be run with each 
staining run. Derivative scores, such as total percent positive, and maximum staining intensity, 
will be provided. Cytoplasmic and membrane staining will be evaluated separately.  
 
Plasma samples for pharmacodynamic analysis will be collected on days 1, 15, and 28 of cycle 1 
by using the following assays. 
 
Plasma levels of hepatocyte growth factor (HGF) 
Human HGF/Scatter: Factor immunoassay kit (R&D 
Systems, Minneapolis, MN) that detects pro-HGF, 
rilotumumabbound HGF, and free HGF.  
Plasma levels of soluble MET 
MSD assay using a biotinylated, affinity-purified, 
MET ectodomain-specific (soluble MET) capture 
antibody (R&D Systems, Minneapolis, MN) and an 
MSD sulfotag-conjugated antibody against the 
extracellular domain of recombinant human MET 
(R&D Systems, Minneapolis, MN). 
Plasma levels of soluble of VEGFA and soluble 
VEGFR2 
VEGFA and VEGFR-2 ELISA kits (R&D Systems, 
Minneapolis, MN, USA). 
 
Pharmacodynamic analysis will be primarily based on the population of patients assessable for 
efficacy endpoints. For the analysis of biomarkers the primary evaluation will be based on the 
observed change from baseline. Whenever appropriate, the actual change or the log transformed 
change will be assumed normal distributed and analyzed accordingly. Both actual values and 
estimated parameters with belonging 95% confidence intervals will be presented in summary 
tables and graphically. 
Whenever normal assumption is not appropriate, data will be analyzed in frequency tables. The 
study is not designed to establish formal pharmacodynamics data-efficacy relationships. 
However, exploratory analyses will be performed for the pharmacodynamic and biomarker data 
to explore pharmacodynamic and clinical effect. Different approaches will be investigated, 
among these analysis of regression including baseline value and other relevant co-factors, and 
analysis of repeated measurements including confounding factors and within subject correlation. 
Biomarker data will be evaluated descriptively and may be analyzed for their correlation with 
clinical data, imaging parameters and clinical response/safety if feasible. In all cases data 

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transformation will be applied if relevant to meet model assumptions. This will be investigated 
graphically. 
 
9.2 
Laboratory Correlative Studies 
 
9.2.1 Whole Blood samples for Pharmacodynamic analysis  
9.2.1.1 
Collection of Specimens 
Pharmacodynamic of Cabozantinib will be assessed on C1D1 pre-dose, C1D15 and C1D28. 
For each patient, blood samples will be collected at predefined time points. 
Schedule of blood sampling for BM study 
 
EDTA 
C1D1 
XX 
C1D15 
XX 
C1D28 
XX 
For plasma study, two 4,5 ml EDTA tubes (or one 7 ml EDTA tube) will be taken at each time 
point. 
The sample collection information must be captured on the appropriate CRF page(s). 
 
9.2.1.2 
Handling of Specimens 
Samples will be centrifugated in the next 15 minutes, at 3100g (4000 rpm) for 15 minutes and 
4°c. In case of incapacity to centrifugate in the next 15 minute, samples should be kept cold until 
handling. The aliquoted samples (3 aliquots) will be annotated with the study name (CABONE), 
center study ID number (1, 2, 3, 4), patient study ID number, date (dd/mm/yyyy) and the 
identification (marker ID: HGF, MET, VEGFA and VEGFR2, and time point) and stored at < 
80°c until day of shipping. 
Pharmacodynamics Methods Guidelines will be provided by the sponsor as a separate document. 
 
9.2.1.3 
Shipping of Specimens 
The containers containing the samples will be labeled with coded numbers to ensure full 
compliance with privacy policy. Samples will be grouped in each institution and sent frozen for 
centralized processing. 
Shipping will only be performed by a promoter authorized transporter with respect to good 
practice. 
 
9.2.1.4 
Site Performing Correlative Study 
Plasma studies will be performed at Institut Bergonie, Biopathology Department, Bordeaux –
France. 
Samples will be sent to: 
Docteur Julie DUBOIS 
Institut Bergonie 
Biopathology Department 
229 cours de l’Argonne 
33076 Bordeaux Cedex, France 
 

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9.2.2 Tumor samples  
9.2.2.1 
Collection of Specimen(s) 
Tumor biopsies will be performed on consented adult patients at Day 1 of cycle 1 predose and at 
Day 28 of cycle 1 postdose. 
 
9.2.2.2 
Handling and shipping of Specimen(s) 
One half of the specimen will be formalin fixed and paraffin embedded [FFPE (Formalin-Fixed 
Paraffin-Embedded)] and the second half will be fresh frozen at -80°C. 
The samples will be labelled with coded numbers to ensure full compliance with privacy 
policies. Samples will be grouped in each institution and sent for centralized processing with the 
documents. 
All samples will be stored before they are analyzed. 
The sample collection information must be captured on the appropriate CRF page(s). 
 
9.2.2.3 
Site(s) Performing Correlative Study  
All pathological specimens sampling with documents must be sent to:  
Marie Louty 
Institut Bergonie – Pathology Unit 
Protocol CABONE 
229 cours de l’Argonne 
33076 Bordeaux Cedex, France 
 
9.3 
Imaging Studies 
 
FDG-PET can improve patient management by identifying responders early, before tumor size is 
reduced. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy 
(e.g., in breast (Avril, 2009), ovarian (Schwarz, 2009) and non–small cell lung (Zander, 2011) 
significantly correlates with prolonged survival and other clinical end points now used. Several 
studies performed in Ewing and osteosarcoma patients have shown that changes in tumor 18F-
FDG uptake correlate with tumor necrosis in patients treated with chemotherapy (Hawkins, 2005 
; Schulte, 1999 ; Sato, 2008 ; Ye, 2008 ; Hawkins, 2002). We hypothesize that XL184 treatment-
induced changes in tumor metabolism may be assessed with FDG-PET and that change in tumor 
18F-FDG uptake may correlate with outcome. 
All the patients will undergo FDG-PET before C1D1 and C1D28. Patients should be scanned on 
the same scanner for the baseline and end-of-cycle 1 FDG PET scan to minimize variations in 
SUV measurements. 
PD markers assessed as changes from baseline in imaging, i.e. FDG-PET will be a secondary 
endpoint. 
 
 

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10. STUDY CALENDAR 
 
Follow-up will be the same for young and adult patients. During treatment, clinical exam and 
blood analysis will be performed every week during cycle 1, every two weeks during cycles 2-4, 
and every month thereafter. For each blood analysis, 12 ml will be necessary (hematology and 
biochemistry), for a total of 48 ml during cycle 1, 24 ml during cycles 2-4 and 12 ml per month 
thereafter. 
As effect of Cabozantinib on bone remodeling was only observed on bone models, no specific 
bone assessment and follow-up will be performed during this study. 
 
SCREENING 
CYCLE 1 
CYCLES 2 à 4 
CYCLE 
N 
End of 
treatment (30-
37 days) 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
XL184 
 
X ………………………..continuous ………………………………….X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments 
X 
X ………………………………………………………………………X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Vital signsa 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Clinical laboratory testb 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Urinalysis and UPCR 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
PT/INR, PTT 
X 
X 
 
 
 
X 
 
 
 
X 
 
TFTs (TSH, free T3, free 
T4) 
X 
X 
 
 
 
X 
 
 
 
X 
 
ECGf  
X 
X 
 
 
 
X 
 
 
 
X 
X 
Toxicity 
 
X ………………………………………………………………………X 
X 
Tumor measurement 
X 
Repeated every 2 cycles (ie. 8 weeks). Documentation (radiologic) must be 
provided for patients removed from study for progressive disease 
 
Chest X-ray 
 
 
 
 
 
Xh 
 
 
 
Xh 
 
B-HCG c (if indicated) 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Blood samples 
 
Xd 
 
Xd 
Xd 
 
 
 
 
Xd 
 
PET-FDG 
Xg 
 
 
 
D28 
 
 
 
 
 
 
Biopsy for translational 
research 
X 
 
 
 
Xe 
 
 
 
 
 
 
a: Heart rate, blood pressure, temperature 
b: CBC, differential, platelets, albumin, alkaline phosphatase, SGOT [AST], SGPT [ALT], amylase, bicarbonate, bilirubin, blood urea nitrogen, 
calcium, chloride, creatinine, γ-glutamyltransferase (GGT),  glucose, lactate dehydrogenase (LDH),  lipase, magnesium, phosphorus, 
potassium, sodium, total bilirubin, total protein 
c: Serum test 10-14 days and within 24 hours prior to the first dose of XL 184. Pregnancy test must be repeated at least once every month 
thereafter (serum or urine).  
d: on Day 1, Day 15 and Day 28 of cycle 1 
e: to be performed on Day 1 of cycle 1 predose and on Day 28 of Cycle 1 postdose on the same scanner for the two evaluation 
f: Required in triplicate at baseline. Three ECG should be obtained within 30 minutes but at least 3 minutes apart. 
g: to be done within 1 week prior do Day 1 of Cycle 1 
h: to be performed at the end of cycle 1, 3, 5 etc.. (every 8 weeks between each tumor evaluation) 

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Screening evaluation should be done within 28 days prior to 1st dose of study treatment. 
Evaluations on C1D1 should be done within 4 days prior to the 1st dose of XL184. 
Each other evaluation should be done with an interval of +/- 5 days.  
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained not less than 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) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
 
11.1.1 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as >10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  Lesion in previously irradiated field could be considered as 
measurable if progressive at inclusion. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-

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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.  
 
11.1.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 

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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. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 

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Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  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. 
 
11.1.3 Response Criteria 
11.1.3.1 
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). 

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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. 
 
11.1.3.2 
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). 
 
11.1.3.3 
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. 
 
In this study, only patients with Measurable Disease (i.e., Target Disease) are eligible, and 
as such, the following definitions apply (RECIST 2009):  
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation required 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation required  
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 
Confirmation required  
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 

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Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
***      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. 
 
 
11.1.4 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.  
 
11.1.5 Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
11.1.6 Overall Survival (OS) 
OS is defined as the duration of time from start of treatment to the time of death 
 
11.1.7 Response Review 
11.1.7.1 
Review process: 
Centralized radiological review will be performed for all patients to confirm Disease status at 6 
months in comparison with baseline, Week#8 and Week#16  
In case of discordance between the local radiologist and the expert reviewer, the judgment 
provided by the expert reviewer will be retained and used in statistical analyses. 
 
11.1.7.2 
Review process schedule: 
All tumor evaluations will be sent as soon as there were available. 
Patient’s information must be anonymized and recorded on a provided imaging CD. 
 

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11.1.7.3 
Practical implementation: 
For each shipment, each media should be accompanied by the Radiological Forms provided by 
the sponsor. 
All CDs must be sent to: 
Sabrina SELLAN-ALBERT 
Clinical Research Associate 
Institut Bergonié – 229 cours de l’Argonne – 33076 Bordeaux Cedex, France 
Phone: +33 5 56 33 78 05 – Mail: s.albert@bordeaux.unicancer.fr  
 
 
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 protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
Study participants are responsible for 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. 
 
Either the Coordinating Center or the Lead Organization is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data to the Principal 
Investigator for review.   

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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 
 
If the investigational study agent is provided by CTEP under a Collaborative Agreement 
[Cooperative Research and Development Agreement (CRADA), Clinical Trials Agreement 
(CTA), Agent-CRADA or Clinical Supply Agreement (CSA)] with the Pharmaceutical Company, 
this section must be included in the protocol.  Information on the investigational study agent’s 
Agreement status will be provided in the approved LOI response.  If no Collaborative Agreement 
applies to the investigational study agent, this section should be marked “N/A” and the text 
below deleted.  
 
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”): 

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a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
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 

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The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS  
 
For each stratum (osteosarcoma and Ewing sarcoma), two statistical analyses plan (SAP), will be 
produced: one for the final statistical analysis and one for the interim statistical analysis (see 
section 13.6).  
For each stratum, the SAP will be drafted before the inclusion of the first patient.  
 
13.1 
Study Design/Endpoints 
 
13.1.1 Osteosarcoma 
We rely on a single-arm phase 2 trial based on dual endpoint design (Goffin et al. J Clin Oncol 
2008).  
The primary efficacy endpoint is a composite endpoint encompassing non-progression and 
objective response at 6 months. 
Non-progression is defined as complete response, partial response or stable disease as defined in 
section 11.1.3.  
Objective response is defined as complete response or partial response as defined in section 
11.1.3.  
 
 
13.1.2 Ewing sarcoma 
We rely on a single-arm phase 2 trial based on an optimal two-stage Simon’s design.  
The primary efficacy endpoint is objective response rate at 6 months. 
Objective response is defined as complete response or partial response as defined in section 
11.1.3. 
 
13.1.3 Imaging  
All patients will undergo FDG-PET before C1D1 and C1D28. We will assess the ability of 
metabolic tumor response as measured by FDG-PET at the end of one cycle of treatment to 
predict PFS. 
FDG-PET tumor response at C1D28 will be defined following Young et al. (Eur J Cancer 1999) 
and classified as follows: progressive metabolic disease (PMD), stable metabolic disease (SMD), 
partial metabolic response (PMR), and complete metabolic response (CMR). The count and 
proportions of patients for each type of response at C1D28 will be reported. 
The ability of PMR at C1D28 to predict PFS will be investigated in exploratory survival 
analyses. After verification of the underlying hypotheses of the statistical models, multivariate 
Cox proportional hazards models will be fitted that include both PMR (binary variable) and usual 
known prognostic factors.  

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13.2 
Sample Size/Accrual Rate 
 
The data from the literature about outcome of patients with advanced Ewing or osteosarcomas 
are limited. Objective response may not be an appropriate surrogate marker for therapeutic 
activity in osteosarcoma. Indeed, due to the abundant bone matrix, substantial anti-tumor activity 
may not result in a marked decrease in overall tumor volume. Moreover, non-progression rate is 
a worldwide recognized endpoint to assess new investigational agents in advanced sarcoma 
patients (Van Glabbeke et al. 2002). Median progression-free survival of relapsed osteosarcomas 
patients with unresectable disease and rechallenged with chemotherapy is about 2 months (Leary 
et al., 2013).   
Recent studies investigating biological agents in Ewing sarcomas have concluded that a response 
rate < 10% represent only a modest activity (Ho et al., 2011; Pappo et al., 2011)   
 
13.2.1 Osteosarcoma 
We rely on a single-arm phase 2 trial based on 2-stage dual endpoint design (Goffin et al. J Clin 
Oncol 2008). Cabozantinib will be considered promising if either tumor response rate or 6-month 
non-progression rate is promising. 
 
Hypotheses under Cabozantinib treatment are the following:  
- Hypotheses for non-progression at 6 months: 
- 25% non-progression rate (null hypothesis / median PFS of 3 months),  
- 50% non-progression rate (alternative hypothesis / median PFS of 6 months),  
- Hypotheses for objective response at 6 months: 
- 5% objective response rate (null hypothesis),  
- 20% objective response rate (alternative hypothesis),  
 
Assuming 41 eligible and assessable patients: 
- 
Stage 1 (21 eligible and assessable patients): Inclusions will continue if either objective 
response is observed in at least 2 patients or non-progression is observed for 7 patients. 
Otherwise, the stratum will be terminated early and declared negative. 
- 
Stage 2 (41 eligible and assessable patients): Cabozantinib will be considered worthy of 
further testing in this indication if at least 5 objective responses (at least 12%), or at least 
16 instances of 6-month PFS (at least 39%), were observed among the 41 evaluable 
patients.  
This design yields at least 90% power to detect a true objective response rate of at least 20%.  It 
yields at least 92% power to detect a true 6-month PFS rate of at least 50% (median PFS of 6 
months).  It yields at least .925 probability of a negative result if the true objective response rate 
is no more than 5% and the true 6-month PFS rate is no more than 25% (median PFS of 3 
months), with approximately .53 probability, at least, of early negative stopping in this case.  
These last two probabilities are calculated assuming that tumor response rate and 6- month PFS 
rate are uncorrelated.  If they are positively correlated, as is likely, the probabilities will be a bit 
higher. 
 
Given the disease is rare and the absence of standard treatment in this indication, inclusion will 
not be suspended after the recruitment of the first 21 patients. Inclusion will be pursued, while 

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data on the first 21 patients will be analyzed. 
 
In order to account for not evaluable patients (+/- 10%), 45 patients will be recruited. 
 
The anticipated accrual rate is 2-3 patients/month. 
 
13.2.2 Ewing sarcoma 
We rely on a single-arm phase 2 trial based on an optimal two-stage Simon’s design.  
 
Based on the following hypotheses under Cabozantinib treatment:  
- 5% 6-month objective response rate (null hypothesis),  
- 20% 6-month objective response rate (alternative hypothesis),  
- 5% type I error rate (1-sided),   
- 90% power, 
a total of 41 patients (eligible and assessable for efficacy – see definitions of study populations 
below) will be necessary, with 21 recruited to the first stage.  
 
Stage 1: Following the inclusion of the first 21 patients, if 1 or less patient exhibits objective 
response (complete response, partial response) at 6 months, the study would be terminated early 
(objective response  rate lower than 5%). Otherwise, the second group of 20 subjects will be 
recruited.  
 
Stage 2: If at the end of recruitment, 5 patients or more exhibit objective response (out of the 41 
patients) at 6 months, Cabozantinib would be considered worthy of further testing in this disease 
and the objective response rate will be considered greater than 5%. 
 
Given the disease is rare and the absence of standard treatment in this indication, inclusion will 
not be suspended after the recruitment of the first 17 patients. Inclusion will be pursued, while 
data on the first 17 patients will be analyzed. 
 
In order to account for not evaluable patients (+/- 10%), 45 patients will be recruited. 
 
The anticipated accrual rate is 2-3 patients/month. 
 
13.3 
Definition of study populations 
 
13.3.1 Osteosarcoma 
 
13.3.1.1 
Eligible population 
All patients without major violations of the eligibility criteria are included in this population. In 
case of violation of the eligibility criteria, the steering committee will assess for each patient, 
whether the violation is minor or major. 
 
13.3.1.2 
Population assessable for efficacy  
All patients eligible and who received at least one complete or two incomplete treatment cycles. 

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13.3.1.3 
Population assessable for safety 
All patients will be assessable for safety from the time of their first administration of 
Cabozantinib. 
 
13.3.2 Ewing sarcoma 
 
13.3.2.1 
Eligible population 
Same definition as for osteosarcoma. 
 
13.3.2.2 
Population assessable for the efficacy criteria 
Same definition as for osteosarcoma. 
 
13.3.2.3 
Safety population 
Same definition as for osteosarcoma. 
 
 
13.4 
Stratification Factors 
 
Not applicable 
 
13.5 
Analysis of Secondary Endpoints 
 
Endpoints will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma) 
following the SAP.  
 
13.5.1 Best overall response 
Best overall response is defined in section 11.1.4.3 and will be assessed on the population 
assessable for efficacy criteria. This endpoint will be described using frequency, percentage and 
95% confidence interval (binomial law). 
 
13.5.2 Progression-free survival 
Progression-free survival (PFS) is defined in section 11.1.6 and will be assessed on the 
population assessable for efficacy criteria. PFS will be analysed using the Kaplan-Meier method. 
The median survival rates will be reported with a 95% confidence interval. Median follow-up 
will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be 
carried out based on Cox’s proportional risk method and after checking the risk proportionality 
hypothesis.  
 

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13.5.3 Overall  survival 
Overall survival (OS) is defined in section 11.1.7 and will be assessed on the population 
assessable for efficacy criteria. OS will be analyzed using the Kaplan-Meier method. The median 
survival rates will be reported with a 95% confidence interval. Median follow-up will be 
calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out 
based on Cox’s proportional risk method and after checking the risk proportionality hypothesis. 
 
13.5.4 Safety 
Treatment safety will be assessed using the CTCAE version 4 on the safety population. 
Quantitative variables will be described using mean and standard errors if the normality 
assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be used. 
Qualitative variables will be described using frequency, percentage and 95% confidence interval 
(binomial law). 
 
13.6 
Interim statistical analysis 
 
13.6.1 Osteosarcoma 
An interim statistical analysis will be carried out after the inclusion of the first 21 eligible and 
assessable patients. The trial will be terminated if no more than 1 objective response (5%), and 
no more than 6 instances of 6-month PFS (no more than 29%) were observed among the initial 
21 patients. Otherwise, the second group of 20 subjects will be recruited. A statistical report will 
be produced by the statistician of the study. Inclusion will not be suspended during this interim 
analysis. 
 
No additional interim statistical analysis is foreseen. 
 
13.6.2 Ewing sarcoma 
An interim statistical analysis will be carried out after the inclusion of the first 21 eligible and 
assessable patients. The trial will be terminated if 1 or less patient exhibits objective response. 
Otherwise, the second group of 20 subjects will be recruited. A statistical report will be produced 
by the statistician of the study. Inclusion will not be suspended during this interim analysis. 
 
No additional interim statistical analysis is foreseen. 
 
13.7 
For phase 2 protocols only: Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
Cabozantinib. 
 
13.7.2 Evaluation of Efficacy 
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 

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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).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the definition for “Population assessable for efficacy” (see 
section 13.3) will be included in the main analysis of the response rate.  Patients in 
response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate. 
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.). However, these subanalyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported.  The 95% 
confidence intervals should also be provided.  
 
 
14. QUALITY ASSURANCE AND TRIAL MONITORING 
 
14.1 
Monitoring of the trial 
 
14.1.1 Steering committee 
The study will be supervised and monitored by a Steering Committee comprising members 
participating in the study: 
• 
Dr A. Italiano, Co-ordinating Investigator and Chairman of the Commitee,  
• 
Dr BN. Bui, Investigator and medical oncologist, 
• 
Pr S. Mathoulin-Pélissier, Head of the Clinical Research and Epidemiology Unit, 
• 
Dr C. Bellera, biostatistician, 
• 
Dr B. Lortal, Pharmacist 
• 
S Sellan-Albert, Co-ordinating Clinical research assistant   
This committee must ensure the following:  
• 
Implementation and regular follow-up of the study 
• 
Patient protection, 
• 
That the trial is conducted ethically, in accordance with the protocol, 
• 
That the trial benefit/risk ratio is evaluated and the scientific results are checked during or at 
the end of the trial.  
 
It decides on any relevant amendment to the protocol that is required in order to continue the trial 
(protocol amendments prior to submission to the EC and the relevant Health Authorities, 
decisions on whether to open or close research sites, discussion of results and the strategy for the 
publication of these results). It must inform the sponsor of any decisions taken. Decisions 

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concerning a major amendment or a change to the budget must be approved by the sponsor. 
 
14.1.2 Independent Data Monitoring Committee 
An independent Data Monitoring Committee (IDMC) may be created at the request of the 
relevant Authority, the sponsor or the Steering Committee. The IDMC plays an advisory role for 
the Sponsor, who has the final decision regarding the implementation of recommendations put 
forward by the IDMC. 
Composition of the IDMC 
• 
This Committee must comprise at least one qualified oncologist, one pharmacologist and 
one statistician, all of whom will have experience in the monitoring and analysis of clinical 
trials. One of these members will be appointed as the Trial Rapporteur.  
• 
Each of these members must be unconnected with the trial and cannot, therefore, be one of 
the trial investigators.  
• 
These members are appointed by the Sponsor in consultation with the trial co-ordinator and 
the Steering Committee.  
 
Responsibilities of the IDMC 
The IDMC is responsible for the following: 
• 
Analyzing preliminary efficacy and safety data, 
• 
Making recommendations on the continuation, early discontinuation (in the case of toxicity 
or lack of efficacy) or publication of the trial results, 
• 
Drafting the minutes after each meeting and monitoring their confidentiality. 
 
Organization rules of the IDMC will follow the internal procedures of Institut Bergonié.  
 
14.2 
Quality assurance 
 
14.2.1 Data collection 
The data will be collected on an electronic case report form and directly input via the Internet. 
Only the investigators and the Investigator’s Clinical Research Assistants (CRAs) appointed by 
the later and duly authorized by the sponsor will be authorized to enter the data. 
Data will be handled by an online trial management software on the Internet (Macro, Infermed 
Company); it will be transferred and monitored remotely in real time. 
The study CRA and/or any other person appointed by the sponsor will be available to assist the 
investigators in carrying out the study and to ensure that the trial is carried out in accordance 
with the protocol. 
The study CRA will contact the investigators regarding the study implementation visit.  
All of the necessary data will be collected on an electronic case report form provided by the 
sponsor. The generic names of the concomitant medication will be given in French. 
Corrections made to the original data must be justified. These corrections will be automatically 
dated and signed by the authorized member of staff via the personalized password allocated at 
the start of the study. 

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The case report form will be validated by the investigator or the CRA at the authorized center 
whenever data is entered. 
Laboratory data exceeding normal limit values will be commented upon if they are considered 
clinically significant. Data other than that requested within the scope of the protocol can be 
collected as additional data; their interest will be specified. 
 
14.2.2 Monitoring 
In order to guarantee the authenticity and credibility of the data in accordance with the principles 
of GCP (Good Clinical Practice) dated 24 November 2006, the sponsor shall implement a quality 
assurance system comprising: 
 the management and monitoring of the trial in accordance with the procedures stipulated by 
the Bergonié Institute, 
 the quality control of the research site data by the CRA whose role is to: 
o check compliance with the protocol, GCP and current legislation and regulations, 
o check the consent and eligibility of each patient taking part in the trial, 
o check the consistency and coherence of case report form date against the source 
documents. 
o check that each serious adverse event is reported, 
o monitor the traceability of the study medication (dispensation, storage and drug 
accountability), 
o check, where applicable, that the persons likely to take part in the trial are not 
already participating in another trial that could prevent them from being included 
in the clinical trial proposed. The CRA shall also ensure that the patients have not 
participated in a trial for which an exclusion period currently applies. 
 The possible audit of study centers 
 The centralized review of certain protocol criteria. 
The check procedures will include: 
 Study progression, 
 Protocol compliance, 
 The updating of information on the Internet site. 
The checking of data by comparing the information on the electronic case report form and the 
original clinical or laboratory data is one of the monitoring procedures. Data will be check as 
determined in the monitoring plan. 
The following will be checked, in particular, for each patient (100% level): patient identification, 
informed consent (procedure and signature), selection criteria, therapeutic procedure, adverse 
events, principal response variables. The personal data relating to each patient shall remain 
confidential. On the electronic case report form or any other form dispatched, the patients will be 
identified solely by their initials (2/name – 2/surname) and an inclusion number. However, the 
investigators must keep a list identifying the patients in their folders. 
The CRAs responsible for the quality control of this clinical trial are duly appointed by the 
sponsor for this particular purpose and must have access, with the consent of those involved, to 

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individual trial participant data required strictly in accordance with this control procedure. The 
CRAs are subject to professional secrecy under the conditions defined by Articles R 5121-13 of 
the Public Health’s code. The traceability of monitoring visits is guaranteed by a written 
monitoring report. 
The investigators shall undertake to give CRAs direct access to the medical records of each 
patient in order to allow the CRAs to ensure optimal quality control of the trial. The same applies 
to health authority representatives. 
 
14.2.3 Handling of missing data 
The monitoring of data for adverse events will be carried out regularly in order to effectively 
limit the amount of missing data likely to prevent or hamper trial implementation and analysis. 
 
14.2.4 Audits 
The sponsor, the local authorities or the authorities to which information about this study has 
been submitted can decide to have an audit. All the documents relating to this study must be 
available for such an inspection after prior notification. 
 
 
15. REGULATORY ASPECTS AND ETHICAL CONSIDERATIONS 
 
Clinical Research Management Unit – Institut Bergonié 
Contacts: Pauline Beaufrère – Tel.: +33 5 56 33 32 70 – e-mail: p.beaufrere@bordeaux.unicancer.fr 
or Stéphanie Louchet –  Tel.: +33 5 56 33 04 76 – e-mail: s.louchet@bordeaux.unicancer.fr 
 
The study will be carried out in accordance with: 
 The ethical principles of the current version of the “Declaration of Helsinki”  
 Good Clinical Practice (GCP): I.C.H. version 4 of 1 May 1996 and decision dated 24 
November 2006 (Official Bulletin of 30 November 2006, text 64). 
 European Directive (2001/20/EC) on clinical trial procedures. 
 Huriet’s law (No. 88-1138) dated 20 December 1988, concerning the protection of persons 
taking part in Biomedical Research with the provisions of the Public Health law (No. 2004-
806) of 9 August 2004 and implementating decree No. 2006-477 of 26 April 2006 relating to 
biomedical research. 
 The French law on Data Protection and Civil Liberties, No. 78-17 of 6 January 1978 
amended by law No. 2004-801, dated 6 August 2004, concerning the protection of persons 
with regards to the processing of personal data. 
 The application of Circular DHOS/INCA/MOPRC/2006/475 of 7 November 2006: the 
Sponsor shall undertake to register the Trial and thus make it accessible to the general public, 
in the INCa (French Cancer Institute) register via the Internet site: www.e-cancer.fr. Each 
trial published in the INCa register will be sent to the NCI for registering on the following 
site: www.clinicaltrials.gov. The trial will be registered before the first patient is entered into 

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the study. The Sponsor is responsible for updating the study data in order to guarantee the 
reliability of the information available on-line. 
 Law no. 2004-800 dated 6 August 2004, concerning bioethics, amended by law No. 2012-
387, dated 22 March 2012. 
 
15.1 
Clinical trial authorization 
 
This trial is registered under Eudract N° 2014-XXXXXX-XX. 
The protocol has been approved by the South West and Overseas Territories III Ethics 
Committee, Bordeaux.  Approval was given on |__|__|/|__|__|/|__|__|__|__|. 
The Relevant Authority, the Agence Nationale de Sécurité du Médicament et des Produits de 
Santé (ANSM - French Agency for the Safety of Health Care Products) authorized the clinical 
trial on |__|__|/|__|__|/|__|__|__|__|. 
Any amendments to the protocol concerning study objectives, patient population and principal 
methods will require an amendment, which must be approved by the EC and l'ANSM.  The 
sponsor will inform the EC and ANSM of expected and/or unexpected serious adverse events in 
accordance with current regulations and within 30 days after of completion of the trial. 
The sponsor will send the summary of the final report to the relevant Authority within one year 
of completion of the trial. 
The sponsor has made a commitment to compliance the Reference methodology for the 
processing of personal data carried out in biomedical research: Reference methodology MR-001. 
This commitment of compliance is registred under No 118019 of the 07/11/2006. 
 
15.2 
Insurance policy 
 
The Institut Bergonié has taken out an insurance policy with société HDI-Gerling, Tour opus12, 
77, Esplanade de la défense, 92914 PARIS LA DEFENSE through an insurance broker, namely 
Biomédic Insure (Parc d'Innovation Bretagne Sud, CP 142, 56038 Vannes, tel. 02 97 69 19 19) 
in case compensation is payable to investigators or patients taking part in the study. 
 
15.3 
Informing and obtaining consent from patients 
 
The investigator in charge of the patient will provide the latter with relevant information relating 
to the study objectives, potential benefits and possible adverse events. The study methods will be 
outlined. The patient can refuse treatment before or at any time during the study, without 
experiencing any adverse repercussions in terms of his/her subsequent care. 
The patient’s written consent will be obtained prior to entry into the study by using the Patient 
Information Leaflet and Informed Consent Form (appendix 9 to 12). These forms must be 
combined in the same document in order to ensure that all of the information is given to the trial 
participant. 
The consent form must be personally dated and signed by the trial participant and the 
investigator. The original will be given to the patient and the second, archived in the 
investigator’s folder. Upon request, a copy will be sent to the sponsor in a sealed envelope. 

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15.4 
Sponsor’s responsabilities 
 
The sponsor of the clinical trial, the Institut Bergonié, will take the initiative for this clinical trial. 
The Institute will manage the trial and ensure that finance is provided. 
The sponsor’s main responsibilities are to: 
 Take out civil liability insurance, 
 Obtain the Eudract No. and register the trial in the European database (European Drug 
Regulatory Authorities Clinical Trials), 
 Obtain clinical trial authorization for the initial project and any amendments from the EC and 
ANSM; approval by the EC and decision taken by ANSM.  
 Notify the relevant authority any suspected unexpected serious adverse reaction (SUSAR), 
 Give trial-related information to the site directors, pharmacists and investigators, 
 Notify the relevant authority of the trial start and end dates, 
 Draft the final trial report and sent the summary to ANSM, 
 Send the trial results to the relevant authority, EC and investigators, 
 Archive essential trial documents in the sponsor’s folder for a minimum period of 15 years 
after the trial has ended. 
 
15.5 
Investigators’ responsabilities 
 
The principal investigator of each establishment concerned undertakes to conduct the clinical 
trial in accordance with the protocol that was approved by the ethics committee and the relevant 
authority (ANSM). 
The investigator must not make any changes to the protocol without the written consent of the 
sponsor or without the ethics committee and the relevant authority having authorized the 
proposed changes. 
It is the responsibility of the principal investigator is: 
 to provide the sponsor with his/her curriculum vitae as well as those of his/her co-
investigators, 
 to identify the members of his/her team who are participating in the trial and to define their 
responsibilities, 
 to start patient recruitment after authorization has been obtained from the sponsor, 
 to ensure that he/she is available for investigators’s meeting anf for “monitoring”. 
 
It is the responsibility of each investigator: 
 to comply with the confidential nature of the trial, 

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 to obtain informed consent, signed and dated personally by each trial participant, before any 
screening procedures specific to the trial are carried out, 
 to regularly complete the case report forms (CRFs or e-CRFs) for each of the patients 
enrolled in the trial and to allow the Clinical Research Assistant (CRA) duly authorised by 
the Sponsor a direct access to source documents so that the latter can validate the data on the 
CRF or e-CRF, 
 to promptly notify the sponsor of any serious adverse event and/or new information 
occurring during the trial, 
 to date, correct and validate corrections on the case report forms (CRFs or e-CRFs) and the 
Data Clarification Forms (DCFs), 
 to accept regular visits CRA and eventually visits of auditors duly authorised by the Sponsor 
or inspectors of regulatory authorities, 
 to inform trial participants of the overall results of the research on first demand. 
 
15.6 
Authority to execute the trial 
 
The investigator shall certify that he/she is authorized to enter into this agreement and that the 
terms and conditions of the protocol and agreement do not conflict with other agreements that 
the investigator may have entered into with any other party, or any other arrangement agreed by 
the Institution where the investigator is employed. 
 
15.7 
Regulations governing the collection of human biological samples 
 
During the medical procedures to be carried out, samples will be collected for medical purposes. 
A fraction of these samples will be kept and used for scientific research purposes.  
The patient will be informed of this research and provided that he/she approves by signing an 
informed consent, these samples intended for research will be: 
 Initially prepared and stored using a specific technique to preserve them under excellent 
conditions. 
 and secondly, used within the scope of this research.   
The preparation, storage and use of these samples will not in any way affect current or future 
medical care administered to the patient for the purpose of diagnosis or treatment. 
The results of this research may, in future, appear in scientific publications.  All of the data shall 
remain anonymous. 
Obtaining and using additional samples 
This biomarker study is made up of exploratory research that is described in the section 
“Ancillary Study”. 
On completion of the trial, provided that the patient agrees and provided that not all of the 
samples have been used, the said samples can be used for subsequent scientific research purposes 
without the approval of the Ethics Committee (EC) and the signing of a new consent form by the 
patients included. 

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15.8 
Fédération des comités de patients pour la recherche clinique en cancérologie 
(FCPRCC) (Federations of patient committees for clinical research in oncology) 
 
The Fédération des Comités de Patients pour la Recherche Clinique en Cancérologie (FCPRCC) 
(Federation of Patient COmmittees for Clinical Research in Oncology) was created on the 
initiative of the Fédération des Centres de Lutte Contre le Cancer (FNCLCC) (Federation of 
Anti-Cancer Centers) and the Ligue Nationale Contre le Cancer (National Anti-Cancer League) 
in order to review clinical trial protocols in oncology. This Federation of Patient Committees is 
co-ordinated by the Office for Clinical and Therapeutic Trials and groups together the League 
patient committees as well as other health care establishments. The Sponsor undertakes to 
transmit the protocol to the Federation for review. The Federation undertakes to propose 
improvements focusing primarily on the quality of the information leaflet, the availability of a 
treatment and monitoring plan and the suggestion of measures aimed at improving patient 
comfort. 
 
15.9 
Data processing 
 
In accordance with the French Law on Data Protection and Civil Liberties of 06 August 2004 
and its implementing decrees, the Sponsor shall follow the methodology of reference MR001 of 
the Commission Nationale de l’Informatique et des Libertés (French National Commission for 
Data Protection and Liberties). 
Furthermore, if the biomedical research data is computer processed or managed by computerized 
systems, each Center: 
 shall check and document the fact that the computerized systems used in the research comply 
with requirements drawn up in relation to data integrity, accuracy and reliability, as well as 
compliance with expected performances (i.e. validation); 
 shall implement and ensure the monitoring of standard operating procedures relating to the 
use of these systems; 
 shall ensure that the design of these systems allows for data to be amended such that the 
amendments are documented and that any item of data input cannot be deleted (i.e. 
maintaining data and amendment audit trail) ; 
 shall implement and ensure the monitoring of a secure system that prevents any unauthorized 
data access; 
 shall update the list of persons authorized to amend the data; 
 shall keep appropriate back-up copies of the data; 
 shall maintain blind status, where applicable (e.g. during data entry and processing); 
 shall ensure that personal data used within the scope of the trial is processed in accordance 
with the conditions defined by law No. 78-17 dated 6 January 1978 relating to data 
processing, files and liberties modified by law No. 2004-801 of 6 August 2004 and its 
implementing regulations. 
If the data is converted during processing, it must always be possible to compare the original 

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data and observations with the data after conversion. 
The system used to identify subjects taking part in the trial must not present with any ambiguity 
and must allow all of the data collected for each of these subjects to be identified whilst 
maintaining the confidentiality of the personal data, in accordance with law No. 78-17, duly 
amended. 
The archiving data is performed according to the applicable regulations and under the 
responsibility of investigator. All data and the patient indentification codes will be kept for at 
least 15 years after the completion or discontinuation of the trial. 
 
 
16. CONFIDENTIALITY AND OWNERSHIP OF DATA 
 
All of the information communicated or obtained and the data and results generated by the trial 
legally belong to as their obtaining the Institut Bergonié, which can use this data at its own 
discretion.  
According to article R 5121-13 of the French Public Health Code, investigators and people who 
will have  to collaborate in the trial shall be bound by professional secrecy with regard to the 
particular nature of the products studied, trial, trial participants, and results. In particularly, all 
documentation relating to the trial sent to the investigator should be considered confidential 
information. 
Without the consent of the sponsor, the investigator cannot give information about trials at 
anyone, except the Minister in charge of Public Health, public health medical inspectors, public 
health pharmacists inspectors, the General Director and inspectors of ANSM.  
The trial cannot be the subject of any written or verbal comments without the sponsor’s consent. 
 
 
17. PUBLICATION AND VALORISATION 
 
17.1 
Scientific communication 
 
All of the information arising from this study shall be considered confidential (cf. section 12). 
All forms of publication must be submitted to the Steering Committee for review and approval 
prior to publication (allowing at least 15 working days for abstracts and oral presentations, and 
45 working days for written publications). The Steering Committee shall check the accuracy of 
the information submitted (in order to avoid any inconsistency with that submitted to the Health 
Authorities), and ensure that confidential information is not inadvertently disclosed.  It will also 
provide additional information as required. In any case, the sponsor will control the first 
publication. 
Furthermore, all memos, manuscripts or presentations must comprise a heading referring without 
fail to the Institut Bergonié, all of the institutions, investigations, co-operating groups and 
learned societies that have contributed to the implementation of the trial, and listing any 
organizations that have provided financial support. 
For the principal publication, either in French or English, the authors are: 
• the study coordinator 

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• the investigators will be listed on a pro rata basis according to the number of patients 
recruited 
• a representative of the trial statistics unit (in the first 3 positions according to degree of 
involvement in the preparation of publications) 
 
17.2 
Information to patients 
 
According to Article L.1122-1 of the French Code of Public Health Investigator undertakes to 
inform trial participants of the overall results of the research on first demand. 
 
 

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survival analysis of 171 patients from the EICESS studies, Ann of Oncol,  9: 275–281. 
 
Paulussen M1, A.W. Craft, I. Lewis, et al. (2008). Results of the EICESS-92 Study: two 
randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide 
in standard-risk patients and assessment of benefit of etoposide added to standard treatment in 
high-risk patients. J Clin Oncol. 20;26:4385-93. 
 
Rong S, et al. (1993). Met expression and sarcoma tumorogenicity. Cancer Res, 53: 5355-5360. 
Roskoski, R., Jr. (2008). VEGF receptor protein-tyrosine kinases: structure and regulation.  
Biochem Biophys Res Commun.  375:287-291. 
 
Sampson E.R, et al. (2011). The orally bioavailable met inhibitor PT-2341066 inhibits 
osteosarcoma growth and osteolysis/matrix production in a xenograft model. J Bone Miner Res, 
26: 1283-1294. 
 
Sato J, Yanagawa T, Dobashi Y, Yamaji T, Takagishi K, Watanabe H. Prognostic significance of 
18F-FDG uptake in primary osteosarcoma after but not before chemotherapy: a possible 
association with autocrine motility factor/phosphoglucose isomerase expression. Clin Exp 
Metastasis 2008;25(4):427-35. 
 
Scharf V.F, et al. (2013). Effect of bevacizumab on angiogenesis and growth of canine 
osteosarcoma cells xenografted in athymic mice. Am J Vet Res, 74: 771-778. 
 
Schwarz JK et al. The Role of 18F-FDG PET in Assessing Therapy. Response in Cancer of the 
Cervix and Ovaries, J. Nucl. Med. 2009: 50: 64S-73S. 
 
Schmidt, L., F.M. Duh, F. Chen, et al.  (1997). Germline and somatic mutations in the tyrosine 
kinase domain of the MET proto-oncogene in papillary renal carcinomas.  Nat Genet.  16:68-73. 
 
Schulte M, Brecht-Krauss D, Werner M, Hartwig E, Sarkar MR, Keppler P, Kotzerke J, 
Guhlmann A, Delling G, Reske SN. Evaluation of neoadjuvant therapy response of osteogenic 
sarcoma using FDG PET. J Nucl Med 1999;40(10):1637-43 

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Sennino, B., R.M. Naylor, S.P. Tabruyn, et al. (2009). Abstract A13:  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:A13. 
 
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cabozantinib. Proceedings of the 104th Annual Meeting of the American Association for Cancer 
Research; 2013 Apr-6-10; Washington, DC. Philadelphia (PA): AACR. Abstract LB353. 
 
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adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System 
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Subbiah V, P. Anderson, A.J. Lazar, et al. (2009). “Ewing’s sarcoma: standard and experimental 
treatment options”. Current Treatment Options in Oncology, 10: 126-140.  
 
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receptors: anti-angiogenic therapy in the treatment of cancer.  Mol Aspects Med.  32:88-111. 
 
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inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.  Mol Cancer 
Ther.  10:2298-2308 
 
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pathway genes, including VEGFA, in human osteosarcoma. Cancer, 117: 4925-4938. 
 
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sarcoma to neoadjuvant therapy: evaluated by 18F-FDG-PET. Ann Nucl Med 2008;22(6):475-80. 
 
You, W.K., B. Sennino, C.W. Williamson, et al. (2011). VEGF and c-Met blockade amplify 
angiogenesis inhibition in pancreatic islet cancer.  Cancer Res.  71:4758-4768. 
 
Zander T et al. Early Prediction of Nonprogression in Advanced Non–Small Cell Lung Cancer 
Treated With Erlotinib By Using [18F]Fluorodeoxyglucose and [18F]Fluorothymidine Positron 
Emission Tomography, J. Clin. Oncol.,2011:1701-1708. 
 
Zhang, S., H. Zhau, A. Osunkoya, et al. (2010). Vascular endothelial growth factor regulates 
myeloid cell leukemia 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 
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the 
patient at the time of enrollment.  Use or modify the text as appropriate for the study agent, so 
that the patient is aware of the risks and can communicate with their regular prescriber(s) and 
pharmacist.  A convenient wallet-sized information card is also included for the patient to clip 
out and retain at all times.] 
 
The patient __________________________________ is enrolled on a clinical trial using the 
experimental agent XL184 (cabozantinib).  This clinical trial is sponsored by the National 
Cancer Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.  
 
[Agent name] interacts with many drugs that are processed by your liver.  Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this study.  It 
is also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
[Use or delete sections below as appropriate.] 
 
XL184 interacts with (a) certain specific enzyme(s) in your liver.  
• The enzyme(s) in question is CYP3A4.  This enzyme breaks down XL184, gradually 
reducing the level of the active drug in your system.    
• Other medicines may affect the activity of the enzyme.  XL184 must be used very carefully 
with these medicines, or you may need to switch to alternate medications. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers 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.   

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• 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.   
• [The following are examples of text for common over-the-counter medications or 
supplements that may interact with the study agent.]  Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking [agent name]. 
o [Add other specific medications here, if necessary.] 
 
 
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).  This clinical trial is sponsored by the NCI.  XL184 
(cabozantinib) interacts with drugs that are processed by your liver.  
Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you 
start taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical 
trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
XL184 (cabozantinib) interacts with a specific liver enzyme called 
CYP3A4, and must be used very carefully with other medicines that 
interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers 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 
SCREENING FORM 
 
 
 

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APPENDIX E 
INCLUSION FORM 
 
 
 
 
 
 
 

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APPENDIX F 
PATIENT MEDICATION DIARY 
 
 

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APPENDIX G 
SERIOUS ADVERSE EVENT NOTIFICATION FORM 
 
 
 
 
 
 

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APPENDIX H 
PREGNANCY NOTIFICATION FORM 
 
 
 
 

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APPENDIX I 
COCKCROFT FORMULA 
 
 
Creatinine clearance (ml/min) =  
   [(140-age (years)) x weight (Kg)] 
x G1  
      72 x serum creatinine (mg/dl) 
 
1G (Gender) = 0.85 if Female; 1 if Male  
 
Reference: Cockcroft, DW, Gault, H. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976; 16(1):31-41 [84]. 
 
 
 

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APPENDIX J 
DOSING TABLE FOR PATIENTS < 16 YEARS OF AGE 
 
 
Dose Level 0: 40 mg/m² 
BSA (m²) 
Calculated dose 
No. of tablet 
1.2 – 1.5 
40 mg 
2 x 20 mg 
> 1.5 
60 mg 
1 x 60 mg 
 
Dose Level 1: 30 mg/m² 
BSA (m²) 
Calculated dose 
No. of tablet 
1.2 – 1.5 
20 mg 
1 x 20 mg 
> 1.5 
40 mg 
2 x 20 mg 
 
Dose Level 2: 20 mg/m² 
BSA (m²) 
Calculated dose 
No. of tablet 
1.2 – 1.5 
Stop treatment 
Stop treatment 
> 1.5 
20 mg 
1 x 20 mg